Active ingredients: Dutasteride
Avodart 0.5 mg soft capsules
Why is Avodart used? What is it for?
Avodart is used to treat men with an enlarged prostate (benign prostatic hyperplasia) - a non-malignant increase in the size of the prostate caused by excessive production of a hormone called dihydrotestosterone.
The active ingredient is dutasteride. It belongs to a class of drugs called 5-alpha reductase inhibitors.
If the prostate increases in volume, it can lead to urinary problems such as difficulty passing urine and the need to urinate frequently. This can also result in the flow of urine becoming slower and less strong. If left untreated, there is a risk that the flow of urine will be completely blocked (acute urinary retention). This requires immediate medical treatment. In some cases, surgery is required to remove or shrink the prostate. Avodart reduces the size of the prostate. production of dihydrotestosterone and this promotes the decrease in prostate volume and relieves symptoms.This reduces the risk of acute urinary retention and the need for surgery.
Avodart can be used with another medicine called tamsulosin (used to treat symptoms of an enlarged prostate).
Contraindications When Avodart should not be used
Do not take Avodart
- if you are allergic (hypersensitive) to dutasteride, other 5-alpha reductase inhibitors, soy, peanut or any of the other ingredients of Avodart.
- if you have severe liver disease.
Tell your doctor if you think any of the above apply to you.
This medicine is only indicated for men. It must not be taken by women, children or adolescents.
Precautions for use What you need to know before taking Avodart
Take special care with Avodart
- In some clinical trials, more patients taking dutasteride and another medicine called an alpha blocker such as tamsulosin experienced heart failure than patients taking dutasteride alone or an alpha blocker alone. Heart failure means that the heart does not pump blood as well as it should.
- Make sure your doctor is aware of your liver problems. If you have ever had any liver disease, further checks may be needed while you are taking Avodart.
- Women, children and adolescents should avoid contact with leaking Avodart capsules, as the active ingredient is absorbed through the skin. In case of skin contact, immediately wash the affected area with soap and water.
- Use a condom during intercourse. Dutasteride has been found in the semen of men taking Avodart. If your partner is or could be pregnant, you must avoid exposing her to your semen as dutasteride can affect the normal development of a boy. Dutasteride has been shown to reduce sperm count, semen volume and sperm motility. This can decrease her fertility.
- Avodart affects the PSA (prostate specific antigen) test, which is used in some cases to detect the presence of prostate cancer. Your doctor should be aware of this effect and may still order the test to find out if you have a prostate cancer. prostate cancer. If you need to have a PSA test, tell your doctor that you are taking Avodart. Men taking Avodart should have a PSA test regularly.
- In a clinical study of men at increased risk of prostate cancer, men taking Avodart had severe prostate cancer more frequently than men not taking Avodart. The effect of Avodart on this severe form of prostate cancer is unclear.
- Avodart can cause breast enlargement and tenderness. If this becomes of concern, or if you notice breast lumps or nipple discharge, you should speak to your doctor about these changes as they could be signs of a serious condition, such as breast cancer.
Ask your doctor or pharmacist for advice if you have any questions about taking Avodart
Interactions Which drugs or foods may change the effect of Avodart
Tell your doctor if you are taking or have recently taken any other medicines, even those without a prescription. Some medicines can interact with Avodart and can increase the chance of having side effects. These medicines include:
- verapamil or diltiazem (for hypertension)
- ritonavir or indinavir (for HIV)
- itraconazole or ketoconazole (for fungal infections)
- nefazodone (an antidepressant)
- alpha blockers (for prostate enlargement or hypertension).
Tell your doctor if you are taking any of these medicines. Your dose of Avodart may need to be reduced.
Taking Avodart with food and drink
Avodart can be taken with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
Women who are pregnant or who may be pregnant should not handle leaking capsules. Dutasteride is absorbed through the skin and can interfere with the normal development of a male baby. This is especially risky in the first 16 weeks of pregnancy.
