Duodart

/ GSK

Adults (including elderly): The recommended dose of Duodart is one capsule (0.5 mg/ 0.4 mg) taken orally approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Contact with the contents of the dutasteride capsule contained within the hard-shell capsule may result in irritation of the oropharyngeal mucosa. Where appropriate, Duodart may be used to substitute concomitant dutasteride and tamsulosin hydrochloride in existing dual therapy to simplify treatment. Where clinically appropriate, direct change from dutasteride or tamsulosin hydrochloride monotherapy to Duodart may be considered.
Renal impairment: The effect of renal impairment on dutasteride-tamsulosin pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment.
Hepatic impairment: The effect of hepatic impairment on dutasteride-tamsulosin pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the use of Duodart is contraindicated.

Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH). Reduction in the risk of acute urinary retention (AUR) and surgery in patients with moderate to severe symptoms of BPH.

Hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, tamsulosin (including tamsulosin-induced angio-edema), soya, peanut or any of the other excipients. Patients with a history of orthostatic hypotension. Patients with severe hepatic impairment. Women, children and adolescents.

Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies.
Cardiac Failure: In two 4-year clinical studies, the incidence of cardiac failure (a composite term of reported events, primarily cardiac failure and congestive cardiac failure) was higher among subjects taking the combination of dutasteride and an alpha blocker, primarily tamsulosin, than it was among subjects not taking the combination. In these two trials, the incidence of cardiac failure was low (≤1%) and variable between the studies.
Effects on prostate specific antigen (PSA) and prostate cancer detection: Digital rectal examination, as well as other evaluations for prostate cancer or other conditions which can cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with Duodart and periodically thereafter. Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Duodart causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment. Patients receiving Duodart should have a new PSA baseline established after 6 months of treatment with Duodart. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Duodart may signal the presence of prostate cancer (particularly high grade cancer) or noncompliance to therapy with Duodart and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-reductase inhibitor. In the interpretation of a PSA value for a patient taking dutasteride, previous PSA values while on dutasteride treatment should be sought for comparison. Treatment with Duodart does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established. 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 Duodart. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Duodart therapy, no adjustment to its value appears necessary.
Prostate cancer and high grade tumours: Results of one clinical study (the REDUCE study) in men at increase risk of prostate cancer revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men compared to placebo. The relationship between dutasteride and high grade prostate cancer is not clear. Men taking Duodart should be regularly evaluated for prostate cancer risk including PSA testing.
Renal impairment: The treatment of severely renally impaired patients (creatinine clearance of less than 10 ml/min) should be approached with caution as these patients have not been studied.
Hypotension
Orthostatic: As with other alpha-blockers, a reduction in blood pressure can occur during treatment with tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with Duodart should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved. In order to minimise the potential for developing postural hypotension the patient should be haemodynamically stable on alpha-blocker therapy prior to initiating use of PDE5 inhibitors.
Symptomatic: Caution is advised when alpha adrenergic blocking agents including tamsulosin are coadministered with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). Alpha adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension.
Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with Duodart in patients for whom cataract surgery is scheduled is therefore not recommended. During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with Duodart in order to ensure that appropriate measures will be in place to manage the IFIS during surgery. Discontinuing tamsulosin 1 – 2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established.
Leaking Capsule: Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.
Strong Inhibitors of CYP3A4: Tamsulosin containing products, including duodart, should not be co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole) as this can significantly increase tamsulosin exposure.
Inhibitors of CYP2D6 and moderate inhibitors of CYP3A4: Tamsulosin containing products, including duodart , should be used with caution when co-administered with moderate inhibitors of CYP3A4 (e.g. erythromycin), strong (e.g. paroxetine) or moderate (e.g. terbinafine) inhibitors of CYP2D6, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure.
Hepatic impairment: Duodart has not been studied in patients with liver disease. Caution should be used in the administration of Duodart to patients with mild to moderate hepatic impairment.
Excipients: This medicinal product contains the colouring agent Sunset Yellow (E110), which may cause allergic reactions.
Breast neoplasia: Breast cancer has been reported in men taking dutasteride in clinical trials and during the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride.
For full details see prescribing information.

