Duoflow

Oblong hard gelatin capsule of brown color and cap of beige color with C001 printed in black ink in the cap. Content of the capsule: oblong soft gelatin capsule of light yellow color, filled with transparent liquid and pellets of tamsulosin of white to off white color.
Each hard capsule contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride (equivalent to 0.367 mg tamsulosin).
Excipients/Inactive Ingredients: Dutasteride soft gelatin capsule: Propylene glycol monocaprylate, type II, Butylhydroxytoluene (E321), Gelatine (gelling grade, type B, 150 Bloom), Glycerol, Titanium Dioxide (E171).
Tamsulosin hydrochloride pellet: Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 percent, Microcrystalline cellulose, Dibutyl sebacate, Polysorbate 80, Colloidal hydrated silica, Calcium stearate.
Hard gelatin capsule (No. 0EL): Black iron oxide (E172), Red iron oxide (E172), Titanium dioxide (E171), Yellow iron oxide (E172), Gelatine (gelling grade, type B, 150 Bloom), Black ink.

Pharmacology: Pharmacodynamics: DUOFLOW is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with BPH: dutasteride, a dual 5α-reductase inhibitor (5 ARI) and tamsulosin hydrochloride, an antagonist of α1a-adrenoreceptors.
The pharmacodynamics of DUOFLOW as a fixed dose combination would not be expected to be different from those of dutasteride and tamsulosin co-administered as separate components.
Dutasteride: Dutasteride is a dual inhibitor of 5 alpha-reductase. It inhibits both type 1 and type 2, 5 alpha-reductase isoenzymes, which are responsible for the conversion of testosterone to 5 alpha-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.
Dutasteride lowers DHT levels, reduces prostate volume, improved lower urinary tract symptoms and urine flow and reduces the risk of AUR and BPH-related surgery.
The maximum effect of daily doses of dutasteride on the reduction on DHT is dose-dependent and is observed within 1-2 weeks. After 1 week and 2 weeks of daily dosing of dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
In BPH patients treated with 0.5 mg of dutasteride daily, the median decrease in DHT was 94% at 1 year and 93% at 2 years and the median increase in serum testosterone was 19% at both 1 and 2 years. This is an expected consequence of 5 alpha-reductase inhibition and did not result in any known adverse events.
Tamsulosin: Tamsulosin inhibits α1a-adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α1-receptors in the prostate are of the α1a subtype.
Tamsulosin increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction. It also improved the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of lower urinary tract play an important role. Alpha-1 adrenergic blockers can reduce blood pressure by lowering peripheral resistance.
Pharmacokinetics: Bioequivalence was demonstrated between DUOFLOW and original combination of dutasteride and tamsulosin.
Dutasteride: Absorption: Following administration of dutasteride 0.5 mg dose, peak serum concentrations of dutasteride occur within 2 to 3 hours.
Absolute bioavailability is approximately 60%.
Distribution: Volume of distribution is 300 to 500 L. Dutasteride is highly bound to plasma protein (Albumin (99%); alpha-1 acid glycoprotein (96.6%)). In a study of heathy subjects receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range, 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, 11.5% of serum dutasteride concentrations partitioned into semen at 12 months.
Metabolism: Dutasteride is metabolized by the human cytochrome P450 isoenzymes CYP3A4/5.
In vitro, 2 dutasteride metabolites are much less potent than dutasteride against both isoforms of human 5-alpha reductase. The activity of another metabolite (6-beta-hydroxydutasteride) is comparable with that of dutasteride.
Elimination: Dutasteride is excreted primarily via feces (5% unchanged). Terminal half-life is 5 weeks.
Elderly: Dutasteride half-life increased with age (approximately 170 hours in men 20 to 49 years of age, approximately 260 hours in men 50 to 69 years of age, and approximately 300 hours in men older than 70 years).
Tamsulosin: Absorption: Essentially completely absorbed following oral administration under fasting conditions; peak plasma concentrations attained within 4-5 hours. Food delays time to peak plasma concentration by about 2 hours. When administered under fasting conditions, bioavailability and peak plasma concentration are increased by 30 and 40-70%, respectively, compared with fed state.
Distribution: Appears to distribute into extracellular fluids in humans. In animals, distributed into kidney, prostate, liver, gallbladder, heart, aorta, and brown fat, with minimal distribution into brain, spinal cord, and testes. Plasma protein binding is 94-99% (mainly to α1-acid glycoprotein).
In patients with moderate hepatic impairment, protein binding is altered, resulting in changes in overall plasma concentrations; however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.
In patients with renal impairment, protein binding is altered, resulting in changes in overall plasma concentrations, however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.
Metabolism: Extensively metabolized by CYP enzymes (specific isoenzyme(s) not identified) in the liver. Metabolites undergo further conjugation prior to excretion.
Elimination: Excreted in urine (76%) and feces (21%). Because of absorption rate-controlled pharmacokinetics of tamsulosin capsules, apparent half-life is about 9-13 hours in healthy individuals and 14-15 hours in patients with BPH.
Elderly: In males 55-75 years of age, intrinsic clearance is decreased and elimination half-life is prolonged, resulting in a 40% increase in AUC compared with males 20-32 years of age.