Use a condom during intercourse. Dutasteride has been found in the semen of men taking Avodart. If your partner is pregnant or could be pregnant, you must avoid letting them come into contact with your semen. Avodart has been shown to reduce sperm count, semen volume and sperm movement. Therefore male fertility can decrease.
Ask your doctor for advice if a pregnant woman has come into contact with dutasteride.
Driving and using machines
Avodart is unlikely to affect the ability to drive or use machines.
Important information about some of the ingredients of Avodart
This medicine contains soy lecithin which may contain soy oil. If you are allergic to peanuts or soy, do not use this medicine.
Dose, Method and Time of Administration How to use Avodart: Posology
Always take Avodart exactly as your doctor has told you. If you don't take it regularly, checking your PSA levels could be affected. If in doubt, consult your doctor or pharmacist.
How much Avodart to take
- The usual dose is one capsule (0.5 mg) to be taken once a day. Swallow the capsules whole with water. Do not chew or open the capsules. Contact with the contents of the capsules may irritate the mouth or throat.
- Treatment with Avodart is long-term. Some people notice an early improvement in symptoms. However, others may need to take Avodart for 6 months or more before it starts to work. Keep taking Avodart for as long as your doctor tells you.
Overdose What to do if you have taken too much Avodart
If you take more Avodart than you should
If you take more Avodart capsules than prescribed, contact your doctor or pharmacist for advice.
If you forget to take Avodart
If you forget to take a dose, do not take extra capsules. Take the next dose as usual.
If you stop taking Avodart
Do not stop taking Avodart without first consulting your doctor. It may take 6 months or more for you to notice improvement.
- If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Avodart
Like all medicines, Avodart can cause side effects, although not everybody gets them.
- Very rare allergic reaction Signs of allergic reactions can include:
- rash (which can be itchy)
- urticaria
- swelling of the eyelids, face, lips, arms or legs.
Contact your doctor immediately if you get any of these symptoms and stop taking Avodart.
Common side effects
These may affect up to 1 in 10 patients treated with Avodart:
- impotence (inability to achieve or maintain an "erection)
- decreased sex drive (libido)
- difficulty with ejaculation
- breast enlargement or soreness (gynecomastia)
- dizziness with the intake of tamsulosin.
Uncommon side effects
These may affect up to 1 in 100 patients treated with Avodart:
- hair loss (usually from the body) or hair growth.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not store Avodart above 30 ° C.
Do not use Avodart after the expiry date which is stated on the carton or the aluminum foil of the blisters.
The expiry date refers to the last day of the month.
If you have any unused Avodart capsules, do not throw them into wastewater or household waste. Return them to the famacist who will arrange how to dispose of them. This will help protect the environment.
OTHER INFORMATION
What Avodart contains
The active ingredient is dutasteride.
Each soft capsule contains 0.5 mg of dutasteride.
The excipients are:
- capsule core: mono and diglycerides of caprylic / capric acid and butylhydroxytoluene (E321).
- capsule shell: gelatin, glycerol, titanium dioxide (E171), yellow iron oxide (E172), triglycerides (medium chain), lecithin.
What Avodart looks like and contents of the pack
Avodart soft capsules are yellow, oblong, opaque, soft gelatin capsules imprinted with GX CE2.
They are available in packs of 10, 30, 50, 60 and 90 capsules.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AVODART 0.5 MG SOFT CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 0.5 mg of dutasteride.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Soft capsule.
The soft gelatin capsules are opaque, yellow, oblong, imprinted with GX CE2.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).
Reduction of the risk of acute urinary retention and surgery in patients with moderate to severe symptoms of benign prostatic hyperplasia.
For information on treatment effects and populations analyzed during clinical trials see section 5.1.
04.2 Posology and method of administration
Avodart can be administered alone or in combination with the alpha blocker tamsulosin (0.4 mg) (see sections 4.4, 4.8 and 5.1).
