1. Name Of The Medicinal Product
Combodart
2. Qualitative And Quantitative Composition
Each hard capsule contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride, (equivalent to 0.367 mg tamsulosin).
Contains Sunset Yellow (E 110). Each capsule contains
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Capsule, hard
Oblong, hard-shell capsules with a brown body and an orange cap imprinted with GS 7CZ in black ink.
Each hard capsule contains tamsulosin hydrochloride modified release pellets and one dutasteride soft gelatin capsule.
4. Clinical Particulars
4.1 Therapeutic Indications
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.
For information on effects of treatment and patient populations studied in clinical trials please see section 5.1.
4.2 Posology And Method Of Administration
Adults (including elderly):
The recommended dose of Combodart 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, Combodart 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 Combodart 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 (see section 4.4 and 5.2).
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 (see section 4.4 and section 5.2). In patients with severe hepatic impairment, the use of Combodart is contraindicated (see section 4.3).
4.3 Contraindications
Combodart is contraindicated in:
- women and children and adolescents (see section 4.6 ).
- 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.
- patients with severe hepatic impairment.
4.4 Special Warnings And Precautions For Use
Combodart should be prescribed after careful benefit risk assessment and after consideration of alternative treatment options including monotherapies.
In a 4-year clinical study, 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 tamsulosin, than it was among subjects not taking the combination. No causal relationship between dutasteride (alone or in combination with an alpha blocker) and cardiac failure has been established (see section 5.1).
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 with BPH prior to initiating therapy with Combodart and periodically thereafter.
Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Generally, a total serum PSA concentration greater than 4 ng/mL (Hybritech) requires further evaluation and consideration of prostate biopsy. Physicians should be aware that a baseline PSA less than 4 ng/mL in patients taking Combodart does not exclude a diagnosis of prostate cancer. Combodart causes a decrease in serum PSA levels by approximately 50%, after 6 months, in patients with BPH, even in the presence of prostate cancer. Although there may be individual variation, the reduction in PSA by approximately 50% is predictable as it was observed over the entire range of baseline PSA values (1.5 to 10 ng/mL). Therefore to interpret an isolated PSA value in a man treated with Combodart for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer. Any sustained increases in PSA levels while on Combodart should be carefully evaluated, including consideration of noncompliance to therapy with Combodart.
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 Combodart. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Combodart therapy, no adjustment to its value appears necessary.
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.
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 Combodart should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved.
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 Combodart 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 Combodart 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.
Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules (see section 4.6). If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.
Combodart has not been studied in patients with liver disease. Caution should be used in the administration of Combodart to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).
This medicinal product contains the colouring agent Sunset Yellow (E110), which may cause allergic reactions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
There have been no drug interaction studies for Combodart. 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 section 4.4.
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 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 (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.
4.6 Pregnancy And Lactation
Combodart is contraindicated for use by women. There have been no studies to investigate the effect of Combodart on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components (see section 5.3).
Fertility
Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men (see section 5.1). 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 (see section 4.4). Small amounts of dutasteride have been recovered from the semen in subjects receiving dutasteride. Based on studies in animals, it is unlikely that 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). However, 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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects of Combodart on the ability to drive and use machines have been performed. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension such as dizziness when taking Combodart.
4.8 Undesirable Effects
There have been no therapeutic clinical trials conducted with Combodart; however bioequivalence of Combodart with co-administered dutasteride and tamsulosin has been demonstrated (see section 5.2). 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. Information on the adverse event profiles of the individual components (dutasteride and tamsulosin) is also provided.
DUTASTERIDE AND TAMSULOSIN CO-ADMINISTRATION
Clinical Trial Data
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.
The following 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; the incidence of these events during the four years of treatment is shown in the table below:
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a Combination = dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.
b Includes breast tenderness and breast enlargement.
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 above).
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 events from post-marketing experience are identified from spontaneous post-marketing reports; therefore the true incidence is unknown.
Immune system disorders
Unknown: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema.
Skin and subcutaneous tissue disorders
Uncommon: Alopecia (primarily body hair loss), hypertrichosis.
TAMSULOSIN MONOTHERAPY
Clinical Trial Data and Postmarketing Data
The adverse reactions and frequency categories listed in the table below are based on information available in the public domain. 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.
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During postmarketing surveillance, reports of Intraoperative Floppy Iris Syndrome (IFIS), a variant of small pupil syndrome, during cataract surgery have been associated with alpha-1 blocker therapy, including tamsulosin (see section 4.4).
