PRODUCT MONOGRAPH

HAIR REGROWTH FORMULA

(Minoxidil Topical Solution USP)

2% (20 mg/mL)

HAIR REGROWTH TREATMENT

Vita Health Products Inc. Date of Preparation:

150 Beghin Avenue, Winnipeg, MB September 15, 2010
R2J 3W2

Control #: 140446

1
 NAME OF DRUG

HAIR REGROWTH FORMULA

(Minoxidil Topical Solution USP)

2 % (20 mg/mL)

THERAPEUTIC CLASSIFICATION

Hair Regrowth Treatment

ACTIONS AND CLINICAL PHARMACOLOGY

When applied topically, minoxidil topical solution has been shown to stimulate
hair growth in individuals with alopecia androgenetica (male pattern baldness).
Although the exact mechanism of action of minoxidil in the treatment of alopecia
androgenetica is not known, there may be more than one mechanism by which
minoxidil stimulates hair growth; they include:

- vasodilation of the microcirculation around the hair follicles which may

stimulate hair growth;
- direct stimulation of the hair follicle cells to enter into a proliferative phase:
resting phase (telogen) follicles being stimulated to pass into active phase
(anagen) follicles;
- alteration of the effect of androgens on genetically predetermined hair
follicles: minoxidil may affect the androgen metabolism in the scalp by
inhibiting the capacity of androgens to affect the hair follicles.

2
Following topical application of minoxidil topical solution, minoxidil is poorly
absorbed from normal intact skin, with an average of 1.4% (range 0.3-4.5%) of
the total applied dose reaching the systemic circulation. The effects of
concomitant dermal diseases or occlusion on absorption are unknown. Serum
minoxidil levels resulting from topical administration are governed by the drug's
percutaneous absorption rate; increases in surface area of application
do not result in proportionate increases in the serum minoxidil level. Steady state
is achieved by the end of the third dosing interval (36 hours) when the drug is
administered twice daily. Approximately 95% of the systemically absorbed
minoxidil from topical dosing is eliminated within 4 days. The metabolic
biotransformation of minoxidil absorbed following topical application has not been
fully determined.

Known metabolites exert much less pharmacologic effects than minoxidil itself
and all are excreted principally in the urine. Minoxidil does not bind to plasma
proteins; its renal clearance corresponds to glomerular filtration rate and it does
not cross the blood brain barrier. Minoxidil and its metabolites are
hemodialyzable, although this does not rapidly reverse its pharmacological effect.

Increased hair growth has not been associated with increased systemic
absorption of topical minoxidil. The onset of hair growth stimulation requires twice
daily applications of HAIR REGROWTH FORMULA for four or more months, and
is variable among patients. Upon discontinuation of topically applied minoxidil,
new hair growth has been anecdotally reported to stop and restoration of
pretreatment appearance to occur within three to four months.

3
 INDICATIONS AND CLINICAL USE

HAIR REGROWTH FORMULA (minoxidil topical solution) is used to help regrow

hair on the top of the scalp. To stimulate hair growth in individuals with
androgenetic alopecia (male pattern baldness).

CONTRAINDICATIONS

HAIR REGROWTH FORMULA (minoxidil topical solution) is contraindicated in

patients who:
1. are less than 18 years old or female;
2. have ever had an allergic reaction to minoxidil, propylene glycol or
alcohol;
3. use any other topical prescription product on the scalp;
4. your skin (scalp) is red, inflamed, burned, sunburned, infected, irritated,
broken, recently shaved or painful to the touch.

WARNINGS

Stop using HAIR REGROWTH FORMULA (minoxidil topical solution) and see
your doctor if you experience:
1. chest pain, rapid heart beat;
2. faintness and/or dizziness;
3. sudden, unexplained weight gain of more than 2.5 kilograms (5 pounds);
4. swollen hands or feet;
5. redness, irritation or lesions develop on treated areas of the scalp.

4
Use in Pregnancy and Nursing:
The safety for use of minoxidil topical solution in pregnancy has not been
established. Orally administered minoxidil has been shown to reduce the
conception rate in rats and to show evidence of increased fetal resorption in
rabbits when administered at five times the human oral dose. There was no
evidence of teratogenic effects in rats and rabbits. Systemically absorbed
minoxidil is secreted in human milk.

Use in Children:
Safety and effectiveness of minoxidil topical solution in patients under 18 years of
age has not been established.

Patients with underlying Cardiovascular Disease:

Patients should not use HAIR REGROWTH FORMULA if they have a history of
underlying coronary artery disease, cardiac dysrhythmias, congestive heart
failure, or valvular heart disease. Patients with hypertension, including those
under treatment with antihypertensive agents, should be monitored closely and
their medication adjusted if necessary. HAIR REGROWTH FORMULA should be
used with caution in patients with any other cardiovascular disease present.

PRECAUTIONS

General:
1. Avoid contact with eyes. In case of accidental contact, rinse with large
amounts of water.
2. Avoid breathing spray mist (for spray forms).
3. This nonprescription product is not approved for use in women.
4. Accidental ingestion of minoxidil topical solution can cause serious
adverse effects. Contact a poison control center or doctor immediately.

5
Use in the elderly:
Studies involving subjects over the age of 65 years have not been performed
hence the safety and effectiveness of HAIR REGROWTH FORMULA in these
patients has not been established.

Drug Interactions:
There are currently no known drug interactions associated with the use of
minoxidil topical solution. Although it has not been clinically demonstrated, there
exists the possibility of potentiating orthostatic hypotension in patients
concurrently taking guanethidine.

