DUODART Dutasteride / Tamsulosin Hydrochloride 500mcg / 400mcg Capsule 1's

Dutasteride+Tamsulosin HCl (Duodart) treats and prevents progression of benign prostatic hyperplasia (BPH) through alleviating symptoms, reducing prostate size (volume), improving urinary flow rate and reducing the risk of acute urinary retention (AUR) and the need for BPH-related surgery.

 

Adult males (including elderly): The recommended dose of Dutasteride+Tamsulosin HCl (Duodart) is one capsule (500 mcg/400 mcg) taken orally approximately 30 minutes after the same meal each day. 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.
Renal impairment: The effect of renal impairment on Dutasteride+Tamsulosin HCl (Duodart) pharmacokinetics has not been studied. However, no adjustment in dosage is anticipated for patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: The effect of hepatic impairment on Dutasteride+Tamsulosin HCl (Duodart) pharmacokinetics has not been studied (see Pharmacology: Pharmacokinetics under Actions and Precautions).

 

Overdosage

Should be taken on an empty stomach: Take w/in 30 min after a meal. Take at the same time each day. Swallow whole, do not chew/open.

Dutasteride+Tamsulosin HCl (Duodart) is contraindicated in patients with known hypersensitivity to Dutasteride, other 5-alpha-reductase inhibitors, Tamsulosin HCl or any component of the preparation.
Dutasteride+Tamsulosin HCl (Duodart) is contraindicated for use in women and children (see Use in Pregnancy & Lactation).