Adults (including the elderly)
The recommended dosage of Avodart is one capsule (0.5 mg) per day orally. The capsules should be swallowed whole and should not be chewed or opened as contact with the capsule contents can cause irritation of the oropharyngeal mucosa. The capsules can be taken with or without food. Although early improvement may be observed, they may be required up to 6 months before response to treatment is achieved No dose adjustment is required in the elderly.
Kidney failure
The effect of renal impairment on dutasteride pharmacokinetics has not been studied. No dose adjustment is expected in patients with renal insufficiency (see section 5.2).
Hepatic insufficiency
The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied therefore caution should be exercised in patients with mild to moderate hepatic impairment (see section 4.4 and section 5.2). The use of dutasteride is contraindicated in patients with severe hepatic impairment (see section 4.3).
04.3 Contraindications
Avodart is contraindicated in:
- women, children and adolescents (see section 4.6)
- patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, soy, peanut or any of the other excipients
- patients with severe hepatic insufficiency.
04.4 Special warnings and appropriate precautions for use
Combination therapy should be prescribed after careful consideration of the benefit risk due to the potential increased risk of adverse events (including heart failure) and after consideration of alternative treatment options including monotherapies (see section 4.2).
Heart failure
In two 4-year clinical trials, the incidence of heart failure (a composite term of reported events, mainly heart failure and congestive heart failure) was higher among subjects treated with the combination of Avodart and an alpha blocker especially tamsulosin, compared with to that found among subjects not treated with the association. In these two studies, the incidence of heart failure was low (≤1%) and variable between studies (see section 5.1).
Effects on prostate specific antigen (PSA) and prostate cancer detection
Rectal examination as well as other evaluations for prostate cancer should be done in patients before starting treatment with Avodart and periodically thereafter.
The serum concentration of prostate specific antigen (PSA) is an important component in detecting the presence of prostate cancer. Avodart causes a decrease in the mean concentration of serum PSA levels of approximately 50% after 6 months of treatment.
Patients being treated with Avodart should have a re-assessment of baseline PSA established after 6 months of treatment with Avodart. Afterwards it is recommended to check the PSA values regularly. Any confirmed increase from the lowest PSA level during treatment with Avodart may signal the presence of prostate cancer (particularly high grade cancer) or the lack of compliance treatment with Avodart and should be carefully considered, even if these values are still within the normal range for men not taking a 5α reductase inhibitor (see section 5.1). In the interpretation of a PSA value for a patient taking Avodart, previous PSA values must be evaluated for comparison.
Treatment with Avodart does not interfere with the use of PSA as a tool to support the diagnosis of prostate cancer after a new baseline has been established (see section 5.1).
Total serum PSA levels return to baseline within six months of stopping treatment. The ratio of free fraction to total PSA remains constant even under the effect of Avodart. If the doctor chooses to use the free PSA percentage to diagnose prostate cancer in men treated with Avodart, no adjustment is necessary.
Prostate cancer and high grade cancers
Results from a clinical trial (the REDUCE study) in men at high risk of prostate cancer revealed a "higher incidence of Gleason 8-10 prostate cancer in dutasteride-treated men compared to placebo-treated men. between dutasteride and high grade prostate cancer is unclear. Men taking Avodart should be regularly evaluated for prostate cancer risk, including PSA testing (see section 5.1).
Capsules not intact
Dutasteride is absorbed through the skin, therefore women, children and adolescents should avoid contact with leaking capsules (see section 4.6). In case of contact with leaking capsules, the affected area should be washed immediately with soap and water.
Hepatic impairment
Dutasteride has not been studied in patients with liver disease. Caution should be exercised in the administration of dutasteride to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).
Breast cancer
Breast cancer has been reported in men treated with dutasteride in clinical studies (see section 5.1) and during the post-marketing period. Physicians should instruct their patients to promptly report any changes in breast tissue such as lumps or nipple discharge. It is currently unclear whether there is a causal relationship between the onset of male breast cancer and the long-term use of dutasteride.