ADVERSE REACTIONS

The most frequently encountered adverse effects in clinical trials with minoxidil
topical solution were minor dermatologic reactions. In light of the findings that
systemic levels of minoxidil from topical application are low in relation to systemic
levels from oral dosing, this distribution of encountered adverse effects is to be
expected. Local irritation was the most common adverse reaction reported,
including scaling, erythema/flushing, dermatitis, dry skin, hypertrichosis (in areas
other than where minoxidil topical solution was applied) burning sensation and
rash.

Infrequent adverse reactions including allergic reactions (sensitivity, hives,

generalized erythema, and facial swelling); dizziness; tingling sensation;
headache; weakness; neuritis; edema; eye irritation; altered taste; ear infection
(otitis external; and visual disturbances have been reported). Rarely reported
adverse reactions included alopecia, hair abnormalities, chest pain, blood
pressure changes, pulse changes, hepatitis, and kidney stones.

The occurrence rates for adverse reactions derived from the total adverse
reactions of all patients (placebo, one-third of these patients received placebo

6
treatment for four months 2 % minoxidil and 3 % minoxidil treated) enrolled in two
pivotal efficacy/safety studies (2,326 patients) are as follows:

Dermatological:
(3 %): itching.
(1 - 2%): scaling, erythema, dermatitis, dry skin.
(0.1 - 1.0%): Hypertrichosis, burning sensation, rash, folliculitis, desquamation,
alopecia (hair loss), skin abscess, acne, eczema, eruptions, excoriation, flaking
scalp, hair abnormalities, nail disorders, seborrhea, other skin irritations.

Cardiovascular:
(1 - 2%): flushing.
(0.1 - 1.0%): chest pain, changes in blood pressure, changes in pulse rate,
fainting.

Central Nervous System:

(1 - 2%): headache, dizziness.

Allergic:
(1 - 2 %): fever.
(0.1 - 1.0%): allergic reaction, non-specific allergic reaction, hives, allergic
rhinitis, facial swelling and sensitivity, chills.

Renal:
(1 - 2%): edema.
(0.1 - 1.0%): kidney stones.

Respiratory:
(0.1 - 1.0%): shortness of breath.

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Neurological:
(1 - 2 %): neuritis.
10.1 - 1.0%): weakness.

Hepatic:
(0.1 - 1.0%): hepatitis

Special Senses:
(0.1 - 1.0%): eye irritations, bitter taste, ear infection (otitis external, taste
alteration, visual disturbance).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Accidental ingestion of HAIR REGROWTH FORMULA (minoxidil topical solution)

may produce systemic effects related to vasodilatory action of minoxidil (5 ml of
the 2 % topical solution contains 100 mg minoxidil, the maximum recommended
adult oral dose for the treatment of hypertension). There have been only a few
instances of deliberate or accidental over dosage with oral minoxidil tablets.

In a reported case of accidental ingestion, a 3-year-old male swallowed 1-2 ml of

a 3% concentration of topical minoxidil solution. After vomiting he was treated in
an emergency room. The child was found to be alert and active with no obvious
signs of distress. His temperature was 37C, pulse 152, respiration 32, and
systolic blood pressure 110 by palpation. Cardiovascular, chest, lungs, abdomen,
head, skin and neurological examinations were normal. Blood levels taken
indicated a total minoxidil level (glucuronide and unchanged) of 320.6 ng/mL.
The child was discharged without sequelae.

Signs and symptoms of drug over dosage would most likely include
cardiovascular effects associated with fluid retention, lowered blood pressure and
tachycardia. Fluid retention can be managed with appropriate diuretic therapy.

8
Tachycardia can be controlled by administration of a beta-adrenergic blocking
agent.

If exaggerated hypotension is encountered, it is most likely to occur in

association with residual sympathetic nervous system blockade from previous
therapy (guanethidine-like effects or alpha-adrenergic blockade). The
recommended treatment is intravenous administration of normal saline.

Sympathomimetic drugs, such as norepinephrine or epinephrine, should be

avoided because of their excessive cardiac-stimulating action. Phenylephrine,
angiotensin II, vasopressin and dopamine, which reverse the effects of orally
administered minoxidil, should only be used if inadequate perfusion of a vital
organ is evident.

Oral LD50 in rats has ranged from 1321 to 3492 mg/kg; in mice 2457 to 2648
mg/kg. Minoxidil and its metabolites are hemodialyzable, although this does not
rapidly reverse its pharmacological effect.

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 DOSAGE AND ADMINISTRATION

FOR EXTERNAL USE ONLY. Use HAIR REGROWTH FORMULA (minoxidil

topical solution) only as directed.

1. Apply a 1 mL dose twice per day directly on the dry top scalp (see
diagram) in the hair loss area. Spread product with fingertips to cover
all the thinning or bald area.

2. Do not apply to parts of the scalp other than that shown in the diagram or
to other parts of the body.

3. Wash hands after use.

4. Do not exceed recommended dose. If you miss a dose, continue with your
next scheduled dose. Do not double dose.

5. Avoid swimming, showering or physical activity involving excessive

perspiration for at least 4 hours after application.

6. Continued use for at least 4 months is usually needed to notice hair

regrowth. If you do not see hair regrowth in 12 months, stop using the
product and see your doctor.

7. Do not apply product to the scalp if the skin is red, inflamed, burned,
sunburned, irritated, infected, broken or painful to the touch.

10
8. Hair loss may continue for up to 2 weeks after you start using the product.
This hair loss is temporary. If you continue to lose hair after 2 weeks, see
your doctor.

9. Hair regrowth generally peaks at about one year after which there is a
slow decline in regrowth over subsequent years.

10. Continuous use is needed to maintain hair regrowth. If you stop using the
product, the normal hair loss process will start again. You will probably
lose the newly regrown hair in 3-4 months.

11. If you wash your scalp before applying HAIR REGROWTH FORMULA,
use a mild shampoo and dry hair thoroughly before application.