DUOFLOW 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.

Recommended Dose and Mode of Administration: Adult males (including elderly): The recommended dose of DUOFLOW is one capsule (0.5 mg/0.4 mg) 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 pharmacokinetics has not been studied. However, 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.

Overdose and Treatment: No data are available with regard to overdosage of combination of dutasteride and tamsulosin. The following statements reflect the information available on the individual components.
Dutasteride: In volunteer studies single doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) for 7 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 therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate.
Tamsulosin: In case of acute hypotension occurring after overdosage with tamsulosin hydrochloride cardiovascular support should be given. Restoration of blood pressure and normalization of heart rate may be accomplished by lying the patient down. If this is inadequate, administration of volume expanders and if necessary, vasopressors indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit in removing tamsulosin from the body.

DUOFLOW is contraindicated in patients with known hypersensitivity to dutasteride, other 5-alpha-reductase inhibitors, tamsulosin hydrochloride or any component of the preparation.
DUOFLOW is contraindicated for use in women and children.

Effects on Ability to Drive and Use Machine: There have been no studies to investigate the effect of combination of dutasteride and tamsulosin on the ability to perform tasks that required 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 combination of dutasteride and tamsulosin.
Dutasteride: Prostate-specific antigen (PSA) effects: In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. Dutasteride may also cause decreased in serum PSA in the presence prostate cancer. To interpret serial PSAs in men taking a 5-alpha reductase inhibitor, establish a new PSA baseline at least 3 months after starting dutasteride treatment and periodically monitor PSA thereafter. Any confirmed increase from the lowest PSA value may signal the presence prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5-alpha reductase inhibitor. Noncompliance may also affect PSA test results.
To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, double the PSA value for comparison with normal values in untreated men.
The free-to-total PSA ratio (percent-free PSA) remains constant, even under the influence of a 5-alpha reductase inhibitor. If health care providers elect to use percent-free PSA as an aid in the detection of prostate cancer in men receiving a 5-alpha reductase inhibitor, no adjustment to its value appears necessary.
PSA increased while on a 5-alpha reductase inhibitor should be considered suspicious; obtain serial PSA measurements and evaluate.
Prostate cancer: When compared with placebo, 5-alpha-reductase inhibitors have been associated with an increase in the incidence of high-grade prostate cancers. In clinical trials, there was an increased incidence of Gleason score 8 to 10 prostate cancer for men taking dutasteride compared with men taking placebo (dutasteride 1% vs placebo 0.5%).
Breast cancer: There have been rare reports of male breast cancer reported in men taking dutasteride 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.
Blood donation: Men being treated with a 5-alpha reductase inhibitor should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period to prevent administration of 5-alpha reductase inhibitor to a pregnant female transfusion recipient.
Reproductive effects: The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy volunteers. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of more than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride's effect on semen characteristics for an individual patient's fertility is not known.
Hepatic function impairment: Use caution in patients with liver function abnormalities; dutasteride is metabolized extensively in the liver.
Monitoring: Assess patients to rule out other urological diseases, including prostate cancer, prior to treatment and periodically thereafter. Establish a new PSA baseline at least 3 months after starting dutasteride treatment and periodically monitor PSA thereafter.
Objective and subjective signs of relief of benign prostatic hyperplasia, including improvement in urinary flow, reduction in symptoms of urgency, and relief of difficulty in micturition.
Tamsulosin: Postural hypotension: Potential for postural hypotension, dizziness, or vertigo; syncope may occur.
Priapism: Rarely, alpha-1 antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition.
Allergic reactions: Rash, pruritus, urticaria, and angioedema of the tongue, lips, and face reported; positive rechallenge in some patients.
Sulfa sensitivity: Allergic reaction to tamsulosin reported rarely in patients with sulfa sensitivity. Use with caution in patients with serious or life-threatening sulfa sensitivity.
Prostate cancer: Exclude possibility of prostate cancer prior to initiation of therapy.
Intraoperative floppy iris syndrome: Intraoperative floppy iris syndrome (IFIS) observed during phacoemulsification cataract surgery in some patients receiving α1-adrenergic blocking agents, including tamsulosin. Most reported cases were in patients who continued such therapy at the time of cataract surgery.
Use in Pregnancy: Dutasteride: Active ingredient of crushed or broken capsules can be absorbed through the skin. Women should avoid contact with crushed or broken capsules and the semen from a male partner exposed to 5-alpha reductase inhibitors, as they may negatively impact fetal development.
Use in Children: Dutasteride: Dutasteride is contraindicated for use in pediatric patients.

