Contact Information
Registered Office/ Head Office:
Ashford Laboratories Pvt. Ltd.,
31/36, 5th Floor, Dheeraj Heritage,
S. V. Road, Santacruz (West),
Mumbai (Bombay) - 400 054. India.
Tele- fax: + 91 22 6675 8866
Email:info@ashfordlab.com

Japan Office:
Ashford Laboratories,
4-11-24-1402 Fukae Kitamachi,
Higashi Nada Ku, Kobe 658-0013,
Japan.
Tele- fax: +81 0784 122579
Email:japan@ashfordlab.com
ULTRA REGROWTH SYSTEM (URS 1378) Each Set contains:

LOTION (60ML)
Active Ingredients:
Minoxidil 6 % w/v, Finasteride USP 0.1% w/w

Inactive Ingredients:
Alcohol, Propylene Glycol, Purified Water.

CAPSULES (30 CAPSULES)
Active Ingredients:
Finasteride, Vitamins and Amino Acids.

Inactive Ingredients:
Magnesium stearate, colloidal Silicon Dioxide, talcum.

      URS ML 1378 LOTION       URS ML 1378 CAPSULES
URS ML 1378 LOTIONTOP NAME OF THE MEDICINAL PRODUCT
URS ML 1378
QUALITATIVE AND QUANTITATIVE COMPOSITION
Minoxidil 60 mg/ml (6% w/v), Finasteride 100mg (0.1% w/w)
PHARMACEUTICAL FORM
Cutaneous Solution
CLINICAL PARTICULARS
Therapeutic indications
URS ML 1378 is indicated for the treatment of alopecia androgenetica in men.

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 URS ML 1378, individual responses cannot be predicted.

Posology and method of administration
Men aged 18-65:
Hair and scalp should be thoroughly dry prior to topical application of URS ML 1378. A dose of 1 ml URS ML 1378 cutaneous solution should be applied to the total affected areas of the scalp twice daily. The total dosage should not exceed 2 ml. If fingertips are used to facilitate drug application, hands should be washed afterwards. It may take twice daily applications for 2 months or more before evidence of hair growth can be expected.

If hair regrowth occurs, twice daily applications of URS ML 1378 are necessary for continued hair growth. Anecdotal reports indicate that regrown hair may disappear three to four months after stopping URS ML 1378 application and the balding process will continue.

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

Children and the Elderly Not recommended. The safety and effectiveness of URS ML 1378 in users aged under 18 or over 65 has not been established.

Contraindications
URS ML 1378 is contraindicated:
  in women
  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.

Special warnings and precautions for use
Before using URS ML 1378, the user should determine that the scalp is normal and healthy.

The patient should stop using URS ML 1378 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 URS ML 1378.

URS ML 1378 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.

URS ML 1378 cutaneous 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 amounts of cool tap water.

URS ML 1378 contains propylene glycol, which may cause skin irritation.

Some patients have experienced changes in hair colour and/or texture with URS ML 1378 use.

Users should be aware that, whilst extensive use of URS ML 1378 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.

Interaction with other medicinal products and other forms of interaction
Topical drugs, such as tretinoin or dithranol, 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.

Pregnancy and lactation
There is no evidence as to drug safety in human pregnancy nor is there evidence from animal work that it is free from hazard. URS ML 1378 should not be used during pregnancy or lactation.

Effects on ability to drive and use machines
Based on the pharmacodynamic and overall safety profile of minoxidil, it is not expected that URS ML 1378 would interfere with the ability to drive or operate machinery.

Undesirable effects
Several thousand patients have used topical minoxidil in clinical trials where a comparison with an inactive solution was made. Dermatological reactions (e.g. 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.

Reactions reported in commercial marketing experience include: hypertrichosis (unwanted non-scalp hair including facial hair growth in women), local erythema, itching, dry skin/scalp flaking, and exacerbation of hair loss.

