In clinical studies, single doses of Urofin up to 400 mg and multiple doses of Urofin up to 80 mg/day for three months (n=71) did not result in dose related side effects. No specific treatment of overdose with Urofin Tablets 1mg is recommended.
Urofin should not be used in children / adolescents.
'special warning and precaution for use', 4.6 'pregnancy and lactation', and 5.1 'pharmacodynamic properties'). Should not be taken by men who are taking Urofin 5 mg Tablets or any other 5α-reductase inhibitor for benign prostatic hyperplasia or any other condition.Hypersensitivity to Urofin or to any of the excipients listed in 6.1.
Not applicable.
The adverse reactions during clinical trials and / or post-marketing use are listed in the table below.
The frequencies of undesirable effects are following: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to ≤1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
The frequency of adverse reactions reported during post- marketing use cannot be determined as they are derived from spontaneous reports.
| Immune system disorders: | Not known: Hypersensitivity reactions, including rash, pruritus, urticaria and angioedema (swelling of the lips, tongue, throat, and face). |
| Cardiac disorders: | Not known: Palpitation |
| Psychiatric disorder: | Uncommon$: Decreased libido, depression |
| Hepatobiliary disorders: | Not known: Increased hepatic enzymes. |
| Reproductive system and breast disorders: | Uncommon$: Erectile dysfunction, ejaculation disorder (including decreased volume of ejaculate) Not known: Breast tenderness and enlargement (gynecomastia), Testicular pain, infertility* |
$ incidences presented as difference from placebo in clinical studies at Month 12
)Drug-related sexual undesirable effects were more common in the Urofin-treated men than the placebo-treated men, with frequencies during the first 12 months of 3.8% vs 2.1%, respectively. The incidence of these effects decreased to 0.6% in Urofin-treated men over the following four years. Approximately 1% of men in each treatment group discontinued due to drug related sexual adverse experiences in the first 12 months, and the incidence declined thereafter.
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 Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard.
Studies in women
Lack of efficacy was demonstrated in post-menopausal women with androgenetic alopecia who were treated with Urofin 1 mg tablets 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 standardized photographs, compared with the placebo group.
5.2 Pharmacokinetic propertiesAbsorption
Relative to an intravenous reference dose, the oral bioavailability of Urofin is approximately 80%. The bioavailability is not affected by food. Maximum Urofin 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 Urofin is approximately 76 liters.
At steady state following dosing with 1 mg/day, maximum Urofin plasma concentration averaged 9.2 ng/ml and was reached 1 to 2 hours post dose; AUC (0-24 hr) was 53 ng-hr/ml.
Urofin has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A small amount of Urofin has also been detected in the seminal fluid of subjects receiving the drug.
Biotransformation
Urofin is metabolized primarily via but does not affect the cytochrome P450 3A4 system. Following an oral dose of 14C-Urofin in man, two metabolites of Urofin were identified that possess only a small fraction of the 5α-reductase inhibitory activity of Urofin.
Elimination
Following an oral dose of 14C-Urofin 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 Urofin 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-dialyzed patients with renal impairment.
5.3 Preclinical safety dataNon-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction toxicology studies in male rats have demonstrated reduced prostate and seminal vesicular weights, reduced secretion from accessory genital glands and reduced fertility index (caused by the primary pharmacological effect of Urofin). The clinical relevance of these findings is unclear.
