Source: Health Products Regulatory Authority (ZA) Publisher: Zydus Healthcare SA (Pty) Ltd, Southdowns Office Park, Building B, Ground Floor, 22 Karee Street, Centurion, Pretoria 0157
ZEDRAST is contraindicated in:
Careful benefit risk assessment is recommended before prescribing combination therapy (due to the potential increased risk of adverse events, including cardiac failure), as well as consideration of alternative treatment options including monotherapies (see section 5.2).
Male patients taking ZEDRAST should be evaluated for prostate cancer on a regular basis (see sections 4.8 and 5.1). A study conducted in patients with a high risk for prostate cancer has shown a higher incidence of Gleason 8–10 prostate cancers in those receiving dutasteride, in comparison to those receiving a placebo. The relationship between ZEDRAST and Gleason 8–10 prostate cancers is uncertain, therefore regular evaluations are recommended.
Prior to initiating therapy with ZEDRAST and periodically thereafter, digital rectal examination, as well as other evaluations for prostate cancer should be performed on patients.
The serum PSA concentration is an important component in the detection of prostate cancer. Further examination and consideration of prostate biopsy is usually required with a serum PSA concentration >4 ng/mL (Hybritech). A baseline PSA <4 ng/mL in patients taking ZEDRAST does however not exclude a diagnosis of prostate cancer.
ZEDRAST causes a decrease in mean serum PSA levels by approximately 50% after 6 months of treatment. Despite individual variation, the reduction in PSA values of approximately 50% was observed over the entire range of baseline PSA values (1,5 to 10 ng/mL). In patients receiving ZEDRAST, a new PSA baseline should be established after six months of treatment and the PSA values monitored regularly thereafter.
After a new baseline has been established, treatment with ZEDRAST does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer.
Even if the values are still within the normal range for patients not taking a 5α-reductase inhibitor, any sustained increases from lowest PSA level in patients taking ZEDRAST may be an indication of prostate cancer or nonadherence to the therapy and should be carefully evaluated. The previous PSA values should be used in comparison when interpreting the PSA value of a patient taking ZEDRAST.
The total serum PSA levels return to baseline within 6 months of discontinuing ZEDRAST. Treatment with ZEDRAST does not influence the ratio of free to total PSA and in patients taking ZEDRAST, no adjustment to the value of the free PSA is necessary when used as an aid in the detection of prostate cancer.
Studies have shown a marginally higher incidence of cardiac events (such as cardiac failure and congestive cardiac failure) in men taking a combination of dutasteride and an α-blocker (primarily tamsulosin), in comparison to men not taking the combination. The incidence of cardiac failure was however still lower in men taking the combination, than in those not taking either of the medicines. A conclusion on the increase in cardiovascular risk is not supported by other data available on dutasteride and α-blockers (see section 5.1).
During both clinical trials and the post-marketing period, there have been reports of breast cancer in men taking dutasteride. Epidemiological studies however do not support the increase in risk of developing male breast cancer while taking a 5α-reductase inhibitor (see sections 4.8 and 5.1). Caution is recommended and patients must be instructed to report any changes in breast tissue while taking ZEDRAST.
ZEDRAST contains dutasteride, which is absorbed through the skin. Women, children and adolescents must avoid contact with leaking capsules (see section 4.3). In the event of contact with a leaking capsule, the contact area should immediately be washed with soap and water. ZEDRAST should not be chewed or opened as contact with the capsule may result in irritation of the oropharyngeal mucosa.
No studies have been done regarding the use of ZEDRAST in patients with hepatic disease. ZEDRAST undergoes extensive metabolism and has a terminal half-life of 3 to 5 weeks.
Caution is therefore advised in the administration of ZEDRAST to patients with mild to moderate hepatic impairment (see sections 4.2 and 5.2).
The use of ZEDRAST is contraindicated in children and adolescents (see section 4.3).