Some consumers reported increased hair shedding upon initiation of therapy with URS ML 1378. 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 URS ML 1378 and consult their doctor.

Particular attention was 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.

Users should stop using URS ML 1378 if they experience chest-pain, tachycardia, faintness, dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness or irritation of the scalp. Rare cases of hypotension have been reported.

Overdose
Increased systemic absorption of minoxidil may potentially occur if higher-than-recommended doses of URS ML 1378 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 URS ML 1378.

Because of the concentration of minoxidil in URS ML 1378, accidental ingestion has the potential of producing systemic effects related to the pharmacological action of the drug (2 ml of URS ML 1378 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. Fluid retention can be managed with appropriate diuretic therapy. Clinically significant tachycardia can be controlled by administration of a beta-adrenergic blocking agent.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
The effect of URS ML 1378 has been assessed in a phase III clinical trial conducted over a 48 week treatment period.

In this study URS ML 1378 (5% minoxidil cutaneous solution) was compared to the product vehicle without the minoxidil active ingredient and also to 2% minoxidil cutaneous solution.

The primary efficacy criterion was non-vellus hair count in a 1.0cm2 reference area of affected scalp. The mean changes observed in this parameter in these studies were significantly in favour of active treatment. A significant dose effect was also demonstrated. The results are summarized in the following table:

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

URS ML 1378 Pairwise comparison
(n=139)
Minoxidil 6%
(n=142)
Minoxidil 2%
(n=71)
Vehicle
 Baseline 151.1 143.6 152.4
Mean change from baseline Mean change from baseline Mean change from baseline
 8 week +29.7 +24.9 +14.3 5%>2%>vehicle
 16 week +35.3 +29.8 +15.3 5%>2%>vehicle
 32 week +29.0 +22.2 +7.7 5%>2%>vehicle
 48 week +18.6 +12.7 +3.9 5%>2%>vehicle

Efficacy was further assessed by comparing photographs taken at various timepoints with baseline.

Assessment was undertaken by patients using a 100mm visual analogue scale and assessing scalp coverage where point 0 represented much less scalp coverage, 50mm no difference and 100mm much more scalp coverage. In addition, an assessment was undertaken by 2 blinded reviewers who compared photographs taken at baseline and after 48 weeks. Differences were assessed using a 7 point categorical scale viz:
 Dense growth
 Moderate growth
 Minimal growth
 No change
 Minimal loss
 Moderate loss
 Dense loss

The results of these analyses were as follows:

                                                                         Patient evaluation of change in scalp coverage

URS ML 1378 Pairwise comparison
(n=139)
Minoxidil 6%
(n=142)
Minoxidil 2%
(n=71)
Vehicle
  mm mm mm
 16 week 63.5 58.2 51.4 5%>2%>vehicle
 32 week 63.4 58.0 52.0 5%>2%>vehicle
 48 week 62 56.9 51.0 5%>2%>vehicle

                                                                   Photographic Evaluation of Clinical Response (Reviewer 1)

  Dense Growth% Moderate Growth% Minimal Growth% No change% Hair Loss% Unable to rate
 Minoxidil 5% 2.2 37.4 22.3 31.7 5.0 1.4
 Minoxidil 2% 2.8 19.7 21.1 50.0 2.8 3.5
 Vehicle 0 7.0 22.5 60.0 9.9 0

                                                                   Photographic Evaluation of Clinical Response (Reviewer 2)

  Dense Growth% Moderate Growth% Minimal Growth% No change% Hair Loss% Unable to rate
 Minoxidil 5% 10.1 20.1 23.7 28.8 6.5 10.8
 Minoxidil 2% 3.5 12.0 22.5 47.2 1.4 13.4
 Vehicle 0 7.0 9.9 60.0 14.1 8.5

Based upon these photographic data, around 60% of the patients experienced an increased scalp coverage after 48 weeks treatment with URS ML 1378 as defined by re-growth of hair; compared with around 23% at an average for those who received vehicle alone. Of these, around 35% treated with URS ML 1378 experienced dense or moderate regrowth compared with around 7% who received vehicle alone. In addition 30% of patients who received URS ML 1378 were adjudged to have no change between the photographic assessments of hair growth compared with 60% who received vehicle alone. Stabilisation of hair loss (expressed both as regrowth of hair and no continuation of hair loss) can therefore be expected in about 4 out of 5 of patients using URS ML 1378 compared with 3 out of 4 patients using vehicle alone.