Prostate cancer: In a 4-year study of over 8,000 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), 1,517 men were diagnosed with prostate cancer. There was a higher incidence of Gleason 8 to 10 prostate cancers in the Dutasteride (Avodart) group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). There was no increased incidence in Gleason 5-6 or 7-10 prostate cancers. No causal relationship between Dutasteride (Avodart) and high grade prostate cancer has been established. The clinical significance of the numerical imbalance is unknown. Men taking Dutasteride+Tamsulosin HCl (Duodart) should be regularly evaluated for prostate cancer risk including PSA testing.
In an additional 2-year follow-up study with the original patients from the Dutasteride (Avodart) chemoprevention study (REDUCE), a low rate of new prostate cancers were diagnosed (dutasteride [n=14, 1.2%] and placebo [n=7, 0.7%]), with no new identified cases of Gleason 8-10 prostate cancers.
Long-term follow up (up to 18 years) of another 5-ARI (finasteride) in a chemoprevention study showed no statistically significant difference between finasteride and placebo in the rates of overall survival (HR 1.02, 95% CI 0.97-1.08) or survival after prostate cancer diagnoses (HR 1.01, 95% CI 0.85-1.20).
Prostate specific antigen (PSA): PSA concentration is an important component of the screening process to detect prostate cancer. Dutasteride+Tamsulosin HCl (Duodart) causes a decrease in mean serum PSA levels by approximately 50% after 6 months of treatment.
Patients receiving Dutasteride+Tamsulosin HCl (Duodart) should have a new PSA baseline established after 6 months of treatment with Dutasteride+Tamsulosin HCl (Duodart). It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Dutasteride+Tamsulosin HCl (Duodart) may signal the presence of prostate cancer or non-compliance to therapy with Dutasteride+Tamsulosin HCl (Duodart) and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-ARI (see Clinical Studies). In the interpretation of a PSA value for a patient taking Dutasteride+Tamsulosin HCl (Duodart), previous PSA values should be sought for comparison.
Treatment with Dutasteride+Tamsulosin HCl (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 Dutasteride+Tamsulosin HCl (Duodart). If clinicians elect to use percent-free PSA as an aid in the detection of prostate cancer in men undergoing Dutasteride+Tamsulosin HCl (Duodart) therapy, no adjustment to its value is necessary.
Digital rectal examination, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with Dutasteride+Tamsulosin HCl (Duodart) and periodically thereafter.
Cardiovascular adverse events: 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 (Avodart) 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. No imbalance was observed in the incidence of cardiovascular adverse events overall in either trial. No causal relationship between Dutasteride (Avodart) (alone or in combination with an alpha blocker) and cardiac failure has been established (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
In a meta-analysis of 12-randomised, placebo- or comparator-controlled clinical studies (n=18,802) that evaluated the risks of developing cardiovascular adverse events from the use of Dutasteride (Avodart) (by comparison with controls), no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30) or stroke (RR 1.20; 95% CI 0.88, 1.64) were found.
Breast cancer: There have been rare reports of male breast cancer reported in men taking Dutasteride (Avodart) in clinical trials and during the post-marketing period. However, epidemiological studies showed no increase in the risk of developing male breast cancer with the use of 5-ARIs. Prescribers should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge.
Hypotension: As with other alpha-1 adrenergic blockers, orthostatic hypotension can occur in patients treated with Tamsulosin, which in rare cases can result in syncope.
Patients beginning treatment with Dutasteride+Tamsulosin HCl (Duodart) should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness and vertigo) until the symptoms have resolved.
Caution is advised when alpha adrenergic blocking agents including tamsulosin are co-administered with PDE5 inhibitors. 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 (see Interactions).
Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients treated with alpha-1 adrenergic blockers, including tamsulosin. IFIS may lead increase the risk of eye complications during and after the operation.
During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with Dutasteride+Tamsulosin HCl (Duodart) in order to ensure that appropriate measures will be in place to manage IFIS if it occurs during surgery.
Discontinuing Tamsulosin 1 to 2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping of therapy prior to cataract surgery has not yet been established.
Leaking capsules: Dutasteride is absorbed through the skin, therefore women and children must avoid contact with leaking capsules. If contact is made with leaking capsules the contact area should be washed immediately with soap and water (see Use in Pregnancy and Lactation).
Inhibitors of CYP3A4 and CYP2D6: Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g. ketoconazole), or to a lesser extent, with strong inhibitors of CYP2D6 (e.g. paroxetine) can increase tamsulosin exposure (see Interactions). Tamsulosin hydrochloride is therefore not recommended in patients taking a strong CYP3A4 inhibitor and should be used with caution in patients taking a moderate CYP3A4 inhibitor (e.g. erythromycin), a strong or moderate CYP2D6 inhibitor, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolisers of CYP2D6.
Hepatic impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolised and has a half-life of three to five weeks, caution should be used in the administration of Dutasteride+Tamsulosin HCl (Duodart) to patients with liver disease (see Dosage and Administration and Pharmacokinetics).
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of Dutasteride+Tamsulosin HCl (Duodart) on the ability to perform tasks that require judgement, motor or cognitive skills. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension such as dizziness when taking Dutasteride+Tamsulosin HCl (Duodart).

 

Use In Pregnancy & Lactation

There have been no clinical trials conducted with Dutasteride+Tamsulosin HCl (Duodart); however, co-administration information is available from the CombAT (Combination of Avodart and Tamsulosin) study, a comparison of Dutasteride 500 mcg and Tamsulosin HCl 400 mcg once daily for four years as co-administration or as monotherapy.
Information on the adverse event profiles of the individual components (Dutasteride and Tamsulosin) is also provided.
Dutasteride and Tamsulosin Co-administration: Clinical Trial Data: The following investigator-judged drug-related adverse events (with a cumulative of greater than or equal to 1%) have been reported during the CombAT study. (See Table 1.)