12. Please see Application Methods for directions for use of the available
applicators.

APPLICATION METHODS

The method of application depends on the type of (disposable) applicator you

use:

Pump-Spray Applicator
(Works best for applying HAIR REGROWTH FORMULA to large areas.)

Extended-Spray-Tip Applicator
(Works best for applying HAIR REGROWTH FORMULA to small areas of the
scalp, or under hair.)

11
Rub-On Applicator
(Works best for applying HAIR REGROWTH FORMULA to small areas of the
scalp.)

To avoid spillage and/or loss of solution continue to use the applicator which you
have selected until the bottle is empty.

PUMP-SPRAY APPLICATOR
Works best for applying HAIR REGROWTH FORMULA to large areas.

(1) Ensure the pump spray applicator is screwed firmly onto the bottle.
(2) After aiming the pump toward the centre of the bald area of the scalp,
press the pump once and spread HAIR REGROWTH FORMULA Solution
with fingertips to cover all the bald area. Repeat for a total of 4 times to
apply a dose of 1 mL.

Avoid breathing spray mist.

EXTENDED-SPRAY-TIP APPLICATOR

Works best for applying HAIR REGROWTH FORMULA to small areas of the
scalp, or under hair.

(1) Ensure the pump spray applicator is screwed firmly onto the bottle.

(2) Remove small spray head from top of pump spray applicator.

(3) Fit the extended spray tip applicator onto the spray shaft and push down
firmly.

12
(4) After aiming the applicator toward the centre of the bald area of the scalp,
press the pump once and spread HAIR REGROWTH FORMULA Solution
with fingertips to cover all the bald area. Repeat for a total of 4 times to
apply a dose of 1 mL.

Avoid breathing spray mist.

RUB-ON APPLICATOR

Works best for applying HAIR REGROWTH FORMULA to small areas of the
scalp.

(1) Ensure rub-on applicator is screwed firmly onto the bottle. Remove outer
cap and keep it.

(2) Hold the bottle upright and squeeze it to half fill the upper chamber. The
level of liquid in the chamber will automatically adjust to deliver one full
dose (1 mL).

(3) Hold the bottle upside down then rub applicator on your scalp to apply
HAIR REGROWTH FORMULA over the entire bald area until the chamber
is completely empty. Replace outer cap over the rub-on applicator when
not in use.

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 PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE:

Name of Drug: Common Name: Minoxidil

Proprietary Name: HAIR REGROWTH FORMULA

Chemical Name: 2,6-Diamino-4-piper-idinopyrimidine 1-oxide

Structural Formula:

Molecular weight: 209.25

Description:
A white to off-white, crystalline powder. Melts in the approximate range of
between 248 and 268, with decomposition. Soluble in alcohol and in propylene
glycol; sparingly soluble in methanol; slightly soluble in water; practically
insoluble in chloroform, in acetone, in ethyl acetate, and in hexane.

Composition:
HAIR REGROWTH FORMULA (minoxidil topical solution) contains 20 mg
minoxidil per ml of solution.

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HAIR REGROWTH FORMULA is a clear, colourless to slightly yellow solution.
The yellow colour will not alter its effectiveness.

Stability and Storage Recommendations; Keep container closed. Store at

controlled room temperature 15' to 30'C.

AVAILABILITY OF DOSAGE FORMS

Each kit contains the following;

HAIR REGROWTH FORMULA (minoxidil topical solution) 20 mg minoxidil per
mL of solution, supplied in an HDPE bottle with the following 3 metered
disposable applicators: pump spray, extended tip and rub on assemblies. FOR
EXTERNAL USE ONLY.

INFORMATION FOR THE CONSUMER

The following pages, 15-24 inclusive, are taken directly from the Consumer
Information Leaflet that is located inside the HAIR REGROWTH FORMULA
carton.

CONSUMER INFORMATION

HAIR REGROWTH FORMULA

Minoxidil Topical Solution

2% (20 mg/mL)

15
What is HAIR REGROWTH FORMULA?

HAIR REGROWTH FORMULA is a hair regrowth treatment in the form of a

topical solution intended to help regrow hair in men.

HAIR REGROWTH FORMULA is used to help regrow hair on the top of the
scalp. To stimulate hair growth in individuals with androgenetic alopecia (male
pattern baldness).

Note: This product is intended for use on top (vertex) of head only and not for
receding hairline.

HAIR REGROWTH FORMULA will not prevent or improve hair loss which may
occur under the following conditions:
1. chemotherapy;
2. diseases causing scarring of the scalp;
3. severe nutritional problems such as very low iron, or excessive vitamin A
intake;
4. low thyroid activity (hypothyroidism);
5. taking some prescription and nonprescription medicines;
6. scalp damaged by hair care products which may burn or scar tissue;
7. scalp damaged by certain hair grooming methods such as ponytails or
cornrowing which require pulling the hair tightly back from the scalp.

Topical minoxidil stimulates modest hair regrowth in about 35% of male patients
with 5 % achieving dense regrowth and 37% achieving minimal regrowth. The
remaining 23% may achieve no noticeable regrowth.

Minimal regrowth is an improvement sufficient to achieve a less severe pattern of

baldness. Moderate regrowth is an increase in hair count that is visible and

16
cosmetically pleasing. Dense hair regrowth is hair long enough to be cut or
combed.

Who may use HAIR REGROWTH FORMULA?

HAIR REGROWTH FORMULA Solution may be used by males 18 years of age

and older only.

DO NOT use HAIR REGROWTH FORMULA if you:

1. are less than 18 years old or female;

2. have ever had an allergic reaction to minoxidil propylene glycol or alcohol;
3. use any other topical prescription product on the scalp;
4. your skin (scalp) is red, inflamed, burned, sunburned, infected, irritated,
broken, recently shaved or painful to the touch.