04.5 Interactions with other medicinal products and other forms of interaction
See section 4.4 for information on decreases in serum PSA levels during dutasteride treatment and for indications for detecting the presence of prostate cancer.
Effects of other drugs on dutasteride pharmacokinetics
Concomitant use of CYP3A4 inhibitors and / or P-glycoprotein inhibitors
Dutasteride is mainly eliminated by metabolism. Education in vitro indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies with potent CYP3A4 inhibitors have been performed. However, in a pharmacokinetic study, in a small number of patients concomitantly treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) the serum concentrations of dutasteride were on average increased 1.6 to 1.8-fold. in comparison to other patients.
Long-term combination of dutasteride with drugs that are potent inhibitors of the CYP3A4 enzyme (eg ritonavir, indinavir, nefazodone, itraconazole, ketoconazole given orally) may increase the serum concentrations of dutasteride. Further inhibition of 5-alpha reductase is unlikely to occur following increased dutasteride exposure. However, a reduction in dutasteride dosing frequency may be considered if side effects are observed. enzyme inhibition, the long half-life may be further prolonged and more than 6 months of concomitant therapy may be required before reaching a new steady state.
The pharmacokinetics of dutasteride are unaffected by the administration of 12 g of cholestyramine one hour after the administration of a single 5 mg dose of dutasteride.
Effects of dutasteride on the pharmacokinetics of other drugs
Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit / induce CYP2C9 or the P-glycoprotein transporter. Interaction studies in vitro indicate that dutasteride does not inhibit CYP1A2, CYP2D6, CYP2C9, CYP2C19 or CYP3A4 enzymes.
During a small 2-week study (N = 24) in healthy male volunteers, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. There were also no indications of pharmacodynamic interactions in this study.
04.6 Pregnancy and lactation
The use of Avodart is contraindicated in women.
Fertility
Dutasteride has been reported to interfere with sperm characteristics (reduction in sperm count, sperm volume and sperm motility) in healthy subjects (see section 5.1). The possibility of a reduction in male fertility cannot be excluded.
Pregnancy
Like other 5-alpha reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, when administered to a pregnant woman, inhibit the development of the external genitalia in a male fetus (see section 4.4). Small amounts of dutasteride were found in the semen of subjects taking 0.5 mg per day of Avodart. It is not known whether a male fetus will be adversely affected if the mother is exposed to the semen of a patient being treated with dutasteride (risk is greatest during the first 16 weeks of pregnancy).
As with all 5-alpha reductase inhibitors, when the patient's "partner" is pregnant or may become pregnant, it is recommended that the patient avoid exposure of their "partner" to semen by using a condom.
For information on preclinical data see section 5.3.
Feeding time
It is not known whether dutasteride is excreted in human milk.
04.7 Effects on ability to drive and use machines
Based on the pharmacodynamic properties of dutasteride, treatment with dutasteride is not expected to interfere with the ability to drive or use machines.
04.8 Undesirable effects
AVODART IN MONOTHERAPY
Approximately 19% of 2,167 patients treated with dutasteride in the 2-year, phase III, placebo-controlled clinical trials experienced adverse reactions during the first year of treatment. The majority of events were mild to moderate and occurred in the reproductive system. There was no change in the adverse event profile in the extension of the open label studies for an additional 2 years.
The following table shows the adverse reactions from controlled clinical trials and from post marketing experience. Adverse events reported from clinical trials are events judged by the investigator to be drug related (with an "incidence greater than or equal to" 1%) reported with a "higher incidence in dutasteride-treated patients than in placebo-treated patients during the first year Adverse events from post-marketing experience were identified from spontaneous post-marketing reports; therefore the real incidence is not known:
AVODART IN COMBINATION WITH THE ALPHA BLOCKING TAMSULOSINE
Data from the 4-year CombAT study comparing dutasteride 0.5 mg (n = 1623) and tamsulosin 0.4 mg (n = 1611) once daily alone and in combination (n = 1610) demonstrated that the incidence of adverse events, judged by the investigator related to the drug, during the first, second, third and fourth years of treatment, was respectively 22%, 6%, 4% and 2% with therapy of dutasteride / tamsulosin combination, 15%, 6%, 3% and 2% with dutasteride monotherapy and 13%, 5%, 2% and 2% with tamsulosin monotherapy. The highest incidence of adverse events in the combination therapy group in the first year of treatment it was due to a higher incidence of reproductive disorders, specifically ejaculation disorders, observed in this group.