URS ML 1378 may therefore be considered by men who wish to achieve a faster onset and greater degree of hair regrowth than would be expected through the use of Regaine Regular Strength.

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:
  increasing the diameter of the hair shaft
  stimulating anagen growth
  prolonging the anagen phase
  stimulating anagen recovery from the telegon phase

As a peripheral vasodilator minoxidil enhances microcirculation to hair follicles. The Vascular Endothelial Growth Factor (VEGF) is stimulated by minoxidil and VEGF is presumably responsible for the increased capillary fenestration, indicative of a high metabolic activity, observed during the anagen phase.

Pharmacokinetic properties
The failure to detect evidence of systemic effects during treatment with URS ML 1378 reflects the poor absorption of topical minoxidil, which averages about 1.7% (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 URS ML 1378 also results in increased absorption.

The use of URS ML 1378 in conjunction with occlusion (plastic dressings), application to sunburn areas, and increasing the surface area of application has minimal to no effect on the absorption of topical minoxidil.

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

Serum minoxidil levels and systemic effects resulting from administration of URS ML 1378 are governed by the drug's absorption rate through the skin. Following cessation of topical dosing of URS ML 1378, approximately 95% of the systemically absorbed drug is eliminated within 4 days. Minoxidil and its metabolites are excreted principally in the urine.

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.

In rat fertility studies, minoxidil at dose levels between 3 and 80 mg/kg exhibited adverse effects on fertility. Animal reproduction toxicity studies have shown a risk to the foetus at exposure levels that in comparison to levels obtained in humans are very high (doses that ranged from 569- to 1139-fold anticipated human exposures) and showed signs of maternal toxicity.
PHARMACEUTICAL PARTICULARS
List of excipients
Propylene glycol Ethanol Water

Incompatibilities
None known.

Shelf life
36 months

Special precautions for storage
URS ML 1378 is flammable. Store below 25°C.

Nature and contents of container
Lotion: Amber color Glass bottle with glass pipette applicator containing 60 ml of solution.

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

URS MC 1378 CAPSULESTOP
NAME OF THE MEDICINAL PRODUCT
URS MC 1378 Capsules
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet of 'URS MC 1378' contains 1 mg of finasteride as the active ingredient.
PHARMACEUTICAL FORM
White color; Size ‘2’ hard gelatin capsules.
CLINICAL PARTICULARS
Therapeutic indications
'URS MC 1378' is indicated for the treatment of men with male pattern hair loss (androgenetic alopecia) to increase hair growth and prevent further hair loss. 'URS MC 1378' is not indicated for use in women or children and adolescents.

Posology and method of administration
The recommended dosage is one 1 mg tablet daily. 'URS MC 1378' may be taken with or without food.

There is no evidence that an increase in dosage will result in increased efficacy.

Efficacy and duration of treatment should continuously be assessed by the treating physician. Generally, three to six months of once daily treatment are required before evidence of stabilisation of hair loss can be expected. Continuous use is recommended to sustain benefit. If treatment is stopped, the beneficial effects begin to reverse by six months and return to baseline by 9 to 12 months.

No dosage adjustment is required in patients with renal insufficiency.

No data are available on the concomitant use of 'URS MC 1378' and topical minoxidil in male pattern hair loss.

Contraindications
'URS MC 1378' is contraindicated for use in women due to the risk in pregnancy (see 4.6 'Pregnancy and lactation') and in patients with hypersensitivity to any component of this product.