See your doctor before using HAIR REGROWTH FORMULA if you:

1. have no family history of gradual thinning hair or gradual hair loss;

2. have sudden or patchy hair loss;
3. do not know the reason for your hair loss.

Warnings:
Stop using HAIR REGROWTH FORMULA and see your doctor if you
experience:

1. chest pain, rapid heart beat;

2. faintness and/or dizziness;
3. sudden, unexplained weight gain of more than 2.5 kilograms (5 pounds);
4. swollen hands or feet;
5. redness, irritation or lesions develop on treated areas of the scalp.

17
Other Warnings:

1. Avoid contact with eyes. In case of accidental contact, rinse with large
amounts of water.
2. Avoid breathing spray mist (for spray forms).
3. This nonprescription product is not approved for use in women.
4. Accidental ingestion of minoxidil topical solution can cause serious
adverse effects. Contact a poison control center or doctor immediately.

Directions:

1. Apply a 1 mL dose twice per day directly on the dry top scalp (see
diagram) in the hair loss area. Spread product with fingertips to cover all
the thinning or bald area.

2. Do not apply to parts of the scalp other than that shown in the
diagram or to other parts of the body.
3. Wash hands after use.
4. Do not exceed recommended dose. If you miss a dose, continue with your
next scheduled dose. Do not double dose.
5. Avoid swimming, showering or physical activity involving excessive
perspiration for at least 4 hours after application.
6. Continued use for at least 4 months is usually needed to notice hair
regrowth. If you do not see hair regrowth in 12 months, stop using the
product and see your doctor.

18
 7. Do not apply product to the scalp if the skin is red, inflamed,
burned, sunburned, irritated, infected, broken or painful to
the touch.

8. Hair loss may continue for up to 2 weeks after you start using the product.
This hair loss is temporary. If you continue to lose hair after 2 weeks, see
your doctor.
9. Hair regrowth generally peaks at about one year after which there is a
slow decline in regrowth over subsequent years.
10. Continuous use is needed to maintain hair regrowth. If you stop using the
product, the normal hair loss process will start again. You will probably
lose the newly regrown hair in 3-4 months.
11. If you wash your scalp before applying HAIR REGROWTH FORMULA,
use a mild shampoo and dry hair thoroughly before application.
12. Please see Application Methods for directions for use of the available
applicators.

APPLICATION METHODS
The method of application depends on the type of (disposable) applicator you
use:
Pump-Spray Applicator
(Works best for applying HAIR REGROWTH FORMULA to large areas.)

19
 Extended-Spray-Tip Applicator
(Works best for applying HAIR REGROWTH FORMULA to
small areas of the scalp, or under hair.)

Rub-On Applicator
(Works best for applying HAIR REGROWTH FORMULA to small
areas of the scalp.)

To avoid spillage and/or loss of solution, continue to use the applicator which you
have selected until the bottle is empty.

PUMP-SPRAY APPLICATOR

Works best for applying HAIR REGROWTH FORMULA to large areas.

(1) Ensure the pump spray applicator is screwed firmly onto the bottle.

20
 (2) After aiming the pump toward the centre of the bald area
of the scalp, press the pump once and spread HAIR
REGROWTH FORMULA Solution with fingertips to cover all
the bald area. Repeat for a total of 4 times to apply a dose
of 1 mL.

Avoid breathing spray mist.

EXTENDED-SPRAY-TIP APPLICATOR

Works best for applying HAIR REGROWTH FORMULA to small areas of the
scalp, or under hair.

(1) Ensure the pump spray applicator is screwed firmly onto the bottle.

(2) Remove small spray head from top of pump spray

applicator. Fit the extended spray tip applicator onto
the spray shaft and push down firmly.

21
 (3) Fit the extended spray tip applicator onto the spray
shaft and push down firmly.

(4) After aiming the applicator toward the centre of the

bald area of the scalp, press the pump once and
spread HAIR REGROWTH FORMULA Solution
with fingertips to cover all the bald area. Repeat for a
total of4 times to apply a dose of 1 mL.

Avoid breathing spray mist.

RUB-ON APPLICATOR
Works best for applying HAIR REGROWTH FORMULA to small areas of the
scalp.

22
(1) Ensure rub-on applicator is screwed firmly onto the bottle. Remove outer
cap and keep it.

(2) Hold the bottle upright and squeeze it once to half

fill the upper chamber. The level of liquid in the
chamber will automatically adjust to deliver one full
dose (1 mL).

(3) Hold the bottle upside down then rub applicator on

your scalp to apply HAIR REGROWTH FORMULA
over the entire bald area until the chamber is
completely empty. Replace outer cap over the rub-on
applicator when not in use.

VITA HEALTH PRODUCTS INC.

Winnipeg, Manitoba

23
 PHARMACOLOGY

Systemic Administration:
Minoxidil produces a dose-related reduction in mean arterial blood pressure
following oral administration to rats, dogs, monkeys and minipigs. The onset of
action was within 2 hours, regardless of the route of administration, and the
activity persisted at near maximum for more than 24 hours.

Minoxidil acts on vascular smooth muscle to reduce resistance to blood flow.

This effect appears to be direct, since it was not antagonized by beta-adrenergic,
cholinergic, or histaminergic blocking agents or by decentralization with higher
spinal anesthesia. The vasculature of dogs remained responsive to the
vasoconstrictor action of norepinephrine, angiotensin II and vasopressin and to
the vasodilator action of acetylcholine, histamine, glyceryl-trinitrate, and
isoproterenol.

In dogs, measurements with radiolabelled microspheres indicated that minoxidil

increased blood flow to the myocardium 8 to 11 fold, 60 - 70% to skin, skeletal
muscle, pancreas and gastrointestinal tract; whereas blood flow to the adrenals,
kidneys, spleen, liver and the central nervous system was unchanged. Vascular
resistance was reduced in all tissues studied with the exception of the liver.