The following investigator-judged drug-related adverse events were reported at an "incidence greater than or equal to" 1% during the first year of treatment in the CombAT study; the incidence of such events during the four years of treatment is shown in the table below:
a) Combination = dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.
b) Heart failure as a composite term consisting of congestive heart failure, heart failure, left ventricular failure, acute heart failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.
c) Breast tenderness and enlargement are included.
OTHER DATA
The REDUCE study revealed a higher incidence of Gleason 8-10 prostate cancer in dutasteride-treated men compared to placebo (see sections 4.4 and 5.1). It has not been established whether the effect of dutasteride in reducing prostate volume or study related factors influenced the results of this study.
The following have been reported in clinical trials and post-marketing use: male breast cancer (see section 4.4).
04.9 Overdose
In studies of Avodart in volunteers, single daily doses of dutasteride up to 40 mg / day (80 times the therapeutic dose) were administered for 7 days without significant safety concerns. In clinical studies, daily doses of 5 mg were administered to subjects for 6 months without manifestations of additional side effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for Avodart, therefore, in cases of suspected overdose, appropriate symptomatic and supportive treatment should be provided.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: testosterone-5-alpha-reductase inhibitors.
ATC code: G04C B02.
Dutasteride reduces circulating levels of dihydrotestosterone (DHT) by inhibiting both type 1 and type 2 5-alpha reductase isoenzymes, which are responsible for the conversion of testosterone to DHT.
AVODART IN MONOTHERAPY
Effects on DHT / Testosterone
The effect of a daily dose of Avodart on DHT reduction is dose dependent and is observed within 1-2 weeks (85% and 90% reduction, respectively).
In patients with benign prostatic hyperplasia treated with 0.5 mg per day of dutasteride, the decrease in median serum DHT values was 94% at one year and 93% at two years and the increase in median serum values of testosterone was 19% at both one and two years.
Effects on the volume of the prostate
A significant reduction in the volume of the prostate was evidenced as early as one month after the start of treatment and continued until the twenty-fourth month (acute urinary retention and surgery related to benign prostatic hyperplasia.
CLINICAL STUDIES
Avodart 0.5 mg daily or placebo was evaluated in 4,325 male subjects with moderate to severe symptoms of benign prostatic hyperplasia, who had prostate volumes ≥ 30 ml and a PSA value within the range of 1.5 - 10 ng / ml, over three primary, multicenter, 2-year, multinational, placebo-controlled, double-blind, primary efficacy studies. The studies then continued with an "open label extension to 4 years with all patients remaining in the study treated with dutasteride at the same 0.5 mg dose."37% of patients initially randomized to placebo and 40% of patients randomized to dutasteride remained in the study for 4 years. Most of the 2,340 subjects (71%) in the open label extension completed the additional two years of open label treatment.
The most important clinical efficacy parameters were the American Urological Association Symptom Index (AUA-SI), maximum urinary flow (Qmax), and the incidence of acute urinary retention and surgery related to benign prostatic hyperplasia.
AUA-SI is a 7-question questionnaire on symptoms related to "benign prostatic hyperplasia with a maximum score of 35". Initially, the mean score was approximately 17. The placebo group after six months, one and two years of treatment had a mean improvement of 2.5, 2.5 and 2.3 points respectively while the Avodart group had an increase of 3.2, 3.8 and 4.5 points respectively. The differences between the groups were statistically significant. The improvement in AUA-SI observed during the first 2 years of double-blind treatment was maintained during the additional 2 years of extension of the open-label studies.