Dutasteride Monotherapy: Clinical Trial Data: In three phase III placebo controlled studies of Dutasteride treatment (n=2167) compared to placebo (n=2158), investigator-judged drug-related adverse events after one and two years of therapy were similar in type and frequency to those observed in the Dutasteride monotherapy arm of the CombAT study (see Table 1).
No change in the adverse event profile was apparent over a further 2 years in an open-label extension phase of these studies.
Post Marketing Data: Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000) including isolated reports. Frequency categories determined from post-marketing data refer to reporting rate rather than true frequency.
Immune system disorders: Very rare: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema.
Psychiatric disorders: Very rare: Depressed mood.
Skin and subcutaneous tissue disorders: Rare: Alopecia (primarily body hair loss), Hypertrichosis.
Reproductive system and breast disorders: Very rare: Testicular pain and testicular swelling.
Tamsulosin Monotherapy: Clinical Trial Data and Post marketing Data: GSK does not hold the safety database for any single ingredient Tamsulosin product; therefore the adverse reactions and frequency categories as follows are based on information available in the public domain. In the table as follows, common and uncommon reactions are consistent with those identified in a clinical trial setting and the frequency categories generally reflect incidence over placebo. Rare and very rare reactions are consistent with those identified from post marketing reports and the frequency categories reflect reporting rates. (See Table 2.)

During post marketing surveillance, reports of Intraoperative Floppy Iris Syndrome (IFIS), a variant of small pupil syndrome, during cataract surgery have been associated with alpha-1 adrenergic blocker therapy; including Tamsulosin (see Precautions).
Post-marketing experience: In addition atrial fibrillation, arrhythmia, tachycardia dyspnoea, epistaxis, vision blurred, visual impairment, erythema multiforme, dermatitis exfoliative and dry mouth have been reported in association with tamsulosin use.

 

There have been no drug interaction studies for Dutasteride+Tamsulosin HCl (Duodart). The following statements reflect the information available on the individual components.
Dutasteride: In vitro drug metabolism studies show that Dutasteride is metabolised by human cytochrome P450 isoenzyme CYP3A4. Therefore blood concentrations of Dutasteride may increase in the presence of inhibitors of CYP3A4.
Phase II data showed a decrease in clearance of Dutasteride 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, 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, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.
Dutasteride neither inhibits human cytochrome P450 drug-metabolizing enzymes in vitro nor induces cytochrome P450 isoenzymes CYP1A, CYP2B, and CYP3A in rats and dogs in vivo.
In vitro studies demonstrate that dutasteride does not displace warfarin, acenocoumorol, phenprocoumon, diazepam, or phenytoin from plasma protein, nor do these model compounds displace dutasteride. Compounds that have been tested for drug interactions in man include tamsulosin, terazosin, warfarin, digoxin, and cholestyramine, and no clinically significant pharmacokinetic or pharmacodynamic interactions have been observed.
Although specific interaction studies were not performed with other compounds, approximately 90% of the subjects in large Phase III studies receiving Dutasteride were taking other medications concomitantly. No clinically significant adverse interactions were observed in clinical trials 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.
Tamsulosin: There is a theoretical risk of enhanced hypotensive effects when Tamsulosin HCl is co-administered with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha-1 adrenergic blockers. Dutasteride+Tamsulosin HCl (Duodart) 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 co-administration 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 (see Precautions).
Concomitant administration of Tamsulosin HCl (400 mcg) 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 HCl. Caution should be used when Dutasteride+Tamsulosin HCl (Duodart) is used in combination with Cimetidine.
A definitive drug-drug interaction study between Tamsulosin HCl 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 HCl.
In three studies, no interactions were seen when Tamsulosin (400 mcg for seven days followed by 800 mcg for seven days) was given concomitantly with Atenolol, Enalapril or Nifedipine for three months; therefore no dose adjustments are necessary when these drugs are co-administered with Dutasteride+Tamsulosin HCl (Duodart).
Concomitant administration of Tamsulosin HCl (400 mcg/day for two days, followed by 800 mcg/day for five to eight days) and a single intravenous dose of Theophylline (5 mg/kg) resulted in no change in the pharmacokinetics of Theophylline; therefore no dose adjustment is necessary.
Concomitant administration of Tamsulosin HCl (800 mcg/day) and a single intravenous dose of Furosemide (20 mg) produced an 11% to 12 % reduction in the Cmax and AUC of Tamsulosin HCl, however these changes are expected to be clinically insignificant and no dose adjustment is necessary.

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