The administration of minoxidil to intact dogs markedly increased cardiac output,

heart rate and left ventricular dp/dt in association with the decreased total
peripheral resistance. These changes in cardiac function did not appear to be a
direct effect. Sympathetic nerve tone was increased as evidenced by increased
urinary excretion of norepinephrine and augmented blood pressure reduction in
response to ganglionic blockade, but sympathetic activity alone did not
account for the increase in heart rate and cardiac output. Chronic stimulation of
the carotid sinus nerves or ganglionic blockade more effectively prevented the

24
cardiac hyperactivity associated with minoxidil treatment suggesting an important
component of the heart changes is withdrawal of vagal tone.

Minoxidil produced an acute reduction in renal salt and water excretion in rats
and dogs but did not significantly influence renal hemodynamics. At
approximately a 15 % expansion of total body exchangeable sodium in the
chronically treated animals, salt and water balance were reestablished at an
expanded, extracellular fluid volume. Hypersecretion of mineral corticosteroids
which occurred during minoxidil treatment did not explain this salt retaining
action. Also sodium clearance increased when minoxidil was delivered directly
into the renal artery and, thus direct activation of electrolyte reabsorptive
transport in the kidney did not account for the retention phenomenon. Minoxidil-
induced salt and water retention and attendant extracellular fluid volume
expansion was reduced by concomitant administration of hydrochlorothiazide.

Minoxidil elevated plasma glucose concentration in rats at doses of 1.5 mg/kg.

Minoxidil did not alter intravenous glucose tolerance to any extent unless very
large doses (100 mg/kg) were used.

Topical Application:
Urinary and fecal 14C excretion was monitored in the conscious rat and monkey
as an index of the percutaneous absorption of topically applied 14C-labelled
minoxidil. In the rat, approximately 18% of the first 14C minoxidil dose was
excreted in the urine, and approximately 22 % was absorbed over a 9-day
period; approximately 26 % was excreted in the urine, and approximately 31 %
was absorbed following a second application. The fractional extent of
topical absorption in the rat was essentially independent of the 14C-minoxidil
concentration. First order urinary excretion rates were routinely observed (T =
1.03 to 1.47 days). Characteristics of the topical absorption of 14C-labelled
minoxidil differed appreciably in the monkey scalp. During the 10-16 days the
monkeys were chaired, approximately 4% of the 1 % solution and 1 % of the 4%

25
solution appeared in the urine. When returned to metabolism cages, a large
component of total urinary excretion occurred; urinary excretion did not follow
first order kinetics. Total absorption in the monkey was 17.4% of a 1 % solution
and 5.7% of a 4% solution.

Following topical application, the urinary metabolite profiles in the rat

corresponded closely to those observed after systemic administration,
suggesting that metabolism was not altered by entry across the skin.

Clinical Pharmacology
Exploratory in-vivo and in-vitro studies, designed to determine the mechanism by
which minoxidil stimulates hair growth in patients with male pattern baldness,
have been completed but have not been successful in definitely demonstrating
the mechanism of action of minoxidil in stimulating hair growth. Studies have
shown that there appears to be an immediate vasodilation of the microcirculation
after topical application of minoxidil and that there is no significant alteration of
the effects of androgens on scalp hair. These studies have also shown
that cultured epidermal cells appear to be stimulated to divide under the influence
of minoxidil and that in-vitro cell cultures of lymphocytes are inhibited in their
response to mitogens when minoxidil is present in culture. The overall
significance of any of these studies is unknown.

A multicentre double-blind and randomized study of 285 patients, with mild to

moderate hypertension, was conducted to ascertain if topical minoxidil can
produce systemic physiologic changes in patients with hypertension, in the
absence of concomitant antihypertensive therapy. Six treatment groups were
evaluated: 1 %, 2 % and 5 % topical minoxidil solutions, 2.5 mg and 5 mg oral
minoxidil doses and placebo were given twice daily for 4 consecutive days.
Systemic pharmacologic effect of absorbed minoxidil was monitored primarily in
terms of reductions of mean diastolic blood pressure (seated) and increased
pulse rate. Other similar measurements were also performed. Based on all

26
primary and supportive measures, 2 % topical minoxidil did not demonstrate
systemic pharmacologic effects (blood pressure reduction, tachycardia and
edema) seen with the oral dosage forms.

Extent of Absorption:
A three-way cross-over study in 14 male volunteers demonstrated that the extent
of minoxidil absorption, by the topical route, is low; with bioavailability averaging
1.4 % and 1.2 % for 2 % and 3 % topical solutions respectively, relative to oral
doses of minoxidil. The disappearance of minoxidil from the systemic circulation
was found to be controlled by its rate of absorption, which is slow, and appears to
occur by a zero order process at steady state. Absorption of minoxidil from
topically applied solution is greater in individuals with whom a simulated bald
spot was generated by shaving (2.4% of applied dose) than in individuals who
were naturally bald (1.4% of applied dose).

Effect of Surface Area:

A four-way cross-over study documented that when 1 mL of 2 % minoxidil
solution was spread over surface areas ranging from 100 cm2 to 200 cm2 the
amount of minoxidil absorbed was minimally affected. Less than a 20% increase
in the amount absorbed was observed with a 100 % increase in surface area.

Dose Proportionality:
Results of a parallel design study of subjects applying 1 mL of a 0.01 %, 0.1 %, 1
% or 2% minoxidil solution twice daily to the scalp for two weeks indicate that
absorption increases nearly linearly over the dose range studied. A cross-over
study evaluating higher strength solutions demonstrated that the amount of
minoxidil recovered in the urine increases less than in proportion to an increase
in dose for the dose range evaluated. Subjects in this study had applied 1 mL of
either a 1 %, 2% or 5% solution to a constant 200 cm2 surface area every 12
hours.