'URS MC 1378' is not indicated for use in women or children and adolescents.

'URS MC 1378' should not be taken by men who are taking 'Proscar' (finasteride 5 mg) or any other 5α-reductase inhibitor for benign prostatic hyperplasia or any other condition.

Special warnings and precautions for use
In clinical studies with 'URS MC 1378' in men 18-41 years of age, the mean value of serum prostate-specific antigen (PSA) decreased from 0.7 ng/ml at baseline to 0.5 ng/ml at month 12. This decrease in serum PSA concentrations needs to be considered, if during treatment with 'URS MC 1378', a patient requires a PSA assay. In this case the PSA value should be doubled before making a comparison with the results from untreated men.

Interaction with other medicinal products and other forms of interaction
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolising enzyme system. Compounds which have been tested in man have included antipyrine, digoxin, glibenclamide, propranolol, theophylline and warfarin and no interactions were found.

Although specific interaction studies were not performed, in clinical studies finasteride doses of 1 mg or more were used concomitantly with ACE inhibitors, paracetamol, alpha blockers, benzodiazepines, beta blockers, calcium-channel blockers, cardiac nitrates, diuretics, H2 antagonists, HMG-CoA reductase inhibitors, prostaglandin synthetase inhibitors (NSAIDs), and quinolones, without evidence of clinically significant adverse interactions.

Pregnancy and lactation
Use during pregnancy
'URS MC 1378' is contra-indicated for use in women due to the risk in pregnancy.

Because of the ability of type II 5α-reductase inhibitors to inhibit conversion of testosterone to dihydrotestosterone (DHT) in some tissues, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male foetus when administered to a pregnant woman.

Exposure to finasteride: risk to male foetus
A small amount of finasteride, less than 0.001% of the 1 mg dose per ejaculation, has been detected in the seminal fluid of men taking 'URS MC 1378'. Studies in Rhesus monkeys have indicated that this amount is unlikely to constitute a risk to the developing male foetus (see Section 5.3).

During continual collection of adverse experiences, post-marketing reports of exposure to finasteride during pregnancy via semen of men taking 1 mg or higher doses have been received for eight live male births, and one retrospectively-reported case concerned an infant with simple hypospadias. Causality cannot be assessed on the basis of this single retrospective report and hypospadias is a relatively common congenital anomaly with an incidence ranging from 0.8 to 8 per 1000 live male births. In addition, a further nine live male births occurred during clinical trials following exposure to finasteride via semen, during pregnancy, and no congenital anomalies have been reported.

Crushed or broken tablets of 'URS MC 1378' should not be handled by women when they are or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male foetus. 'URS MC 1378' tablets are coated to prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed.

Use during lactation
'URS MC 1378' is contraindicated for use in lactation.

Effects on ability to drive and use machines
There are no data to suggest that 'URS MC 1378' affects the ability to drive or use machines.

Undesirable effects
Side effects, which usually have been mild, generally have not required discontinuation of therapy.

Finasteride for male pattern hair loss has been evaluated for safety in clinical studies involving more than 3,200 men. In three 12-month, placebo-controlled, double-blind, multicentre studies of comparable design, the overall safety profiles of 'URS MC 1378' and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 1.7% of 945 men treated with 'URS MC 1378' and 2.1% of 934 men treated with placebo.

In these studies, the following drug-related adverse experiences were reported in 1% of men treated with 'URS MC 1378': decreased libido ('URS MC 1378', 1.8% vs. placebo, 1.3%) and erectile dysfunction (1.3%, 0.7%). In addition, decreased volume of ejaculate was reported in 0.8% of men treated with 'URS MC 1378' and 0.4% of men treated with placebo. Resolution of these side effects occurred in men who discontinued therapy with 'URS MC 1378' and in many who continued therapy. The effect of 'URS MC 1378' on ejaculate volume was measured in a separate study and was not different from that seen with placebo.

By the fifth year of treatment with 'URS MC 1378', the proportion of patients reporting each of the above side effects decreased to < 0.3%.

