MINOXIDIL 50 MG / ML CUTANEOUS SPRAY SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Minoxidil 50 mg/ml cutaneous spray, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 50 mg minoxidil.

Excipient with known effect: propylene glycol 509 mg/ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Cutaneous spray, solution

Clear, colourless to pale yellow solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Minoxidil 50 mg/ml is indicated for the treatment of alopecia androgenetica in men aged 18 –65.

4.2 Posology and method of administration

Posology

Apply 1 ml Minoxidil 50 mg/ml twice daily (morning and evening) to the affected areas of the scalp.

The daily amount applied of 2 × 1 ml solution should not be exceeded, regardless of the size of the affected scalp area.

Paediatric population under 18 years, patients aged 65 years and older

Minoxidil 50 mg/ml must not be used in these patient groups, as no efficacy and safety results from controlled studies are available in these age groups.

Women

For women, Minoxidil 20 mg/ml is available.

Method of administration

Cutaneous use.

Prior to applying Minoxidil 50 mg/ml, it must be ensured that the scalp is dry. Minoxidil 50 mg/ml should not be applied to other parts of the body.

Hands should be washed carefully after applying MINOXIDIL 50 mg/ml, in order to avoid accidental contact with mucous membranes and eyes.

After applying Minoxidil 50 mg/ml, the hair can be styled as normal. However, the scalp should not be moistened for about 4 hours. This will prevent Minoxidil 50 mg/ml from being washed off.

Each pack of Minoxidil 50 mg/ml contains 2 different pump spray applicators:

– pre-assembled applicator for large-area application

– separate applicator with extended tip for smaller areas

Both applicators can be swapped by detaching the one applicator and replacing it with the other.

For a dose of 1 ml 6 spray actuations are needed.

Instructions for use/application

The solution is sprayed directly onto the scalp within the area of hair loss. For this, depress the pump six times. After each actuation, the liquid should be distributed over the affected area with the fingertips, thereby avoiding inhalation of the spray mist.

Duration of use

The onset and extent of hair growth are different in individual patients.

In general, twice-daily treatment for 2 to 4 months is required before an effect is seen. In order to maintain the effect, it is recommended to continue the twice-daily application without interruption. No better result will be achieved by applying Minoxidil 50 mg/ml in larger amounts or more frequently. Regarding a possible therapeutic effect, there is sufficient clinical experience for a treatment period of up to one year.

If no effect is seen after 4 months, treatment should be discontinued.

Too low dosage

If too little Minoxidil 50 mg/ml has been applied or a dose has been missed, the user must not make up for the missing amount. In this case, treatment should be continued at the recommended dose.

4.3 Contraindications

Minoxidil 50 mg/ml must not be used in the following cases:

– hypersensitivity to the active substance or to any of the excipients listed in section 6.1,

– in women, due to occasional signs of cosmetically distressing, reversible, facial hair growth during treatment,

– use of occlusive dressings or other topical medical preparations on the scalp,

– sudden or uneven hair loss,

– in users with any scalp abnormality (including psoriasis, sunburn, shaved scalp or if the scalp is damaged by burns or scarring).

4.4 Special warnings and precautions for use

Prior to treatment with Minoxidil 50 mg/ml, the patient should be thoroughly examined and his medical history taken.

Endocrinological causes, underlying systemic diseases or malnutrition must be excluded. In these cases, if necessary, a specific treatment should be initiated.

The patient should have a normal, healthy scalp. Minoxidil 50 mg/ml should not be used if the cause of hair loss is not known, if the scalp is infected or if the scalp is red, inflamed or painful.

Minoxidil 50 mg/ml is intended only for external use on the scalp. Do not apply Minoxidil 50 mg/ml to other parts of the body.

There is no clinical experience to date with regard to efficacy for hair loss in the temporal region (receding hairline).

The patient should discontinue the product and consult a doctor if a reduction in blood pressure is detected or if one or more of the following manifestations occur: chest pain, accelerated heartbeat, asthenia or dizziness, sudden unexplained weight gain, swollen hands or feet, persistent redness or irritation of the scalp or if other not expected new symptoms appear (see section 4.8).

In some patients, a transient increase in the amount of hair shedding has been observed two to six weeks after the start of treatment. This effect is due to the fact that the resting phase (telogen phase) of the hair cycle is shortened in hair follicles treated with minoxidil and the growth phase (anagen phase) is reached more quickly. This stimulates new hair growth, which pushes the “old”, no longer active hairs out of the scalp. This gives the initial impression of increased hair loss. However, it is accompanied by increased hair regrowth. This effect regresses within a few weeks and can be interpreted as a first sign of the minoxidil effect.

