Digital rectal examination, as well as other evaluations for prostate cancer, must be performed on patients with BPH prior to initiating therapy with Avodart and periodically thereafter.
Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules (see section 4.6 Pregnancy). If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.
Dutasteride was not studied in patients with liver disease. Caution should be used in the administration of dutasteride to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).
Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Generally, a total serum PSA concentration greater than 4 ng/mL (Hybritech) requires further evaluation and consideration of prostate biopsy. Physicians should be aware that a baseline PSA less than 4 ng/mL in patients taking Avodart does not exclude a diagnosis of prostate cancer. Avodart 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 Avodart 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 Avodart should be carefully evaluated, including consideration of noncompliance to therapy with Avodart.
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 Avodart. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Avodart therapy, no adjustment to its value appears necessary.
Section 4.5 - For information on the decrease of serum PSA levels during treatment with dutasteride and guidance concerning prostate cancer detection, please see section 4.4.
Effects of other drugs on the pharmacokinetics of dutasteride
Use together with CYP3A4 and/or P-glycoprotein-inhibitors:
Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients.
Long-term combination of dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of dutasteride. Further inhibition of 5-alpha reductase at increased dutasteride exposure, is not likely. However, a reduction of the dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached.
Administration of 12g colestyramine one hour before a 5mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.
Effects of dutasteride on the pharmacokinetics of other drugs
Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19 or CYP3A4.
In a small study (N=24) of two weeks duration in healthy men, dutasteride