Finasteride has also been studied for prostate cancer risk reduction at 5 times the dosage recommended for male pattern hair loss. In a 7-year placebo-controlled trial that enrolled 18,882 healthy men, of whom 9060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving finasteride 5 mg and 1147 (24.4%) men receiving placebo. In the finasteride 5 mg group, 280 (6.4%) men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs. 237 (5.1%) men in placebo group. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2). The relationship between long-term use of finasteride 5 mg and tumours with Gleason scores of 7-10 is unknown.

The following undesirable effects have been reported in post-marketing use: ejaculation disorder; breast tenderness and enlargement; hypersensitivity reactions including rash, pruritus, urticaria and swelling of the lips and face; and testicular pain.

Overdose
In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in side effects.

No specific treatment of overdosage with 'URS MC 1378' is recommended.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Finasteride is a competitive and specific inhibitor of type II 5α-reductase. Finasteride has no affinity for the androgen receptor and has no androgenic, anti-androgenic, oestrogenic, anti-oestrogenic, or progestational effects. Inhibition of this enzyme blocks the peripheral conversion of testosterone to the androgen DHT, resulting in significant decreases in serum and tissue DHT concentrations. Finasteride produces a rapid reduction in serum DHT concentration, reaching significant suppression within 24 hours of dosing.

Hair follicles contain type II 5α-reductase. In men with male pattern hair loss, the balding scalp contains miniaturised hair follicles and increased amounts of DHT. Administration of finasteride decreases scalp and serum DHT concentrations in these men. Men with a genetic deficiency of type II 5α-reductase do not suffer from male pattern hair loss. Finasteride inhibits a process responsible for miniaturisation of the scalp hair follicles, which can lead to reversal of the balding process.

Studies in men
Clinical studies were conducted in 1879 men aged 18 to 41 with mild to moderate, but not complete, vertex hair loss and/or frontal/mid-area hair loss. In the two studies in men with vertex hair loss (n=1553), 290 men completed 5 years of treatment with URS MC 1378 vs. 16 patients on placebo. In these two studies, efficacy was assessed by the following methods: (i) hair count in a representative 5.1cm2 area of scalp, (ii) patient self assessment questionnaire, (iii) investigator assessment using a seven point scale, and (iv) photographic assessment of standardised paired photographs by a blinded expert panel of dermatologists using a seven point scale.

In these 5- year studies men treated with 'URS MC 1378' improved compared to both baseline and placebo beginning as early as 3 months, as determined by both the patient and investigator assessments of efficacy. With regard to hair count, the primary endpoint in these studies, increases compared to baseline were demonstrated starting at 6 months (the earliest time point assessed) through to the end of the study. In men treated with 'URS MC 1378' these increases were greatest at 2 years and gradually declined thereafter to the end of 5 years; whereas hair loss in the placebo group progressively worsened compared to baseline over the entire 5 year period. In 'URS MC 1378' treated patients, a mean increase from baseline of 88 hairs [p < 0.01; 95% CI (77.9, 97.80; n=433] in the representative 5.1 cm2 area was observed at 2 years and an increase from baseline of 38 hairs [p < 0.01; 95% CI (20.8, 55.6); n=219] was observed at 5 years, compared with a decrease from baseline of 50 hairs [p < 0.01; 95% CI (-80.5, -20.6);n=47] at 2 years and a decrease from baseline of 239 hairs [p < 0.01; 95% CI (-304.4, -173.4); n=15] at 5 years in patients who received placebo. Standardised photographic assessment of efficacy demonstrated that 48% of men treated with finasteride for 5 years were rated as improved, and an additional 42% were rated as unchanged. This is in comparison to 25% of men treated with placebo for 5 years who were rated as improved or unchanged. These data demonstrate that treatment with 'URS MC 1378' for 5 years resulted in a stabilisation of the hair loss that occurred in men treated with placebo.