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

Treatment with Minoxidil 50 mg/ml should not take place in patients with signs of cardiovascular disease or cardiac arrhythmias or in hypertensive patients, including patients on treatment with antihypertensives.

Isolated cases of slight changes in hair colour have been reported by patients with very fair hair upon concomitant use of hair care products or after swimming in heavily chlorinated water.

Inadvertent ingestion can cause severe cardiovascular adverse reactions. This product must therefore be kept out of the reach of children.

When treatment with minoxidil is stopped, shedding of the hairs will occur again. Due to the ethanol and propylene glycol content in Minoxidil 50 mg/ml, repeated spraying of Minoxidil 50 mg/ml on the hair rather than the scalp might result in increased hair dryness and/or stiffness.

Minoxidil 50 mg/ml contains ethanol 96%and can cause eye stinging and irritation. In case of accidental contact with sensitive areas (eyes, skin abrasions, mucous membranes), these must be rinsed with plenty of water.

Inhalation of the spray mist should be avoided.

Propylene glycol may cause skin irritation.

4.5 Interaction with other medicinal products and other forms of interaction To date, no information is available on interactions between Minoxidil 50 mg/ml and other agents. Although not clinically proven, there is a theoretical possibility that absorbed minoxidil may potentiate orthostatic hypotension in patients concomitantly taking peripheral vasodilators.

Minoxidil 50 mg/ml should not be used together with other dermatological products or with agents that enhance skin absorption.

Pharmacokinetic drug interaction studies in humans showed that the percutaneous absorption of minoxidil is enhanced by tretinoin and dithranol as a result of increased permeability of the stratum corneum. Betamethasondi­propionat increases the local tissue concentration of minoxidil and reduces the systemic absorption of minoxidil.

4.6 Fertility, pregnancy and lactation

Minoxidil 50 mg/ml is indicated for use in male patients only and must not be used by pregnant women and breastfeeding mothers.

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).

Breastfeeding

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

4.7 Effects on ability to drive and use machines

This product may cause dizziness or hypertension (see section 4.8). If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

The following frequencies are used for the evaluation of adverse reactions:

The safety of topical minoxidil from clinical trial data is based on data from 7 placebo-controlled randomised clinical trials in adults evaluating either 20 mg/ml or 50 mg/ml minoxidil solution, and two placebo-controlled randomised clinical trials in adults evaluating a 50 mg/ml 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).

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms of intoxication

Application of Minoxidil 50 mg/ml at higher than the recommended dosage and to relatively large body surfaces or areas other than the scalp may possibly lead to increased systemic absorption of minoxidil. To date, there have been no known cases where the topical use of minoxidil solution has resulted in intoxication.

After inadvertent swallowing, the concentration of the active compound minoxidil in Minoxidil 50 mg/ml may lead to systemic effects corresponding to the pharmacological action of the active substance (2 ml Minoxidil 50 mg/ml contains 100 mg minoxidil, which is equivalent to the maximum recommended daily dose for the treatment of hypertension).

Due to the systemic effects of minoxidil, the following adverse reactions may occur:

Cardiac disorders: accelerated heartbeat, hypotension

General disorders: fluid accumulation and subsequent sudden weight gain

Nervous system disorders: dizziness

Treatment of intoxication

Clinically significant tachycardia can be controlled with P-biockers and oedema with diuretics.

An excessive decrease in blood pressure can be treated by intravenous infusion of physiological saline solution. Sympathomimetics such as adrenaline and noradrenaline are to be avoided due to their excessive cardiotonic effect.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatological preparations; other dermatologicals ATC code: D11AX01

Minoxidil 50 mg/ml stimulates hair growth in persons with androgenetic alopecia.

Mechanism of action

The exact mechanism of action by which minoxidil stimulates hair growth is not fully known. However, minoxidil may stop hair loss in androgenetic alopecia by:

increasing the diameter of the hair shaft,

stimulating hair growth in the anagen phase,

extending the anagen phase,

shortening the telogen phase, whereby the anagen phase is reached more quickly.

Pharmacodynamic effects

As a peripheral vasodilator, minoxidil increases the microcirculation to hair follicles. Minoxidil stimulates vascular endothelial growth factor (VEGF) which is probably responsible for the increased capillary permeability and hence shows a high metabolic activity which can be observed during the anagen phase.