27
Frequency of Application:
It has been documented that the average amount of minoxidil recovered in the
urine following 1 mL of 1 % minoxidil solution administered every six hours was
equivalent to that observed following 1 mL of 2 % minoxidil administered every
12 hours.

Volume of Solution:
A cross-over study evaluated the effect of the volume of application on the
amount of minoxidil absorbed. This study documented that for a constant applied
dose (10 mg) over a constant surface area, the volume applied has no influence
on the amount of drug absorbed. Subjects received 1 mL of 1 % minoxidil
solution, 1/2 mL of 2 % minoxidil solution and 1/3 mL of 3 % minoxidil solution.

Location of Application:
No significant accumulation of minoxidil occurred as a result of applying up to
four times the recommended dose of 3 % minoxidil solution to the scalp or chest.
In this parallel-design study, subjects received 1 mL of 3 % minoxidil solution (30
mg) between two and eight times within a 12-hour interval for fourteen
consecutive days. The results also demonstrated that there was no difference in
absorption of minoxidil between the scalp and chest if applied less than eight
times per day. Absorption of minoxidil appeared to be slightly greater in the scalp
than in the chest at eight applications per day. Overall, the results indicate that
absorption of minoxidil solution was independent of the number of applications
within a twelve hour period for the doses administered in this study. This dosage
range, 60 to 240 mg per day, was significantly greater than that used in previous
studies which demonstrated a significant but less than proportional increase in
amount absorbed, following doses of 10 to 50 mg. The lack of an increase in
serum or urine minoxidil levels with increased frequency of application seen in
this study is probably the result of saturation of the stratum corneum with initial
doses of minoxidil.

28
Skin Irritation/Hypersensitivity:
Four studies evaluated skin irritation/hypersensitivity of minoxidil topical
solutions. A doubleblind, complete block-design study determined the relative
irritancy potential of 3 % minoxidil solution and compared it with vehicle alone
and Vitalis hair tonic. Twenty-five (25) subjects (16 males, 9 females)
simultaneously received all three treatments for 21 days. Patch sites from the
back were graded for hypersensitivity reactions.

A randomized, double-blind, complete block-design study determined and

compared the photoirritancy (photo-toxicity) potential of 3 % and 5 % minoxidil
solutions and vehicle. Ten (10) subjects (6 men and 4 women) simultaneously
received all three treatments. Each subject had three patches, each containing
one test solution, applied to their backs or upper arms thrice weekly for three
weeks; each patch remained in place for 48 to 72 hours. Approximately two
weeks after the sensitization phase, challenge applications to assess delayed
hypersensitivity were applied to a previously unpatched site.

A randomized, double-blind, complete block-design study determined and

compared the potential for irritation and sensitization of 3 % and 5 % minoxidil
solutions and vehicle in a repeated insult patch test. One hundred sixty-three
subjects (163; 88 men, 73 women, 2 patients sex inadvertently not specified)
were screened. All subjects simultaneously received all three treatments. Each
subject had three patches, each containing one test solution, applied
to their backs or upper arms thrice weekly for three weeks, each patch remained
in place for 48 to 72 hours. Approximately two weeks after the sensitization
phase, challenge applications to assess delayed hypersensitivity were applied to
a previously unpatched site. A randomized, double-blind, complete block-design
study determined and compared the irritation and photosensitization potentials of
3 % and 5 % minoxidil solutions and vehicle. Thirty-six subjects (36; 21 men and
15 women) were screened. All subjects simultaneously received all three
treatments. Each subject had three patches each containing one test

29
solution, applied on the back or upper arms thrice weekly for three weeks. Each
test area was irradiated each time a patch was changed. Two weeks later, six
challenge applications (two of each test solution) were made to two previously
unpatched test sites.

In these four studies, there was no evidence of irritancy potential, phototoxicity,

no demonstration of delayed-sensitivity and no evidence of induction of photo
allergic or allergic contact sensitization to the test solutions.

Immune Function:
A pilot study compared the immune status of 11 patients with male pattern
baldness, who were treated with topical minoxidil for 30 months, with the immune
status of 12 untreated male control subjects. Peripheral leucocytes were
examined for the presence of various cell subpopulations using monoclonal
antibodies coupled with cytofluorometry and for blastogenic responses to
phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen
(PWM). The results of this study revealed no effect on helper T-cell, Suppressor
T-cell, 8-cell, or natural killer cell numbers. In addition, no difference was
observed in mitogenic responses of the minoxidil patients to any of the mitogens
as compared with responses of the control subjects.

30
 TOXICOLOGY

Animal Studies

Acute Studies:

SPECIES ROUTE LD50 (mg/kg)

Mouse Oral 2457
Intraperitoneal 1001
Intravenous 51
Rat Oral 321
Intraperitoneal 759
Intravenous 49

Signs of Toxicity: CNS depression and acute pulmonary congestion.

Concomitant therapy, with either prednisone and antithymocyte globulin,
hydrochlorothiazide and propranolol or digoxin and furosemide, did not
appreciably alter the LD 50 for minoxidil.

Subacute and Chronic Studies;

3-Day Studies: (Rat, Dog)

Minoxidil was administered orally to rats and dogs at daily doses up to 100 and
10 mg/kg/day respectively for 3 days. In rats, a dose related slight increase in the
number of mitoses in hepatocytes was seen. In beagle dogs, epicardial and
myocardial cellular infiltrations, hypertrophy and hyperplasia of the mesothelial
cells, small focal haemorrhages and myocardial atrial lesions were observed at
1.0 and 10 mg/kg doses. These findings were more frequent and severe at the
higher dose. In mongrel dogs, there were minimal to mild subepicardial
haemorrhages present in the right atrium and/or right auricle which may

31
represent the early stages of right atrial lesions as seen in the longer term
studies.