An additional 48-week, placebo-controlled study designed to assess the effect of 'URS MC 1378' on the phases of the hair-growth cycle (growing phase [anagen] and resting phase [telogen]) in vertex baldness enrolled 212 men with androgenetic alopecia. At baseline and 48 weeks, total, anagen and telogen hair counts were obtained in a 1-cm2 target area of the scalp. Treatment with 'URS MC 1378' led to improvements in anagen hair counts, while men in the placebo group lost anagen hair. At 48 weeks, men treated with 'URS MC 1378' showed net increases in total and anagen hair counts of 17 hairs and 27 hairs, respectively, compared to placebo. This increase in anagen hair count, compared to total hair count, led to a net improvement in the anagen-to-telogen ratio of 47% at 48 weeks for men treated with 'URS MC 1378', compared to placebo. These data provide direct evidence that treatment with 'URS MC 1378' promotes the conversion of hair follicles into the actively growing phase.

Studies in women
Lack of efficacy was demonstrated in post-menopausal women with androgenetic alopecia who were treated with 'URS MC 1378' in a 12 month, placebo-controlled study (n=137). These women did not show any improvement in hair count, patient self-assessment, investigator assessment, or ratings based on standardised photographs, compared with the placebo group.

Pharmacokinetic properties
Absorption
Relative to an intravenous reference dose, the oral bioavailability of finasteride is approximately 80%. The bioavailability is not affected by food. Maximum finasteride plasma concentrations are reached approximately two hours after dosing and the absorption is complete after six to eight hours.

Distribution
Protein binding is approximately 93%. The volume of distribution of finasteride is approximately 76 litres.

At steady state following dosing with 1 mg/day, maximum finasteride plasma concentration averaged 9.2 ng/ml and was reached 1 to 2 hours postdose; AUC (024 hr) was 53 ng•hr/ml.

Finasteride has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A small amount of finasteride has also been detected in the seminal fluid of subjects receiving the drug.

Biotransformation
Finasteride is metabolised primarily via the cytochrome P450 3A4 enzyme subfamily. Following an oral dose of 14C-finasteride in man, two metabolites of the drug were identified that possess only a small fraction of the 5α-reductase inhibitory activity of finasteride.

Elimination
Following an oral dose of 14C-finasteride in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine) and 57% of total dose was excreted in the faeces.

Plasma clearance is approximately 165 ml/min.

The elimination rate of finasteride decreases somewhat with age. Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age. These findings are of no clinical significance and hence, a reduction in dosage in the elderly is not warranted.

Characteristics in patients
No adjustment in dosage is necessary in non-dialysed patients with renal impairment.



Preclinical safety data
In general, the findings in laboratory animal studies with oral finasteride were related to the pharmacological effects of 5α-reductase inhibition.

Intravenous administration of finasteride to pregnant rhesus monkeys at doses as high as 800 ng/day during the entire period of embryonic and foetal development resulted in no abnormalities in male foetuses. This represents at least 750 times the highest estimated exposure of pregnant women to finasteride from semen. In confirmation of the relevance of the Rhesus model for human foetal development, oral administration of finasteride 2 mg/kg/day (100 times the recommended human dose or approximately 12 million times the highest estimated exposure to finasteride from semen) to pregnant monkeys resulted in external genital abnormalities in male foetuses. No other abnormalities were observed in male foetuses and no finasteride-related abnormalities were observed in female foetuses at any dose.
PHARMACEUTICAL PARTICULARS
List of excipients
Magnesium stearate, colloidal Silicon Dioxide, talcum.

Incompatibilities
Not applicable.

Shelf life
36 months.

Special precautions for storage
Do not store above 30°C. Store in original package.

Nature and contents of container
HDPE containers containing 30 capsules each.

Special precautions for disposal and other handling
Crushed or broken tablets of 'URS MC 1378' should not be handled by women when they are or may potentially be pregnant (see 4.6 'Pregnancy and lactation').
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