Prodart 0,5 mg Soft gelatin capsules.

Treatment of Benign Prostatic Hyperplasia (BPH).

Adult males (including elderly) The recommended dose of PRODART is one capsule (0,5 mg) taken orally once a day. Although an improvement may be observed at an early stage, treatment for at least 6 months may be necessary in order to assess objectively whether a satisfactory response to the treatment can be achieved. Special populations Renal impairment The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, no adjustment in dosage is anticipated for patients with renal impairment (see section 5.2). Hepatic impairment The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied (see section 4.4 and 5.2). Method of administration: Oral use. The capsules should be swallowed whole (see section 4.4). PRODART may be taken with or without food.

• PRODART is contraindicated in patients with known hypersensitivity to dutasteride, other 5u03b1 -reductase inhibitors, or to any of the excipients listed in 6.1.
• PRODART is contraindicated for use by women.
• PRODART is contraindicated for use in children.

Leaking capsules Dutasteride as in PRODART is absorbed through the skin, therefore, women and children must avoid contact with leaking capsules (see section 4.3). If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Effects on prostate specific antigen (PSA) and prostate cancer detection Digital rectal examination, as well as other evaluations for prostate cancer, should be performed on patients with benign prostatic hyperplasia (BPH) prior to initiating therapy with PRODART and periodically thereafter. Serum prostate-specific antigen (PSA) concentration is an important component of the screening process to detect prostate cancer. Generally, a serum PSA concentration > 4 ng/mL (Hybritech) requires further evaluation and consideration of prostate biopsy. Physicians should be aware that a baseline PSA < 4 ng/mL in patients taking PRODART does not exclude a diagnosis of prostate cancer. PRODART causes a decrease in serum PSA levels by approximately 50 %, after 6 months, in patients with BPH, even in the presence of prostate cancer.

Although there may be individual variation, the reduction in PSA by approximately 50 % is predictable as it was observed over the entire range of baseline PSA values (1,5 to 10 ng/mL). Therefore, to interpret an isolated PSA value in a man treated with PRODART for 6 months or longer, 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 PRODART should be carefully evaluated, including consideration of non-compliance to therapy with PRODART. Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of PRODART. If physicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing dutasteride therapy, no adjustment to its value is necessary.

Cardiovascular adverse events In a reported two 4-year clinical studies, the incidence of cardiac failure (a composite term of reported events, primarily cardiac failure and congestive cardiac failure) was marginally higher among subjects taking the combination of dutasteride and an alpha blocker, primarily tamsulosin, than it was among subjects not taking the combination. However, the incidence of cardiac failure in these reported trials were lower in all actively treated groups compared to the placebo group, and other data available for dutasteride or alpha-blockers do not support a conclusion on increased cardiovascular risks.

Breast neoplasia Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple changes.

Hepatic impairment PRODART was not studied in patients with liver disease and the effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolised and has a half-life of 3 to 5 weeks, caution should be exercised in the administration of dutasteride as in PRODART to patients with mild to moderate hepatic impairment (see section 4.2 and section 5.2).

Risk of non-alcoholic fatty liver disease (NAFLD) From the available data it is has been observed that androgen deficiency is a risk factor for non-alcoholic fatty liver disease (NAFLD). As with other 5u03b1 - reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone. Consequently, there is a risk that patients receiving dutasteride may develop NAFLD.

Effects of other medicines on the pharmacokinetics of dutasteride Use together with CYP3A4 inhibitors: In vitro drug metabolism studies show that dutasteride as in PRODART is metabolised by human cytochrome P450 isoenzyme CYP3A4. Therefore, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4. Studies showed a decrease in clearance of dutasteride as in PRODART when co-administered with the CYP3A4 inhibitors verapamil (37 %) and diltiazem (44 %). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist, was co-administered with dutasteride. A decrease in clearance and subsequent increase in exposure to dutasteride as in PRODART, in the presence of CYP3A4 inhibitors, is unlikely to be clinically significant due to the wide margin of safety (up to 10 times the recommended dose has been given to patients for up to six months), therefore no dose adjustment is necessary. In vitro, dutasteride is not metabolised by human cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Dutasteride neither inhibits human cytochrome P450 drug-metabolising enzymes in vitro nor induces cytochrome P450 isoenzymes CYP1A, CYP2B, and CYP3A in rats and dogs in vivo. Long-term combination of dutasteride, as in PRODART, with medicines that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally), may increase serum concentrations of dutasteride. Administration of 12 g colestyramine on hour after a 5 mg single doses of dutasteride as in PRODART, did not affect the pharmacokinetics of dutasteride.

Effects of PRODART on the pharmacokinetics of other medicines In vitro studies demonstrate that dutasteride as in PRODART, does not displace warfarin, diazepam, or phenytoin from plasma protein, nor do these model compounds displace dutasteride. Dutasteride has no effect on the pharmacokinetics of digoxin. This indicates that dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. Medicines that have been tested for interactions in man include tamsulosin, terazosin, warfarin, digoxin, and cholestyramine, and no clinically significant interactions have been observed. Although specific interaction studies were not performed with other medicines, approximately 90 % of the subjects receiving dutasteride were taking other medications concomitantly. No clinically significant adverse interactions were observed when dutasteride was co-administered with anti-hyperlipidemics, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics. An interaction study with tamsulosin or terazosin administered in combination with dutasteride for two weeks showed no evidence of pharmacokinetic or pharmacodynamic interactions. A larger study in which dutasteride was co-administered with tamsulosin for up to 9 months showed that combination of dutasteride with an alpha blocker was well tolerated.

PRODART is contraindicated for use in women. Pregnancy As with other 5 alpha reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus (see section 4.4). Small amounts of dutasteride have been recovered from the semen in subjects receiving PRODART 0,5 mg day. It is not known whether a male foetus may be adversely affected if his mother is exposed to the semen of a patient being treated with dutasteride (the risk of which is greatest during the first 16 weeks of pregnancy). When a patientu2019s partner is or may potentially be pregnant, it is recommended that the patient avoids exposure of his partner to semen by the use of a condom. Breastfeeding It is not known whether PRODART is excreted in human milk. Fertility Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men (see section 5.1). The possibility of reduced male fertility cannot be excluded.

Based on the pharmacodynamic properties of dutasteride, treatment with PRODART would not be expected to interfere with the ability to drive or operate machinery.

The frequency of adverse reactions reported with PRODART are summarised in the tables below according to the MedDRA system organ class (SOC).

Table 1: Tabulated list of adverse reactions from clinical trials System organ class Adverse reaction Frequency Year 1 Year 2 Reproductive system and breast disorders Impotence frequent frequent Altered (decreased) libido frequent less frequent Ejaculation disorders frequent less frequent Gynaecomastia* frequent frequent *Includes breast tenderness and breast enlargement

Table 2: Tabulated list of adverse reactions from post-marketing data System organ class Adverse reaction Frequency Immune system disorders Allergic reactions including rash, pruritus, urticaria, localised oedema, and angioedema unknown Psychiatric disorders Depression unknown Skin and subcutaneous tissue disorders Alopecia (primarily body hair loss), hypertrichosis less frequent Reproductive system and breast disorders Testicular pain and swelling unknown Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

In volunteer studies, single doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) for seven days have been administered without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to patients for 6 months with no additional adverse effects to those seen at therapeutic doses of 0,5 mg. There is no specific antidote for dutasteride as in PRODART, therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate.