Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2020 Publisher: Alphapharm Pty Ltd, Level 1, 30 The Bond, 30 – 34 Hickson Road, Millers Point NSW 2000, www.mylan.com.au
Finide is contraindicated in the following:
Since the beneficial response to finasteride may not be manifested immediately, patients with large residual urine volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy.
Finasteride may not reduce inconvenience to patients arising from benign prostatic hyperplasia (BPH) symptoms in patients with mild to moderate enlargement in prostate (<40 mL size).
No clinical benefit has yet been demonstrated in patients with prostate cancer treated with finasteride.
Patients with BPH and elevated PSA were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these BPH studies, finasteride did not appear to alter the rate of prostate cancer detection and the overall incidence of prostate cancer was not significantly different in patients treated with finasteride or placebo.
Digital rectal examinations, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with finasteride and periodically thereafter. Serum PSA is also being used as one of the components of the screening process to detect prostate cancer.
Generally, a baseline PSA >10 nanogram/mL (Hybritech) prompts further evaluation and consideration of biopsy; for PSA levels between 4 and 10 nanogram/mL, further evaluation is advisable. There is considerable overlap in PSA levels among men with and without prostate cancer. Therefore, in men with BPH, PSA values within the normal reference range do not rule out prostate cancer, regardless of treatment with finasteride. A baseline PSA <4 nanogram/mL does not exclude prostate cancer.
Finasteride causes a decrease in serum PSA levels by approximately 50% in patients with BPH even in the presence of prostate cancer. This decrease in serum PSA levels should be considered when evaluating PSA laboratory data and does not rule out concomitant prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Analysis of PSA data from over 3,000 patients in the four-year, double blind, placebo controlled Proscar Long-term Efficacy and Safety Study (PLESS) confirmed that in typical patients treated with finasteride for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.
ANY SUSTAINED INCREASES IN PSA LEVELS WHILE ON FINASTERIDE SHOULD BE CAREFULLY EVALUATED, INCLUDING CONSIDERATION OF NONCOMPLIANCE WITH FINASTERIDE THERAPY.
Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%) [see Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)]. Similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride). 5α-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established.
See Section 5.2 PHARMACOKINETIC PROPERTIES, HEPATIC INSUFFICIENCY
See Section 4.2 DOSE AND METHOD OF ADMINISTRATION, DOSAGE IN RENAL INSUFFICIENCY
See Section 4.2 DOSE AND METHOD F ADMINISTRATION
Finasteride is not indicated for use in children. Safety and effectiveness in children have not been established.
When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels decrease in patients treated with finasteride. In most patients, a rapid decrease in PSA is seen within the first months, after which time PSA levels stabilise to a new baseline. The post-treatment baseline approximates half of the pre-treatment value. Therefore, in typical patients treated with finasteride for six months or more, PSA values should be doubled for comparison to normal ranges in untreated men. For clinical interpretation, see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE, EFFECTS ON PROSTATE SPECIFIC ANTIGEN AND PROSTATE CANCER DETECTION.
No other difference in standard laboratory parameters was observed between patients treated with placebo or finasteride.
No drug interactions of clinical importance have been identified. Compounds which have been tested in humans have included propranolol, digoxin, theophylline, glibenclamide, warfarin and phenazone.
Increases in cytochrome P450 drug metabolising activity were observed in animal studies (in rats, mice and dogs receiving doses of >80, 250 and 45 mg/kg/day respectively). Finasteride is metabolised primarily via the cytochrome P450 3A4 system. Although the risk for finasteride to affect the pharmacokinetics of other drugs is estimated to be small, it is probable that inhibitors and inducers of cytochrome P450 3A4 will affect the plasma concentration of finasteride. However, based on established safety margins, any increase due to concomitant use of such inhibitors is unlikely to be of clinical significance.
In a study in 12 normal volunteers receiving finasteride 5 mg/day for eight days, finasteride significantly increased theophylline clearance by 7% and decreased its half-life by 10% after intravenous administration of aminophylline. These changes are not clinically significant.