1-Month Studies: (Monkey, Dog. Minipig and Rat)

Minoxidil was administered orally to monkeys at 20 mg/kg/day; to dogs at 0.5 and
1 mg/kg/day, and at 20 and 100 mg/kg/day; to minipigs at 20 mg/kg/day; and to
rats at 300 mg/kg/day. Grossly observed cardiac hypertrophy was reported in the
monkey study (the 4-0H metabolite of minoxidil at the same dose showed no
effect). In dogs, lesions of the right atrium and/or auricle were seen at all doses.
Local myocardial cell atrophy and/or degeneration was reported at doses as low
as 1 mg/kg/day. The 20 mg/kg dose produced degenerative right
auricular heart lesions as did the 4-0H metabolite of minoxidil. The high dose
resulted in the death of all dogs probably due to profound alteration in electrolyte
balance. In the minipig study blood pressure was depressed, heart rate elevated
and total body water and exchangeable sodium were increased. Cardiac lesions
due to minoxidil were not seen. In rats, repression of body weight gain,
decreased food consumption, reduced erythrocyte levels increased liver and
heart weights, indications of cardiac hypertrophy and electrolyte imbalance
were observed.

1-Year Studies (Rat, Monkey, Dog)

Minoxidil was administered orally to rats at 10, 30 and 100 mg/kg/day, monkeys
at 3.5, 7 and 14 mg/kg/day and dogs at 3, 10 and 30 mg/kg/day. In rats,
repression in body weight gain occurred and a dose related increase in liver,
kidney, adrenal and heart weights was seen. One high dose female monkey with
chronic glomerulonephritis died from cardiac failure and minoxidil probably
contributed because of its salt and water retaining action. In the dog study,
degenerative right auricular heart lesions were found at all dose levels. Evidence
of chronic electrolyte disturbance was noted in dogs at the highest dose.

32
22-Month Study (Rat)
Minoxidil was administered orally to rats at 3, 10 and 30 mg/kg/day. Increased
heart weights were observed at the highest dose. No carcinogenic potential was
apparent.

Drug Interaction Studies:

There was no evidence of alteration in toxicity when minoxidif was given
concomitantly with (a) hydrochlorothiazide and propranolol in rats and monkeys
for up to 1 month, and (b) furosemide and digoxin in rats for 1 month.
Hydrochlorothiazide partially reduced increases in heart weight and total body
exchangeable sodium produced by minoxidil in a 1 month monkey study.

Resume of Cardiac lesions in Animals:

(a) Dog Atrial Lesion:

Oral doses of 0.5 mg/kg for several days up to 1 month or longer produced a
grossly visible haemorrhagic lesion of the right atrium of the dog. Replacement of
myocardial cells by proliferating fibroblasts and angioblasts, phagocytosis, and
hemosiderin accumulation in macrophages was observed.

(b) Papillary Muscle Lesion:

In dog, rat and minipig necrosis of the papillary muscles and, in some cases,
subendocardial areas of the left ventricle were seen following a few days
treatment. Beta-adrenergic receptor blockade reduced the incidence and
severity.

(c) Hemorrhagic Lesions:

Hemorrhagic lesions were seen in the epicardium, endocardium and walls of
small coronary arteries and arterioles after acute minoxidil treatment in dogs. Left
atrial hemorrhagic lesions were seen in minipigs.

33
Longer term treatment in rats, dogs and monkeys showed cardiac hypertrophy
and cardiac dilation (in rats). Hydrochlorothiazide partly reversed the increased
heart weight in monkeys.

Reproduction Studies:
Male rats received minoxidil in oral doses of 3 or 10 mg/kg/day for 60 days prior
to and during the 14 day breeding period. Female rats received the same dose
for 14 days prior to and during breeding, and throughout gestation. A reduction in
conception rate was observed. No increase in the incidence of fetal resorption in
treated dams was seen. The average number of live pups per litter was
significantly decreased in both treatment groups, but live pups from treated dams
were significantly heavier than live pups from control dams.

Minoxidil, when given orally to pregnant rats and rabbits on gestation days 6
through 15 and 18 respectively, at dose levels of 3 and 10 mg/kg/day showed no
teratogenic effect. Increased fetal resorption occurred in rabbits. The same dose
administered to rats from the 15th day of gestation until pups were weaned at 21
days showed no effect of treatment on various parameters related to gestation.
parturition and lactation.

When a minoxidil suspension was given subcutaneously to pregnant rats in

doses of 0, 1, 11 and 120 mg/kg, no teratogenic changes were found in the
fetuses from the rats dosed at 0, 1 and 11 mg/kg of minoxidil. Increased fetal
mortality, still birth, external malformations and skeletal anomalies and variations
were observed at 120 mg/kg. This dose also caused decreased maternal weight
gain and food consumption and thus the fetal effects noted could have resulted
from maternal toxicity.

34
Topical Application:

Rat
Notable toxicity was seen only in topical studies done in rats. The rat absorbs
approximately 26 % of topical doses of minoxidil topical solution. Therefore, 1 mL
of minoxidil 1 % topical solution applied twice daily (20 mg/day), represents 1857
times the human topical dose on the basis of a 250-gm rat, a 50 kg-human, 26
% absorption in rats and an average of 1.4% absorption in man. One mL of
minoxidil 5 % topical solution applied twice daily (100 mg/day) represents 9286
times the human topical dose.