The data presented here relate to the co-administration of dutasteride and tamsulosin from the 4 year analysis of the CombAT (Combination of Avodart and Tamsulosin) study, a comparison of dutasteride 0.5mg and tamsulosin 0.4mg once daily for four years as co-administration or as monotherapy. Bioequivalence of Duodart with co-administered dutasteride and tamsulosin has been demonstrated. Information on the adverse event profiles of the individual components (dutasteride and tamsulosin) is also provided. Note that not all the adverse events reported with the individual components have been reported with Duodart and these are included for information for the prescriber. Data from the 4 year CombAT study have shown that the incidence of any investigator-judged drug-related adverse event during the first, second, third and fourth years of treatment respectively was 22%, 6%, 4% and 2% for dutasteride + tamsulosin co-administration therapy, 15%, 6%, 3% and 2% for dutasteride monotherapy and 13%, 5%, 2% and 2% for tamsulosin monotherapy. The higher incidence of adverse events in the co-administration therapy group in the first year of treatment was due to a higher incidence of reproductive disorders, specifically ejaculation disorders, observed in this group.
For full details see prescribing information.

There have been no drug interaction studies for Duodart. The following statements reflect the information available on the individual components.
Dutasteride: For information on the decrease of serum PSA levels during treatment with dutasteride and guidance concerning prostate cancer detection, please see special precautions.
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 12 g cholestyramine one hour after a 5 mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.
Effects of dutasteride on the pharmacokinetics of other drugs: In a small study (N=24) of two weeks duration in healthy men, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study. 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.
Tamsulosin: Concomitant administration of tamsulosin hydrochloride with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha-1 adrenergic blockers could lead to enhanced hypotensive effects. Dutasteride-tamsulosin should not be used in combination with other alpha-1 adrenergic blockers. Concomitant administration of tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 2.2 and 2.8 respectively. Concomitant administration of tamsulosin hydrochloride and paroxetine (a strong CYP2D6 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 1.3 and 1.6 respectively. A similar increase in exposure is expected in CYP2D6 poor metabolisers as compared to extensive metabolisers when co-administered with a strong CYP3A4 inhibitor. The effects of coadministration of both CYP3A4 and CYP2D6 inhibitors with tamsulosin hydrochloride have not been evaluated clinically, however there is a potential for significant increase in tamsulosin exposure. Concomitant administration of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every six hours for six days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of tamsulosin hydrochloride. Caution should be used when dutasteride-tamsulosin is used in combination with cimetidine. A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride. No interactions have been seen when tamsulosin hydrochloride was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant furosemide brings about a fall in plasma levels of tamsulosin, but as levels remain within the normal range posology need not be adjusted. In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, diclofenac, glibenclamide and simvastatin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinon. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P450-linked drug metabolising enzyme system), involving amitriptyline, salbutamol and glibenclamide. Diclofenac however, may increase the elimination rate of tamsulosin.

Duodart is contraindicated for use by women. There have been no studies to investigate the effect of Duodart on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components.
Fertility: Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men. The possibility of reduced male fertility cannot be excluded. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.
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. Small amounts of dutasteride have been recovered from the semen in subjects receiving dutasteride. It is not known whether a male foetus will 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). As with all 5 alpha reductase inhibitors, when the patient’s partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom. Administration of tamsulosin hydrochloride to pregnant female rats and rabbits showed no evidence of foetal harm.
Lactation: It is not known whether dutasteride or tamsulosin are excreted in human milk.

No data are available with regard to overdose of Duodart. The following statements reflect the information available on the individual components.
Dutasteride: In volunteer studies, single daily doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to subjects 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, therefore, in suspected overdose symptomatic and supportive treatment should be given as appropriate.
Tamsulosin: Acute overdose with 5 mg tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed which were treated with fluid replacement and the patient could be discharged the same day. In case of acute hypotension occurring after overdose cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins.
Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.