Qmax (maximum urine flow)
The mean baseline Qmax in the studies was approximately 10 mL / sec (normal Qmax ≥15 mL / sec).
After one and two years of treatment the flow in the placebo group improved by 0.8 and 0.9 ml / sec, respectively, and in the Avodart group by 1.7 and 2.0 ml / sec, respectively. The difference between the two groups was statistically significant from the first to the twenty-fourth month. The increase in maximum urine flow rate observed during the first 2 years of double-blind treatment was maintained during the additional 2 years of extension of the open-label studies.
Acute urinary retention and surgery
After two years of treatment, the incidence of acute urinary retention was 4.2% in the placebo group compared to 1.8% in the Avodart group (57% risk reduction). This difference is statistically significant and indicates that 42 patients (95% CI 30-73) need to be treated for two years to avoid one case of acute urinary insufficiency.
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 indicates that 51 patients (95% CI 33-109) need to be treated for two years to avoid surgery.
Hair distribution
The effect of dutasteride on hair distribution has not been formally studied during the phase III program, however, 5-alpha-reductase inhibitors can reduce hair loss and can induce hair growth in subjects with hair loss type male (male androgenetic alopecia).
Thyroid function Thyroid function was evaluated in a one-year study in healthy males. Free thyroxine levels remained stable during dutasteride treatment, while TSH levels were slightly increased (up to 0.4 MCIU / mL) compared to placebo at the end of one year of treatment. However, as TSH levels were variable, the TSH median range (1.4-1.9 MCIU / mL) remained within normal limits (0.5- 5/6 MCIU / mL), of free thyroxine remained stable within the normal range and similar in both placebo and dutasteride, changes in TSH were not considered clinically significant. In all clinical studies, dutasteride was not found to adversely affect thyroid function.
Breast neoplasm
In the 2 years of clinical trials, which provided 3,374 patient-years of dutasteride exposure, and at the time of registration in the 2-year open-label clinical program, there were 2 cases of breast cancer reported in treated patients. with dutasteride and 1 case in a patient receiving placebo. In the 4-year CombAT and REDUCE clinical trials providing 17489 patient-years exposure to dutasteride and 5027-year exposure to dutasteride and tamsulosin combination patient, no cases of breast cancer were reported in any treatment group.
It is currently unclear whether there is a causal relationship between the onset of male breast cancer and the long-term use of dutasteride.
Effects on male fertility
The effects of dutasteride 0.5 mg / day on semen characteristics were evaluated in healthy volunteers aged 18 to 52 years (n = 27 dutasteride, n = 23 placebo) over 52 weeks of treatment and 24 weeks of post treatment follow-up. At week 52, the mean percentages of reduction from baseline in total sperm count, semen volume and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when corrected for changes from the value. baseline in the placebo group. The concentration and morphology of the spermatozoa remained unchanged. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower from baseline. While the mean values for all parameters, at all control intervals, remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), two subjects in the dutasteride group had a decrease in sperm count greater than 90% from baseline at week 52, with partial recovery at week 24 of follow-up. The possibility of a reduction in male fertility cannot be excluded.
AVODART IN COMBINATION WITH THE ALPHA BLOCKING TAMSULOSINE
Avodart 0.5 mg / day (n = 1,623), tamsulosin 0.4 mg / day (n = 1,611) or the combination of Avodart 0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in one Multicenter, multinational, randomized, double-blind parallel group study (CombAT study), in male subjects with moderate to severe symptoms of BPH who had a prostate volume greater than / equal to 30 ml and PSA values within a range of 1.5-10 ng / ml. Approximately 53% of patients had previously been treated with a 5 alpha reductase inhibitor or an alpha blocker. The primary efficacy endpoint during the first 2 years of treatment was the change in the International Prostate Symptom Score (IPSS), an 8-question tool based on the AUA-SI questionnaire with an additional quality of life question. Secondary efficacy endpoints at 2 years of treatment included maximum urinary flow rate (Qmax) and prostate volume. The combination achieved significance for IPSS from month 3 compared to Avodart and from month 9 compared to tamsulosin. For Qmax the combination achieved significance from month 6 on both Avodart and tamsulosin.