4.9 Overdose
No data are available with regard to overdosage of Combodart. 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 overdosage 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 overdosage 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists, ATC code: G04CA52
Dutasteride-tamsulosin is a combination of two drugs: dutasteride, a dual 5 α-reductase inhibitor (5 ARI) and tamsulosin hydrochloride, an antagonist of α1a and α1d adrenoreceptors. These drugs have complementary mechanisms of action that rapidly improve symptoms, urinary flow and reduce the risk of acute urinary retention (AUR) and the need for BPH related surgery.
Dutasteride inhibits both type 1 and type 2, 5 alpha-reductase isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for prostate growth and BPH development. Tamsulosin inhibits α1a and α1d 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.
DUTASTERIDE CO-ADMINISTRATION WITH TAMSULOSIN
There have been no clinical studies conducted with Combodart. The following statements reflect the information available on dutasteride and tamsulosin co-administration therapy.
Dutasteride 0.5 mg/day (n = 1,623), tamsulosin 0.4 mg/day (n = 1,611) or the co-administration of Dutasteride 0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in male subjects with moderate to severe symptoms of BPH who had prostates
The combination of dutasteride and tamsulosin provides superior improvement in symptoms than either component alone. After 2 years of treatment, co-administration therapy showed a statistically significant adjusted mean improvement in symptom scores from baseline of -6.2 units.
These improvements in flow rate and BII were statistically significant for co-administration therapy compared to both monotherapies.
The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically significant for co-administration therapy compared to tamsulosin monotherapy alone.
The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery. After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% reduction in risk p<0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 11.9% for tamsulosin (p<0.001). Compared to dutasteride monotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6% (p=0.18 [95% CI -10.9% to 41.7%]). The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 5.2% for dutasteride.
Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a composite of: IPSS deterioration by
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Baseline values are mean values and changes from baseline are adjusted mean changes.
* Clinical progression was defined as a composite of: IPSS deterioration by
a. Combination achieved significance (p<0.001) vs. tamsulosin at Month 48
b. Combination achieved significance (p<0.001) vs. dutasteride at Month 48
Cardiac failure:
In this 4 year BPH study the incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in either monotherapy group: dutasteride, (4/1623, 0.2%) and tamsulosin, (10/1611, 0.6%) (see section 4.4).
DUTASTERIDE
Dutasteride 0.5 mg/day or placebo was evaluated in 4325 male subjects with moderate to severe symptoms of BPH who had prostates
The most important clinical efficacy parameters were American Urological Association Symptom Index (AUA-SI), maximum urinary flow (Qmax) and the incidence of acute urinary retention and BPH-related surgery.
AUA-SI is a seven-item questionnaire about BPH-related symptoms with a maximum score of 35. At baseline the average score was approx. 17. After six months, one and two years treatment the placebo group had an average improvement of 2.5, 2.5 and 2.3 points respectively while the Avodart group improved 3.2, 3.8 and 4.5 points respectively. The differences between the groups were statistically significant. The improvement in AUA-SI seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.
Qmax (maximum urine flow):
Mean baseline Qmax for the studies was approx 10 ml/sec (normal Qmax
Acute Urinary Retention and Surgical Intervention
After two years of treatment, the incidence of AUR was 4.2% in the placebo group against 1.8% in the Avodart group (57% risk reduction). This difference is statistically significant and means that 42 patients (95% CI 30-73) need to be treated for two years to avoid one case of AUR.
The incidence of BPH-related surgery after two years was 4.1% in the placebo group and 2.2% in the Avodart group (48% risk reduction). This difference is statistically significant and means that 51 patients (95% CI 33-109) need to be treated for two years to avoid one surgical intervention.
Hair distribution
The effect of dutasteride on hair distribution was not formally studied during the phase III programme, however, 5 alpha-reductase inhibitors could reduce hair loss and may induce hair growth in subjects with male pattern hair loss (male androgenetic alopecia).
Thyroid function:
Thyroid function was evaluated in a one year study in healthy men. Free thyroxine levels were stable on dutasteride treatment but TSH levels were mildly increased (by 0.4 MCIU/mL) compared to placebo at the end of one year's treatment. However, as TSH levels were variable, median TSH ranges (1.4 - 1.9 MCIU/mL ) remained within normal limits (0.5 - 5/6 MCIU/mL), free thyroxine levels were stable within the normal range and similar for both placebo and dutasteride treatment, the changes in TSH were not considered clinically significant. In all the clinical studies, there has been no evidence that dutasteride adversely affects thyroid function.
Breast neoplasia:
In the 2 year clinical trials, providing 3374 patient years of exposure to dutasteride, and at the time of registration in the 2 year open label extension, there were 2 cases of breast cancer reported in dutasteride-treated patients and 1 case in a patient who received placebo.
However, the relationship between breast cancer and dutasteride is not clear.
Effects