Pregnancy: DUOFLOW is contraindicated for use by women.
Dutasteride: Dutasteride has not been studied in women because pre-clinical data suggests that the suppression of circulating levels of dihydrotestosterone may inhibit the development of the external genital organs in a male foetus carried by a woman exposed to dutasteride.
Tamsulosin: Administration of tamsulosin hydrochloride to pregnant female rats and rabbits at higher than the therapeutic dose showed no evidence of foetal harm.
Lactation: DUOFLOW is contraindicated for use in women.
It is not known whether dutasteride or tamsulosin are excreted in breast milk.

Dutasteride: Adverse effects reported in at least 1% of patients receiving dutasteride and more frequently than with placebo include impotence, decreased libido, ejaculation disorder, and breast disorders (including breast tenderness and enlargement). Ejaculation disorders have been reported more frequently with combined therapy with dutasteride and tamsulosin than with either drug alone.
Tamsulosin: Headache, infection, asthenia, back pain, chest pain, dizziness, somnolence, insomnia, decreased libido, rhinitis, pharyngitis, increased cough, sinusitis, diarrhea, nausea, tooth disorder, abnormal ejaculation, blurred vision.

Dutasteride: α-Adrenergic Blocking Agents: Concomitant administration of dutasteride with α-adrenergic blocking agents (i.e., tamsulosin, terazosin) has no effect on the steady-state pharmacokinetics of either α-adrenergic blocker. However, the effect of tamsulosin or terazosin on dutasteride pharmacokinetic parameters has not been evaluated.
Calcium-channel Blocking Agents: Concomitant administration of dutasteride with calcium-channel blocking agents that inhibit cytochrome P-450 (CYP) 3A4 isoenzymes (i.e., diltiazem, verapamil) decreases dutasteride clearance resulting in increased exposure to dutasteride. However, dosage adjustment of dutasteride is not recommended since the change in dutasteride exposure is not considered to be clinically important.
Drugs Affecting Hepatic Microsomal Enzymes: Potential pharmacokinetic interaction (decreased clearance and increased serum concentrations of dutasteride) with potent, chronic inhibitors of the CYP3A4 and CYP3A5 isoenzymes. However, the clinical effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug interactions, care should be taken if dutasteride is administered with such drugs (e.g., ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, ciprofloxacin).
Cholestyramine: Administration of a single 5-mg dose of dutasteride followed by a 12-g dose of cholestyramine one hour later did not affect the relative bioavailability of dutasteride.
Digoxin: Concomitant administration of dutasteride at a dosage of 0.5 mg daily for 3 weeks with digoxin did not alter the steady-state pharmacokinetics of digoxin.
Warfarin: Concomitant administration of dutasteride at a dosage of 0.5 mg daily for 3 weeks with warfarin did not alter the steady-state pharmacokinetics of R- or S-warfarin or alter the effect of warfarin on prothrombin time.
Tamsulosin: α-Adrenergic Blocking Agents: Additive effects; concomitant use not recommended.
Atenolol: No change in blood pressure or pulse rate; dosage adjustment not necessary.
Cimetidine: Increased plasma tamsulosin concentrations. Use with caution, particularly with dose >0.4 mg.
Enalapril: No change in blood pressure or pulse rate; dosage adjustment not necessary.
Furosemide: Decreased plasma tamsulosin concentrations; not clinically important.
Nifedipine: No change in blood pressure of pulse rate; dosage adjustment not necessary.
Warfarin: Possible pharmacokinetic interaction. Available data inconclusive; use with caution.
Food Interactions: Dutasteride: Maximum serum concentrations reduced by 10% to 15% when taken with food; not clinically significant. Management: Administer without regards to meals.
Tamsulosin: Fasting increases bioavailability by 30% and peak concentration 40% to 70%. Administer 30 minutes after the same meal each day.

Storage Condition: Store below 30°C. In addition, it should be used within 90 days of opening.

Drugs for Bladder & Prostate Disorders

G04CA52 - tamsulosin and dutasteride ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.

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