The primary efficacy endpoint at 4 years of treatment was the time to onset of the first AUR event (acute urinary retention - acute urinary retention) or BPH-related surgery.
After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% risk reduction p
Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a set of: IPSS deterioration ≥ 4 points, BPH-related AUR events, incontinence, urinary tract infections, and renal failure), change in of the International Prostate Symptom Score (IPSS), the maximum urinary flow rate (Qmax) and the prostate volume. The results after 4 years of treatment are presented below:
Baseline values are mean values and changes from baseline are adjusted mean changes.
* Clinical progression was defined as a composite of: IPSS deterioration ≥ 4 points, BPH-related AUR events, incontinence, urinary tract infections, and renal failure.
# Measured in selected centers (13% of randomized patients)
a Significance achieved with the combination (p
b Significance obtained with the combination (p
HEART INSUFFICIENCY
In a 4-year study for BPH of Avodart in combination with tamsulosin in 4844 men (the CombAT study), the incidence of heart failure as a composite term in the combination group (14/1610; 0.9% ) was higher than that found in both monotherapy groups: Avodart, (4/1623; 0.2%) and tamsulosin, (10/1611; 0.6%).
In a separate 4-year study in 8,231 men aged 50 to 75, with previous negative biopsy for prostate cancer and baseline PSA, between 2.5 ng / mL and 10.0 ng / mL in the case of men between 50 and 60 years, or 3 ng / ml and 10.0 ng / ml in the case of men over 60 years of age (the REDUCE study), there was a higher incidence of heart failure, understood as a composite term, in subjects taking Avodart 0.5 mg once daily (30/4105; 0.7%) compared to subjects taking placebo (16/4126; 0.4%). A post-hoc analysis of this study showed a higher incidence of heart failure as a composite term in subjects taking Avodart and an alpha blocker concomitantly (12/1152; 1.0%), compared to subjects taking Avodart and no alpha blockers (18/2953; 0.6%), placebo and one alpha blocker (1/1399;
PROSTATE CANCER AND HIGH DEGREE CANCER
In a 4-year comparison study of placebo and Avodart in 8,231 men aged 50 to 75 years, with previous negative biopsy for prostate cancer and baseline PSA, between 2.5 ng / ml and 10.0 ng / ml in case of men between 50 and 60 years, or 3 ng / ml and 10.0 ng / ml in case of men over 60 years of age (the REDUCE study), 6,706 subjects had prostate needle biopsy data (mainly required by protocol) available for analysis to determine the Gleason score. There were 1,517 subjects diagnosed with prostate cancer in the study. Most biopsy-detectable prostate cancers in both treatment groups were classified as prostate cancers. low grade (Gleason 5-6; 70%).
A higher incidence of Gleason 8-10 prostate cancers occurred in the Avodart group (n = 29; 0.9%) compared to the placebo group (n = 19; 0.6%) (p = 0.15). In the 1st and 2nd year, the number of subjects with Gleason 8-10 cancer was similar in the Avodart group (n = 17; 0.5%) and in the placebo group (n = 18; 0 , 5%). In year 3 and 4, more Gleason 8-10 tumors were diagnosed in the Avodart group (n = 12; 0.5%) than in the placebo group (n = 1;
In the 4-year BPH study (CombAT) in which there was no protocol biopsy and all prostate cancer diagnoses were based on suspected tumor ("by cause") biopsies, cancer rates of Gleason scores were 8-10 (n = 8; 0.5%) for Avodart, (n = 11; 0.7%) for tamsulosin and (n = 5; 0.3%) for combination therapy.
The relationship between Avodart and high-grade prostate cancer is unclear.
05.2 Pharmacokinetic properties
Absorption
Following oral administration of a single 0.5 mg dutasteride dose, the time to peak serum dutasteride concentration is 1-3 hours. Absolute bioavailability is approximately 60%. The bioavailability of dutasteride is not affected by food.