Although specific interaction studies were not performed, in clinical studies finasteride was used concomitantly with angiotensin converting enzyme (ACE) inhibitors, alpha-blockers, beta-blockers, calcium channel blockers, cardiac nitrates, diuretics, H2-antagonists, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), quinolones and benzodiazepines without evidence of clinically significant adverse interactions.
Treatment of male rabbits with finasteride up to 80 mg/kg/day (543 times human exposure) did not impair fertility. In male rats, treatment for up to 24 or 30 weeks with 80 mg/kg/day (61 times human exposure) resulted in an apparent decrease in fertility associated with a significant decrease in weight of seminal vesicles and prostate. All of these effects were reversible within six weeks of discontinuation of treatment. This decrease in fertility in rats was secondary to the effect of finasteride on the accessory sex organs, resulting in failure to form a seminal plug, which is essential for fertility in rats, but is not relevant to humans.
Pregnancy Category: X
Finasteride is contraindicated for use in women when they are or may potentially be pregnant (see Section 4.3 CONTRAINDICATIONS).
Because of the ability of type II 5-alpha-reductase inhibitors to inhibit conversion of testosterone to dihydrotestosterone, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male foetus when administered to a pregnant woman.
Crushed or broken finasteride tablets 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 (see Section 4.6 FERTILITY, PREGNANCY AND LACTATION, DEVELOPMENTAL STUDIES). Finasteride tablets are coated and will prevent contact with active ingredient during normal handling, provided that the tablets have not been broken or crushed.
Small amounts of finasteride have been recovered in the seminal fluid of subjects receiving finasteride 5 mg daily. The maximum levels detected in two different studies were 10.54 and 21 nanogram/mL which are 50- to 100-fold less than the dose of finasteride (5 microgram) that had no effect on circulating DHT levels in adult males (see Section 4.6 FERTILITY, PREGNANCY AND LACTATION, DEVELOPMENTAL STUDIES).
Dose dependent hypospadias were observed in the male offspring of pregnant rats given finasteride at doses ranging from 100 microgram/kg/day to 100 mg/kg/day at an incidence of 3.6 to 100%. Additionally, pregnant rats produced male offspring with decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development when given finasteride at doses greater than or equal to 30 microgram/kg/day (greater than or equal to 30% of the recommended human dose), and decreased anogenital distance when given finasteride in doses greater than or equal to 3 microgram/kg/day (greater than or equal to 3% of the recommended human dose). The critical period during which these effects can be induced has been defined in rats as days 16 to 17 of gestation.
The changes described above are expected pharmacological effects of type II 5-alpha-reductase inhibitors. Many of the changes, such as hypospadias, observed in male rats exposed in utero to finasteride are similar to those reported in male infants with a genetic deficiency of type II 5-alpha-reductase. No effects were seen in female offspring exposed in utero to any dose of finasteride.
Administration of finasteride to rats during the late gestation and lactation period results in slightly decreased fertility in first generation male offspring (3 mg/kg/day). No developmental abnormalities have been observed in first generation male or female offspring resulting from the mating of finasteride treated male rats (80 mg/kg/day) with untreated females.
No evidence of malformations has been observed in rabbit fetuses exposed to finasteride in utero from days 6 to 18 of gestation at doses of up to 100 mg/kg/day.
The in utero effects of finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20 to 100), a species more predictive of human development than rats or rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 nanogram/day (at least 60 to 120 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no external genital abnormalities in male fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a very high dose of finasteride (2 mg/kg/day; 20 times the recommended human dose or approximately 1 to 2 million times the highest estimated exposure to finasteride from semen) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride related abnormalities were observed in female fetuses at any dose.
Finasteride is not indicated for use in women. It is not known whether finasteride is excreted in human milk.
The effects of this medicine on a person’s ability to drive and use machines were not assessed as part of its registration.