ZEDRAST is primarily eliminated via metabolism, which is catalysed by the human cytochrome P450 isoenzymes CYP3A4 and CYP3A5. Although no interaction studies have been performed with potent CYP3A4 inhibitors, respective increases of 1,6 to 1,8 times were seen in dutasteride concentrations when treated concurrently with verapamil or diltiazem during pharmacokinetic studies. Verapamil and diltiazem are both moderate inhibitors of CYP3A4 and P-glycoprotein and respectively caused 37% and 44% decrease in clearance of dutasteride.
The serum concentrations of ZEDRAST may be increased in long-term co-administration with potent CYP3A4 inhibitors, such as ritonavir, indinavir, itraconazole and oral ketoconazole. The increase in ZEDRAST exposure does not result in additional 5α-reductase inhibition. Should adverse events be noted, a reduction in the frequency of ZEDRAST doses can be considered. The long half-life of ZEDRAST is extended when co-administered with CYP450 enzyme inhibitors and a new steady state may take as much as 6 months of concurrent therapy to reach.
No dose adjustment of ZEDRAST is required in the concomitant administration with CYP450 inhibitors.
The pharmacokinetics of ZEDRAST is not affected by the use of colestyramine when administered one hour apart.
ZEDRAST does not induce nor inhibit the CYP2C9 enzyme or the transporter P-glycoprotein and therefore has no influence on the pharmacokinetics of warfarin and digoxin. In vitro studies indicate that warfarin, diazepam and phenytoin are not displaced from plasma protein by ZEDRAST.
In vitro studies further demonstrate that ZEDRAST does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C19 or CYP3A4.
As indicated by interaction studies, ZEDRAST has no clinically significant effect on the pharmacokinetics or pharmacodynamics of tamsulosin or terazosin.
The use of ZEDRAST is contraindicated in women (see section 4.3).
ZEDRAST is a 5α-reductase inhibitor, inhibiting the conversion of testosterone to dihydrotestosterone. Small amounts of dutasteride may be present in the semen of men taking ZEDRAST (see section 5.2). The risk of adverse effects on the fetus is unknown if the mother is exposed to semen of a patient taking ZEDRAST (the risk of which is greatest during the first 16 weeks of pregnancy). Caution is advised when the partner of a patient taking ZEDRAST is or may potentially be pregnant. It is recommended that the patient avoids exposure of his partner to semen by use of a condom.
It is unknown whether ZEDRAST is excreted into breast milk.
ZEDRAST contains dutasteride. Dutasteride has been reported to affect semen characteristics, such as a reduction in sperm count, semen volume and sperm motility in healthy men (see section 5.1). The possibility of reduced male fertility can not be excluded.
Based on the pharmacodynamic properties of ZEDRAST, no influence on the ability to drive or operate machinery is expected. Caution is however advised before driving a vehicle or operating machinery until the effects of ZEDRAST are known.
The following undesirable effects have been reported during clinical trials and post-marketing experience with dutasteride as monotherapy.
Frequency unknown: allergic reactions (including rash, pruritis, urticaria, localised oedema and angioedema)
Frequency unknown: depression
Less frequent: dizziness
Less frequent: cardiac failure (composite term)a
a Cardiac failure composite term comprised of congestive cardiac failure, cardiac failure, left ventricular failure, acute cardiac failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.
Less frequent: alopecia (primarily body hair loss), hypertrichosis
Frequent: impotence*, altered (decreased) libido*, ejaculation disorders (including decreased semen volume)*, breast disorders (including breast tenderness and breast enlargement)
Frequency unknown: testicular pain and swelling.
* These adverse events are associated with both monotherapy and in combination with tamsulosin. These adverse events may persist after treatment discontinuation. The role of ZEDRAST in this persistence is unknown.
There have been studies reporting a higher incidence of Gleason 8–10 prostate cancers in dutasteride-treated men (see section 4.4). There have also been reports of male breast cancer in clinical trials and post-marketing use (see section 4.4).
Reporting suspected adverse reactions after authorisation of ZEDRAST is important. It allows continued monitoring of the benefit/risk balance of ZEDRAST. Health care providers are asked to report any suspected adverse reactions via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.