Distribution
Dutasteride has a large volume of distribution (300-500 L) and is highly bound to plasma proteins (> 99.5%). Following daily administration, the concentration of dutasteride in serum reaches 65% of the steady-state concentration after one month and approximately 90% after three months.
Steady state serum concentrations of approximately 40 ng / mL (Css) are achieved after six months of 0.5 mg once daily treatment. The amount of dutasteride that passes from serum to seminal fluid averages 11.5%.
Elimination
Dutasteride is extensively metabolised in vivo. In vitro, dutasteride is metabolised by cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite.
Following oral administration of dutasteride 0.5 mg / day until steady state is reached, 1.0% to 15.4% (mean 5.4%) of the administered dose is excreted as unchanged dutasteride in the The remainder is excreted in the faeces as 4 major metabolites each comprising 39%, 21%, 7% and 7% drug related compounds and 6 minor metabolites (less than 5% each). Traces of unchanged dutasteride only (less than 0.1% of the dose) are revealed in human urine.
Elimination of dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non-saturable.
At low serum concentrations (less than 3 ng / mL), dutasteride is rapidly cleared by both concentration dependent and concentration independent elimination processes. Single doses of 5 mg or less have shown rapid clearance and a short half-life of 3 to 9 days.
At therapeutic concentrations, following repeated doses of 0.5 mg / day, the slower linear elimination pathway prevails and the half-life is approximately 3-5 weeks.
Senior citizens
The pharmacokinetics of dutasteride were evaluated in 36 healthy male subjects aged 24 to 87 years by administering a single 5 mg dose of dutasteride. No significant influence of age on dutasteride exposure was observed, however the half-life was shorter in men under 50 years of age. The half-life was not statistically different when comparing the age group 50-69 years. with the over 70 age group.
Kidney failure
The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, therefore no clinically significant increase in dutasteride plasma concentration is expected in patients with renal impairment (see section 4.2).
Hepatic insufficiency
The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied (see section 4.3). Since dutasteride is eliminated primarily by metabolism, plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride to be prolonged (see section 4.2 and section 4.4).
05.3 Preclinical safety data
Current data deriving from toxicity, genotoxicity and carcinogenicity studies did not reveal any particular risk for humans.
Reproductive toxicity studies in male rats showed decreased weight of the prostate and seminal vesicles, decreased secretion from accessory genital glands and decreased fertility indices (due to the pharmacological effects of dutasteride). The clinical significance of these findings is unknown.
As with other 5-alpha reductase inhibitors, feminization was observed in male fetuses of rats or rabbits when dutasteride was administered during gestation. Dutasteride was found in the blood of female rats after mating with dutasteride-treated males. When dutasteride was administered to primates during gestation, feminization of male fetuses was not observed at blood levels at least above those expected after passage through sperm in man. A male fetus is unlikely to be affected. negative following transfer of dutasteride via semen.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule core:
mono and diglycerides of caprylic / capric acid,
butylated hydroxytoluene (E321).
Capsule shell:
jelly,
glycerol,
titanium dioxide (E171),
yellow iron oxide (E172),
medium chain triglycerides,
lecithin.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
4 years
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Opaque PVC / PVDC film blister containing 10 soft gelatin capsules, in packs of 10, 30, 50, 60 and 90 capsules. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Dutasteride is absorbed through the skin, therefore contact with leaking capsules should be avoided. In case of contact with leaking capsules, the affected area should be washed immediately with soap and water (see section 4.4).
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - Verona.
08.0 MARKETING AUTHORIZATION NUMBER
Avodart 0.5 mg soft capsules - 30 capsules A.I.C .: 035895010 / M
Avodart 0.5 mg soft capsules - 90 capsules A.I.C .: 035895022 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
11 March 2004 / July 2007
10.0 DATE OF REVISION OF THE TEXT
April 27, 2012
