Uromax-D Capsule 0.4mg+0.5mg

Product Information

UROMAX-D

Presentation

Uromax-D capsule: Hard-shell capsule with a deep brown body and an orange cap imprinted with “Uromax-D”; each capsule contains

modified release pellets of Tamsulosin Hydrochloride USP 0.4 mg and a liquid filled capsule of Dutasteride INN 0.5 mg.

Indications

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

and surgery in patients with moderate to severe symptoms of BPH.

Dosage and administration

Adults (including elderly): The recommended dose is one Uromax-D capsule (Tamsulosin Hydrochloride 0.4 mg & Dutasteride 0.5 mg)

taken orally approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or

opened. Where appropriate, Uromax-D capsule may be used to substitute concomitant Tamsulosin Hydrochloride and Dutasteride in

existing dual therapy to simplify treatment. Where clinically appropriate, direct change from Tamsulosin Hydrochloride or

Dutasteride monotherapy to Uromax-D capsule may be considered.

Renal impairment: The effect of renal impairment on Tamsulosin-Dutasteride pharmacokinetics has not been studied. No adjustment in

dosage is anticipated for patients with renal impairment.

Hepatic impairment: The effect of hepatic impairment on Tamsulosin-Dutasteride 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

Uromax-D capsule is contra-indicated.

Contra-indications, warnings, etc.

Contra-indications: Tamsulosin-Dutasteride combination is contra-indicated in women and children and adolescents, patients with

hypersensitivity to Dutasteride, other 5-alpha reductase inhibitors, Tamsulosin (including Tamsulosin- induced angio-edema), soya,

peanut or any of other the excipients, patients with a history of orthostatic hypotension and patients with severe hepatic

impairment.

Precautions and warnings: 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 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

Tamsulosin-Dutasteride combination and periodically thereafter. Serum prostate-specific antigen (PSA) concentration is an

important component in the detection of prostate cancer. Tamsulosin-Dutasteride combination causes a decrease in mean serum PSA

levels by approximately 50%, after 6 months of treatment. Patients receiving Tamsulosin-Dutasteride combination should have a new

PSA baseline established after 6 months of treatment. It is recommended to monitor PSA values regularly thereafter. Any confirmed

increase from lowest PSA level while on Tamsulosin-Dutasteride combination may signal the presence of prostate cancer or

noncompliance to therapy with Tamsulosin-Dutasteride combination and should be carefully evaluated, even if those values are still

within the normal range for men not taking a 5 alpha-reductase inhibitor. In the interpretation of a PSA value for a patient

taking Tamsulosin-Dutasteride combination, previous PSA values while on Dutasteride treatment should be sought for comparison.

Treatment with Tamsulosin-Dutasteride combination 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 Tamsulosin-Dutasteride

combination. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing

Tamsulosin-Dutasteride combination therapy, no adjustment to its value appears necessary. Prostate cancer and high grade tumours:

Results of one clinical 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 Tamsulosin-Dutasteride combination 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 Tamsulosin-Dutasteride combination 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 minimize 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) 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 Tamsulosin-Dutasteride combination in patients for whom cataract surgery is scheduled is therefore not recommended.

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. Hepatic impairment: Tamsulosin-Dutasteride

combination has not been studied in patients with liver disease. Caution should be used in the administration of

Tamsulosin-Dutasteride combination to patients with mild to moderate hepatic impairment. 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.

Drug interactions: There have been no drug interaction studies for Dutasteride-Tamsulosin combination. 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. Tamsulosin-Dutasteride should not be used in combination

with other alpha-1 adrenergic blockers. 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 Tamsulosin-Dutasteride 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, involving amitriptyline, salbutamol and

glibenclamide. Diclofenac however, may increase the elimination rate of Tamsulosin.

Use in pregnancy and lactation: Tamsulosin-Dutasteride combination is contra-indicated for use by women. There have been no

studies to investigate the effect of Tamsulosin-Dutasteride combination 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. 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 Tamsulosin

or Dutasteride are excreted in human milk.

Side effect: The data presented here relate to the co-administration of Tamsulosin and Dutasteride from the 4-year analysis of the

CombAT study, a comparison of Tamsulosin 0.4mg and Dutasteride 0.5mg once daily for four years as co-administration or as

monotherapy. Bioequivalence of Tamsulosin- Dutasteride combination with coadministered Tamsulosin and Dutasteride has been

demonstrated. Information on the adverse event profiles of the individual components (Tamsulosin and Dutasteride) is also

provided. Note that not all the adverse events reported with the individual components have been reported with Tamsulosin-

Dutasteride combination 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 Tamsulosin+Dutasteride 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. The investigator-judged drug-related adverse events have been reported

with an incidence of greater than or equal to 1% during the first year of treatment in the CombAT Study, BPH monotherapy clinical

studies and REDUCE study are as shown in the table below. In addition the undesirable effects for Tamsulosin below are based on

information available in the public domain. The frequencies of adverse events may increase when the combination therapy is used.

The frequency of adverse reactions identified from clinical trials: Common; ³1/100 to <1/10, Uncommon; ³1/1000 to <1/100, Rare;

³1/10,000 to <1/1000, Very rare; <1/10,000. Within each SOC grouping,

System organ

class

Adverse

reactions

Tamsulosin+Dutasteride

Dutasteride

Tamsulosin

Nervous

system

disorders

Syncope

–

–

Rare

Dizziness

Common

–

Common

Headache

–

–

Uncommon

Cardiac

disorders

Cardiac

failure

Uncommon

Uncommon

–

Vascular

disorders

Palpitations

–

–

Uncommon

Orthostatic

hypotension

–

–

Uncommon

Respiratory,

thoracic and

mediastinal

disorders

Rhinitis

–

–

Uncommon

Gastrointestinal

disorders

Constipation

–

–

Uncommon

Diarrhoea

–

–

Uncommon

Nausea

–

–

Uncommon

Skin and

subcutaneous

disorders

Vomiting

–

–

Uncommon

Angioedema

–

–

Rare

Stevens-Johnson

syndrome

–

–

Very Rare

Urticaria

–

–

Uncommon

Rash

–

–

Uncommon

Pruritis

–

–

Uncommon

Reproductive

system

and breast

disorders

Priapism

–

Very Rare

Impotence

Common

Common

–

Altered

(decreased) libido

Common

Common

–

Ejaculation

disorders

Common

Common

Common

Breast disorders

Common

Common

–

General disorders

and administration

site disorders

Asthenia

–

–

Uncommon

Overdose: No data are available with regard to over dosage of Tamsulosin-Dutasteride combination. 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 over dosage 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 over dosage

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.

Pharmaceutical precautions

Store in a cool and dry place, protected from light.

Packaging quantity

Uromax-D capsule: Carton containing 28 capsules in alu-alu