As with other 5-alpha-reductase inhibitors, femininisation of male rat foetuses has been seen with administration of Urofin in the gestation period. Intravenous administration of Urofin to pregnant rhesus monkeys at doses up to 800 ng/day during the entire period of embryonic and foetal development resulted in no abnormalities in male foetuses. This dose is about 60-120 times higher than the estimated amount in semen of a man who have taken 5 mg Urofin, and to which a woman could be exposed via semen. The reproductive toxicity is believed to be mediated via the intended inhibition of 5α-reductase. Taken into account the species enzyme difference in sensitivity to Urofin inhibition the margin of pharmacological exposure would be about 4 times. In confirmation of the relevance of the Rhesus model for human foetal development, oral administration of Urofin 2 mg/kg/day (the systemic exposure (AUC) of monkeys was below or in the range of that of men who have taken 5 mg Urofin, or approximately 1 to 2 million times the estimated mount of Urofin in semen) to pregnant monkeys resulted in external genital abnormalities in male foetuses. No other abnormalities were observed in male foetuses and no Urofin-related abnormalities were observed in female foetuses at any dose.â€
Urofin 1 mg is indicated for treatment of the first stage of the hair loss (androgenetic alopecia) in males. Urofin 1 mg stabilizes the process of the androgenetic alopecia in the 18-41 year old males. Its effectiveness in bitemporary recession nor in the loss of hair has not been determined.
Urofin is not indicated for use in women or children and adolescents.
Pharmacotherapeutic group: Other dermatologicals
ATC-Code: D11 AX10
Mechanism of action
Urofin is a 4-azasteroid, which inhibits human Type 2 5α-reductase (present within the hair follicles) with greater than 100-fold selectivity over human Type 1 5α-reductase, and blocks the peripheral conversion of testosterone to the androgen dihydrotestosterone (DHT). In men with male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT. Urofin inhibits a process responsible for miniaturization of the scalp hair follicles, which can lead to reversal of the balding process.
Clinical efficacy
Studies in men:
The efficacy of Urofin 1mg tablets was demonstrated in three studies in 1879 men 18 to 41 years of age with mild to moderate, but not complete, vertex hair loss and frontal/mid-area hair loss. In these studies, hair growth was assessed using four separate measures including hair count, ratings of photographs of the head by an expert panel of dermatologists, investigator assessment, and patient self-assessment. In the two studies in men with vertex hair loss, treatment with Urofin 1mg tablets was continued for 5 years, during which time patients improved compared to baseline in men treated with Urofin 1mg tablets were generally greatest at 2 years and gradually declined thereafter (e.g., hair count in a representative 5.1 cm2 area was increased 88 hairs from baseline at 2 years and 38 hairs from baseline at 5 years), hair loss in the placebo group progressively worsened compared to baseline (decrease of 50 hairs at 2 years and 239 hairs at 5 years). Thus, although improvement compared to baseline in men treated with Urofin 1mg tablets did not increase further after 2 years, the difference between treatment groups continued to increase throughout the 5 years of the studies. Treatment with Urofin 1mg tablets for 5 years resulted in stabilization of hair loss in 90% of men based on photographic assessment and in 93% based on investigator assessment.
In addition, increased hair growth was observed in 65% of men treated with Urofin 1mg tablets based on hair counts, in 48% based on photographic assessment, and in 77% based on investigator assessment. In contrast, in the placebo group, gradual hair loss over time was observed in 100% of men based on hair counts, in 75% based on photographic assessment, and in 38% based on investigator assessment. In addition, patient self-assessment demonstrated significant increases in hair density, decreases in hair loss, and improvement in appearance of hair after treatment over 5 years with Urofin 1mg tablets (see Table below).