In the 94-day dermal rat study (1 mL/day), signs of toxicity were mainly noted in
the 6% minoxidil solution group (60 mg/day). The toxicity consisted of dose-
related increased nasal and ocular porphyrins; area of soreness in the treatment
area (also noted in one control rat); and fecal stains in a few rats of the 6%
group. Females had decreased body weight gains, and the following organ
weight changes were seen: increased spleen weights for both sexes at all dose
levels; increased heart weights for males at all dose levels and for females in the
1 % group (10 mg/day); and increased liver weights for males in the 3% (30
mg/day) and 6% (60 mg/day) groups. There were, however, no drug-related
lesions involving the skin or internal organs.

Signs of toxicity noted after six months of the one-year study in rats (2 mL/day)
consisted of decreased body weight gains in females; increased urinary protein
in males, related to the increase of naturally occurring nephritis; slightly dilated
ventricles of the heart in one and five female rats in the 3% (60 mg/day) and 5%
(100 mg/day) minoxidil solution groups, respectively; increased liver, heart and
spleen weights for males in all tested groups and females in the 3% and 5%
groups increased adrenal and kidney weights for females in the 3%

35
and 5 % groups; dose-related cardiac and liver hypertrophy on histopathology
examination; grossly thickened skin and histologic minimal-to-slight irritation of
the application site in all groups including controls.

The decreased body weights in females, increased organ weights and

histopathologic findings are associated with high systemic doses of minoxidil
and, therefore do not constitute new findings. The systemic doses reached in this
study are approximately 2,000 to 10,000 times the human topical dose. The
minimal irritation and thickening of the skin were not considered
drug-related or of consequence.

Rabbit
On a volume basis (4 mL/day), the dose levels tested in rabbits represent one to
five times the human dose. However, on the basis of a 2.5-kg rabbit and a 50-kg
man, the dose levels represent 20 to 100 times the human topical dose of
minoxidil topical solution. The absorption of topical applications of minoxidil
topical solution has not been investigated in the rabbit. However, assuming a
similar degree of absorption in the rabbit as seen in the rat (26 %L the
dose levels used in the rabbit dermal studies represent approximately 371 and
1857 times the human topical dose.

In the 21-day dermal study in the rabbit, drug-related clinical signs were absent.
Relative and/or absolute heart weights were significantly increased in the males
which received the 3 % and 5 % minoxidil topical solutions, as compared to the
controls. No histopathologic lesions were seen.

In the first six months of the one-year dermal study in rabbits, no distinct clinical
signs of toxicity were seen. Dilated ventricles of the heart were noted for one
female rabbit each in the 3 % and 5 % solution groups.

36
Eye Irritation Studies:
A single 100-mg dose of a 2% minoxidil gel formulation was instilled into the
conjunctival sac of the right eye of three male and three female New Zealand
White rabbits. The left eye was untreated and served as control. At one hour
post-instillation, all six treated eyes exhibited slight-to-moderate conjunctival
irritation, as indicated by slight redness, slight-to-moderate swelling, and
discharge. By 24 hours, the eye irritation remained at approximately the same
level for five rabbits, while the irritation in the eye of one female rabbit
deteriorated to include slight corneal opacity and iridal capillary injection.
However, the irritation gradually subsided by 96 hours post dosing. By day 7
post-treatment, all the treated eyes appeared normal.

A single 100-mg dose of a 3% minoxidil gel formulation was instilled into the
conjunctival sac of the right eye of three male and three female New Zealand
White rabbits. The left eye was untreated and served as control. Slight-to-
moderate conjunctival redness and swelling, and slight-to-severe discharge were
observed in all treated eyes from 1-96 hours post-dosing. In addition, the treated
eyes of two males and one female also exhibited slight corneal opacity
and corneal epithelial exfoliation for 1-24 hours post-dosing. However, the
treated eyes of all six rabbits appeared normal by day 7 post-treatment.

Gel formulations of minoxidil used in the eye irritation studies, contain the same
excipients that are present in minoxidil topical solution, with the exception that a
gelling agent and a stabilizer are present in the gel formulation. The alcohol
content in the gel formulations is lower than that of the topical solution. Since
alcohol is a known eye irritant, it can be concluded that minoxidil topical solution
is also an eye irritant.

37
 BIBLIOGRAPHY

1. Zappacosta AR. Reversal of baldness in patients receiving minoxidil for

hypertension. N Eng J Med 1980; 303:1480-81.

2. Seidman M, Westfried M, Maxey R, et al. Reversal of male pattern

baldness by minoxidil. A case report. Cutis 1981; 28:551-53.

3. Cohen RL, Alves MEAF, Weiss Vc. et al. Direct effects of minoxidil on
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4. Wester RC, Maibach HI, Guy RH, et al. Minoxidil stimulates cutaneous
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5. DeViliez RL: Topical minoxidil therapy in hereditary androgenetic

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6. Novak E, Franz T J, Headington JT, et al. Topically applied minoxidil in

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7. Olsen EA, Weiner MS, Delang ER, et al. Topical minoxidil in early male
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8. Clissolid SP, Heel RC. Topical minoxidil. A preliminary review of its

pharmacodynamic properties and therapeutic efficacy in alopecia areata
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9. Kvedar JC, Baden HP. Topical minoxidil in the treatment of male pattern
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10. Food and Drug Administration. Summary basis for approval 1988; NDA
19-501.

11. Product Monograph. ROGAINE Topical Solution (Minoxidil Topical

Solution) 20 mg/ml, (2 %). The Upjohn Company of Canada, Don Mills,
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13. Labelling Standard for Minoxidil for Topical Use. November 7, 1997.
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14. Ronald C. Savin, MD, and Andrew V. Atton, MD. Minoxidil: Update on its
Clinical Role. January 1993.

15. AHFS 97 Drug Information - American Hospital Formulary Service, 1997.

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39