Finasteride is well tolerated.
In PLESS, 1,524 patients treated with finasteride 5 mg daily and 1,516 patients treated with placebo were evaluated for safety over a period of four years. 4.9% (74 patients) were discontinued from treatment due to adverse reactions associated with finasteride compared with 3.3% (50 patients) treated with placebo. 3.7% (57 patients) treated with finasteride and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which were the most frequently reported adverse reactions.
Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on finasteride was greater than or equal to 1% and greater than placebo over the four years of the study. In years 2 to 4 of the study, there was no significant difference between treatment groups in the incidence of impotence, decreased libido or ejaculation disorder.
Table 1. Finasteride drug related adverse experiences:
| Adverse experience | Treatment | Year 1 % (n) | Years 2, 3 and 4* % (n) |
|---|---|---|---|
| Impotence | Placebo | 3.7 (n=56) | 5.1 (n=77) |
| Finasteride | 8.1 (n=123) | 5.1 (n=77) | |
| Decreased libido | Placebo | 3.4 (n=52) | 2.6 (n=39) |
| Finasteride | 6.4 (n=98) | 2.6 (n=39) | |
| Decreased volume of ejaculate | Placebo | 0.8 (n=12) | 0.5 (n=7) |
| Finasteride | 3.7 (n=56) | 1.5 (n=23) | |
| Ejaculation disorder | Placebo | 0.1 (n=1) | 0.1 (n=1) |
| Finasteride | 0.8 (n=12) | 0.2 (n=3) | |
| Breast enlargement | Placebo | 0.1 (n=1) | 1.1 (n=17) |
| Finasteride | 0.5 (n=8) | 1.8 (n=27) | |
| Breast tenderness | Placebo | 0.1 (n=1) | 0.3 (n=5) |
| Finasteride | 0.4 (n=6) | 0.7 (n=11) | |
| Rash | Placebo | 0.2 (n=3) | 0.1 (n=2) |
| Finasteride | 0.5 (n=8) | 0.5 (n=7) |
* Combined years 2-4
n=1524 and 1516 finasteride vs placebo, respectively
The adverse experience profile in the one-year, placebo controlled, phase III studies and the five-year extensions, including 853 patients treated for five to six years, was similar to that reported in years 2 to 4 in PLESS. There is no evidence of increased adverse experiences with increased duration of finasteride. The incidence of new drug related sexual adverse experiences decreased with duration of treatment with finasteride.
The following additional adverse effects have been reported in post-marketing experience with Finide and/or finasteride at lower doses. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a casual relationship to drug exposure.
Immune system disorders: hypersensitivity reactions such as pruritus, urticaria and angioedema (including swelling of the lips, tongue, throat and face).
Psychiatric disorders: depression; decreased libido that continued after discontinuation of treatment; suicidal ideation.
Reproductive system and breast disorders: sexual dysfunction (erectile dysfunction and ejaculation disorders) that continued after discontinuation of treatment; breast tenderness and enlargement; testicular pain; haematospermia; male breast cancer; male infertility and/or poor seminal quality. Normalisation or improvement of seminal quality has been reported after discontinuation of finasteride.
The PCPT trial was a 7-year randomised, double-blind, placebo-controlled trial that enrolled 18,882 men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received either finasteride 5 mg or placebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%) [See Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE]. In a 4-year placebocontrolled clinical trial with another 5α-reductase inhibitor (dutasteride), similar results for Gleason score 8-10 prostate cancer were observed.
No clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride.
During the 4-to-6-year placebo and comparator-controlled Medical Therapy of Prostate Symptoms (MTOPS) study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2 cases of breast cancer in placebo-controlled men but no cases in men treated with finasteride. During the 7-year placebo-controlled PCPT that enrolled 18,882 men, there was 1 case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with placebo. There have been postmarketing reports of male breast cancer with the use of finasteride 1 mg and 5 mg. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
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