Percent of Patients Improved as Assessed by Each of the 4 Measures
|
| Year 1†| Year 2††| Year 5††| |||
| Urofin 1MG TABLETS | Placebo | Urofin 1MG TABLETS | Placebo | Urofin 1MG TABLETS | Placebo | |
| Hair Count | (N=679) 86 | (N=672) 42 | (N=433) 83 | (N=47) 28 | (N=219) 65 | (N=15) 0 |
| Global Photographic Assessment | (N=720) 48 | (N=709) 7 | (N=508) 66 | (N=55) 7 | (N=279) 48 | (N=16) 6 |
| Investigator Assessment | (N=748) 65 | (N=747) 37 | (N=535) 80 | (N=60) 47 | (N=271) 77 | (N=13) 15 |
| Patient Self-Assessment: Satisfaction with appearance of hair overall | (N=750) 39 | (N=747) 22 | (N=535) 51 | (N=60) 25 | (N=284) 63 | (N=15) 20 |
†Randomization 1:1 Urofin 1MG TABLETS to placebo
††Randomization 9:1 Urofin 1MG TABLETS to placebo
In a 12-month study, in men with frontal/mid-area hair loss, hair counts were obtained in a representative 1 cm2 area (approximately 1/5 the size of the area sampled in the vertex studies). Hair counts, adjusted to a 5.1 cm2 area, increased by 49 hairs (5%) compared to baseline and by 59 hairs (6%) compared to placebo. This study also demonstrated significant improvements in patient self-assessment, investigator assessment, and ratings of photographs of the head by an expert panel of dermatologists. Two studies of 12 and 24 weeks duration showed that a dose 5-fold the recommended dose (Urofin 5 mg daily) produced a median decrease in ejaculate volume of approximately 0.5 mL (-25%) compared with placebo. This decrease was reversible after discontinuation of treatment. In a study of 48 weeks of duration, Urofin 1 mg daily produced a median decrease in ejaculate volume of 0.3 mL (-11%) compared with a 0.2 mL (-8%) decrease for placebo. No effect was observed on sperm count, motility or morphology. Longer-term data are not available. It has not been feasible to undertake clinical studies, which directly elucidate possible negative effects on fertility. However, such effects are judged as very unlikely (see also 5.3 Preclinical safety data).
Studies in women
Lack of efficacy was demonstrated in post-menopausal women with androgenetic alopecia who were treated with Urofin 1 mg tablets 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 standardized photographs, compared with the placebo group.
Absorption
Relative to an intravenous reference dose, the oral bioavailability of Urofin is approximately 80%. The bioavailability is not affected by food. Maximum Urofin 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 Urofin is approximately 76 liters.
At steady state following dosing with 1 mg/day, maximum Urofin plasma concentration averaged 9.2 ng/ml and was reached 1 to 2 hours post dose; AUC (0-24 hr) was 53 ng-hr/ml.
Urofin has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A small amount of Urofin has also been detected in the seminal fluid of subjects receiving the drug.
Biotransformation
Urofin is metabolized primarily via but does not affect the cytochrome P450 3A4 system. Following an oral dose of 14C-Urofin in man, two metabolites of Urofin were identified that possess only a small fraction of the 5α-reductase inhibitory activity of Urofin.
Elimination
Following an oral dose of 14C-Urofin 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 Urofin 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-dialyzed patients with renal impairment.
Paediatric population
Urofin must not be used in children / adolescents (< 18 years). There are no data demonstrating efficacy or safety of Urofin in children under the age of 18.
Effects on Prostate Specific Antigen (PSA)
In clinical studies with Urofin 1 mg Tablets 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 Urofin Tablets 1mg, a patient requires a PSA assay. In this case it should be considered to double PSA value before making a comparison with the results from untreated men.
Effects on fertility
See 4.6 Fertility, pregnancy and lactation
Breast cancer has been reported in men taking Urofin during clinical trials and in the post-marketing period.
Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge.
The effect of hepatic insufficiency on the pharmacokinetics of Urofin has not been studied.
Excipients
This medicinal product contains lactose-monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
Mood alterations and depression
Mood alterations including depressed mood, depression and, less frequently, suicidal ideation have been reported in patients treated with Urofin 1 mg. Patients should be monitored for psychiatric symptoms and if these occur, treatment with Urofin should be discontinued and the patient advised to seek medical advice.
Urofin 1 mg has no or negligible influence on the ability to drive or use machines.
Posology
For oral use only.
The recommended dosage is one 1 mg tablet daily. Urofin Accord 1mg may be taken with or without food. The tablet should be swallowed whole and must not be divided or crushed.
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 stabilization 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.
Method of administration
For oral use only.
Dosage in renal insufficiency
No dosage adjustment is required in patients with renal insufficiency.
Dosage in hepatic insufficiency
There are no data available in patients with hepatic insufficiency
Women who are pregnant or may become pregnant should not handle Urofin tablets especially if crushed or broken because of the possibility of absorption of Urofin and the subsequent potential risk to a male foetus.
Any unused product or waste material should be disposed of in accordance with local requirements.
