Combomax Capsule 0.4 mg+0.5 mg

Uses

Tamsulosin Hydrochloride & Dutasteride capsule is indicated in- 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.

Combomax Capsule 0.4 mg+0.5 mg is also used to associated treatment for these conditions: Benign Prostatic Hyperplasia (BPH), Symptomatic Benign Prostatic Hyperplasia

How Combomax Capsule 0.4 mg+0.5 mg works

The 5α-reductase is a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the initial development and subsequent enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the synthesis of approximately one-third of circulating DHT, type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including the scalp, and liver. The type II 5a-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-complete suppression of DHT. Compared to a 70% reduction of serum DHT levels caused by finasteride, a near-complete suppression of serum DHT-more than 90% is seen with dutasteride.

By forming a stable complex with both type II and type II 5α-reductase, dutasteride inhibits its enzymatic action of converting testosterone to 5α-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. It is proposed that DHT is the principal androgen responsible for prostatic growth in later life-normal masculinization of the external genitalia and maturation of the prostate gland during development-thus reducing the serum DHT levels results in reduced prostatic volume and increased epithelial apoptosis. Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5α-reductase isoenzymes and when evaluated under in vitro and in vivo conditions, the dissociation of the drug from the drug-enzyme complex is reported to be extremely slow. Dutasteride does not bind to the human androgen receptor.

Dosage

Combomax Capsule 0.4 mg+0.5 mg dosage

Adults (including elderly): The recommended dose is one 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, this 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 this 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 this capsule is contra-indicated.

Side Effects

The most common adverse reactions reported in subjects receiving combination therapy were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders and dizziness. The percentages of subjects with ejaculation disorders, decreased libido and impotence were higher in the combination therapy group compared with either monotherapy groups.

Toxicity

LD50 values

The estimated dermal LD50 of dutasteride in rabbits is > 2,000 mg/kg.

Overdose

In studies of volunteers receiving single doses of dutasteride up to 40 mg (which is 80 times the therapeutic dose) for 7 days, there were no reports of clinically significant adverse events. Low incidences of impotence, reduced libido, gynecomastia, and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients. There are no known antidotes for dutasteride. In case of overdose, appropriate symptomatic and supportive treatment should be given.

Nonclinical Toxicology

In a 2-year carcinogenicity mouse study, there was an increased incidence of benign hepatocellular adenomas in female mice receiving 250 mg/kg/day. An increased incidence of Leydig cell hyperplasia was observed in male rats receiving doses of 7.5 mg/kg/day and greater. At tumorogenic doses, the luteinizing hormone (LH) levels in rats were increased by 167%. There was no demonstrated a genotoxic potential of dutasteride or its metabolites in a bacterial mutagenesis assay, a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. At much higher doses than the maximum recommended human dose (MRHD) in sexually mature male rats, dutasteride caused a dose- and time-dependent decrease in fertility, reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day), reduced weights of the epididymis, prostate, and seminal vesicles, and microscopic changes in the male reproductive organs. At exposures 425- and 315-fold the expected clinical exposure of dutasteride in rats and dogs, respectively, there were some signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes.

Pregnancy and Lactation

As DHT is a necessary hormone for the development of male genitalia, exposure to dutasteride in pregnant women bearing male fetuses may cause fetal harm. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Although it is not known whether dutasteride is excreted in human milk, the use of dutasteride in women of childbearing potential, including nursing women. In elderly patients, the half-life of dutasteride may increase. As the renal elimination of dutasteride is very minimal, the use of dutasteride in patients renal insufficiency is reported to be safe. There are no specific dosage adjustment recommendations for use in elderly patients or patients with renal impairment.

Precaution

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.

Interaction

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.

Volume of Distribution

Dutasteride displays a large volume of distribution ranging from 300 to 500 L. Following daily oral administration of 0.5 mg dutasteride healthy subjects for 12 months, the semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) with 11.5% of serum dutasteride concentrations being partitioned into semen.

Elimination Route

Following oral administration of a single dose of 0.5 mg dutasteride, the peak serum concentrations were reached within 2 to 3 hours. Following daily oral administration of 0.5 mg dutasteride, the steady-state concentration of 40 ng/mL is expected to be achieved at 6 months following initial administration. In healthy subjects, the absolute bioavailability was 60%, ranging from 40% to 94%. While food intake reduced the maximum serum concentrations by 10 to 15%, food intake is reported to have a negligible effect on the bioavailability of the drug.

Half Life

The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. This long half-life accounts for the serum concentrations remaining detectable for up to 4 to 6 months after discontinuation of treatment.

Clearance

In a study of healthy volunteers receiving single oral doses of dutasteride ranging from 0.01 to 40 mg, dutasteride displayed a low linear clearance of 0.58 L/h. The estimated inter-individual variability for the linear clearance was high.

Elimination Route

Dutasteride and its metabolites mainly undergo fecal excretion. About 1-15% of the dose is excreted as the unchanged parent compound, while 2-90% of the total dose is excreted in the form of dutasteride-related metabolites in the feces. Trace amounts of unchanged dutasteride, with less than 1%, can also be detected in the urine. Therefore, on average, the dose unaccounted for approximated 55%, with a range between 5% and 97%.

Pregnancy & Breastfeeding use

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.

Contraindication

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.

Special Warning

Pediatric use: Dutasteride is not indicated for use in the pediatric population. Safety and effectiveness in the pediatric population have not been established.

Geriatric use: No overall differences in safety or efficacy were observed between elderly and adult subjects.

Elderly use: No dosage adjustment is necessary for subjects with renal impairment or for the elderly.

Hepatic impairment: Due to the absence of data in patients with hepatic impairment, no dosage recommendation can be made.

Acute 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.

Storage Condition

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

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