Excessive hair loss is halted with regular use after a few weeks. Furthermore, new hair growth may occur. This becomes noticeable at the earliest approximately four months after the start of therapy.Cosme­tically satisfactory regrowth of terminal hair is observed in up to 40% of patients treated with minoxidil 20 mg/ml after one year of treatment. The success rate rises to approximately 50% with Minoxidil 50 mg/ml.

The onset of action and the extent of scalp hair thickening varies depending on the patient. In particular, advanced or more than 10 years’ standing androgenetic alopecia is less responsive to minoxidil. This is probably due to the lack of hair roots, the presence of which is necessary for the effect.

Upon discontinuation of treatment, growth of new hair ceases and within 3 to 4 months, the condition reverts to that before the start of therapy.

5.2 Pharmacokinetic properties

Absorption

When minoxidil solution is topically applied, about 1–2% of the active substance is systemically absorbed, compared to 90–100% with oral formulations.

The following study data refer to the topical minoxidil-containing medicinal products of the originator MAH:

In a study on men, the mean minoxidil serum concentration AUC for the 20 mg/ml solution was 7.54 ng*hr/ml, compared to a mean AUC of 35 ng*hr/ml for 2.5 mg of an oral formulation. The mean plasma concentration (Cmax) for the topical solution was 1.25 ng/ml compared to 18.5 ng/ml following oral administration of 2.5 mg.

In another study on men, systemic absorption of a 50 mg/ml foam formulation was about half as much as that of a 50 mg/ml solution. The mean AUC (0–12 h) and Cmax for the 50 mg/ml foam, i.e. 8.81 ng*hr/ml and 1.11 ng/ml, respectively, were about 50% of AUC (0–12 h) and Cmax for the 50 mg/ml solution, i.e. 18.71 ng*hr/ml and 2.13 ng/ml, respectively.

For the 50 mg/ml foam, the time to peak plasma concentration (tmax) of 5.42 h was similar to the tmax for the solution, i.e. 5.79 h. No haemodynamic effect of minoxidil is evident up to a mean serum concentration of 21.7 ng/ml.

Distribution

The volume of distribution after intravenous administration of 4.6 mg and 18.4 mg minoxidil was 73.1 L and 69.2 L, respectively.

Biotransformation

Following topical administration, about 60% of absorbed minoxidil is metabolised to glucuronides, primarily via the liver.

Elimination

The half-life of topical minoxidil is 22 hours, compared to 1.49 hours with oral dosage forms. 97% of minoxidil is excreted via the urine and 3% via the faeces.

Mean renal clearance of minoxidil and its glucuronides, based on data from oral dosage forms, is 261 ml/min and 290 ml/min, respectively.

Upon discontinuation of treatment, about 950 mg/ml of the minoxidil absorbed after topical administration is excreted within 4 days.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Mutagenicity

Minoxidil showed no evidence of mutagenic or genotoxic potential in a series of in vivo and in vitro assays.

Carcinogenicity

A high incidence of hormone-induced tumours was observed in rats and mice. These tumours were caused by a secondary hormonal effect (hyperprolacti­naemia), which was observed only in rats at extremely high doses and was similar to the effect of reserpine.

The use of topical minoxidil has shown no effect on the hormonal status of women. Therefore, hormone-induced tumours do not pose a carcinogenic risk to humans.

Teratogenicity

Reproductive toxicity studies on rats and rabbits, with very high exposure rates compared to the anticipated exposure level in humans, have revealed signs of maternal toxicity and a risk to the foetus. There is a low risk to the human foetus.

Fertility

Minoxidil doses of more than 9 mg/kg (at least 25 times the human exposure), administered subcutaneously in rats, were associated with a reduced rate of conception and implantation, as well as a reduction in the number of viable pups.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethanol 96% (v/v)

propylene glycol purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

Shelf life after opening: 6 weeks.

6.4 Special precautions for storage

Do not freeze.

Contains ethanol which is flammable. Store away from heaters or naked flames.

6.5 Nature and contents of container

60 ml white HDPE bottle

Packs with 60 ml solution or 3 × 60 ml solution.

The medicinal product Minoxidil 50 mg/ml contains two pump spray applicators, one preassembled applicator and one applicator with extended tip.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Mibe Pharma UK Ltd

4 Coleman Street, 6th Floor;

London, United Kingdom,

EC2R 5AR

8 MARKETING AUTHORISATION NUMBER(S)

PL 49452/0007

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/01/2018