Date of approval.
Date of revision.
Dutasteride Softgels Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Dutasteride Soft Capsules
English Name: Dutasteride Soft Capsules
Hanyu Pinyin: Dutaxiong’an Ruanjiaonang
Ingredients
The active ingredient of this product is dutasteride.
Chemical name: (5α,17β)-N-{2,5-bis(trifluoromethyl)phenyl}-3-oxo-4-aza-androst-1-ene-17-carboxamide.
Chemical structure formula.
Molecular formula: C27H30F6N2O2
Molecular weight: 528.5
【Properties】.
This product is soft capsule, the content is colorless or light yellow transparent oil.
Indications
Treatment of moderate and severe symptoms of benign prostatic hyperplasia (BPH) with prostate enlargement, reducing the risk of acute urinary retention (AUR) and BPH-related surgery.
Specification
0.5mg
Dosage]
Adults (including the elderly).
The recommended dose is one capsule (0.5mg) once daily, taken orally. The capsule should be swallowed whole, not chewed or opened, because the contents have an irritating effect on the oropharyngeal mucosa. Capsules may or may not be taken with or without food. Although improvement in symptoms is observed early in treatment, it takes up to 6 months to achieve therapeutic effect. No dose adjustment is required in the elderly.
Renal Impairment.
The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. No dose adjustment is anticipated in patients with renal impairment (see [Pharmacokinetics]).
Hepatic Impairment.
The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. However, use with caution in patients with mild to moderate hepatic impairment (see [Precautions]/[Pharmacokinetics]). This product is contraindicated in patients with severe hepatic impairment ([Contraindication]).
Adverse reactions
Foreign clinical trial data of the same species
Adverse reactions reported in clinical trials with dutasteride alone or in combination with tamsulosin.
The combination of dutasteride and tamsulosin has not been approved in China.
The most common adverse reactions were impotence, decreased libido, breast disorders (including breast enlargement and pain) and ejaculation disorders. The most common adverse reactions when combined with tamsulosin were impotence, decreased libido, breast disease (including breast enlargement and pain), ejaculatory disorders and dizziness. The incidence of ejaculatory dysfunction was 11% with combination therapy, 2% with dutasteride alone, and 4% with tamsulosin alone.
In single-agent placebo-controlled clinical trials, 4% of patients in the treatment group and 3% of patients in the placebo group withdrew from the trial due to adverse reactions, with impotence being the most common adverse reaction leading to withdrawal (incidence 1%).
The incidence of adverse reactions leading to withdrawal was 6% in clinical trials of combination therapy with tamsulosin and 4% when dutasteride or tamsulosin was administered alone. The most common adverse reaction leading to withdrawal in all treatment groups was erectile dysfunction (incidence 1% to 1.5%).
Dutasteride alone for BPH
In 3 identical 2-year placebo-controlled, double-blind, phase III clinical trials, more than 4300 men with BPH were randomized to placebo or a 0.5 mg daily dose of dutasteride, each followed by a 2-year open extension study. During the double-blind trials, approximately 1772 of 2167 patients treated with dutasteride and 1510 patients experienced adverse reactions in the first and second years of treatment, and 1009 and 812 patients experienced adverse reactions in the third and fourth years of the following 2-year open extension study. The incidence of adverse reactions in the treatment group with an incidence of ≥1% is shown in Table 1 to be higher than that in the placebo group.
Table 1. Adverse reactions with an incidence ≥1% higher in the dutasteride treatment group than in the placebo group during periods longer than 24 months of treatment (randomized, double-blind, placebo-controlled trial)
Adverse reactions Adverse reactions time of occurrence 0-June July-December 13-18 months 19-24 months dutasteride n=2167n=1901n=1725n=1605 placebo n=2158n=1922n=1714n=1555 impotencea dutasteride 4.7% 1.4% 1.0% 0.8% placebo 1.7% 1.5% 0.5% 0.9% Decreased libidoa dutasteride 3.0%0.7%0.3%0.3%placebo 1.4%0.6%0.2%0.1%Ejaculatory disordersa dutasteride 1.4%0.5%0.5%0.1%placebo 0.5%0.3%0.1%0.0%Mammary disordersb dutasteride 0.5%0.8%1.1%0.6%placebo 0.2%0.3%0.3% 0.1%a These adverse reactions in sexual function were associated with dutasteride treatment (both monotherapy and in combination with tamsulosin). These adverse reactions persisted after termination of treatment. The role of dutasteride in this aftereffect cannot be determined.
b Including breast pain and breast enlargement.
Long-term treatment (up to 4 years)
Risk of high-grade prostate cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8231 men aged 50 to 75 years with serum PSA values of 2.5 ng/ml to 10 ng/ml and who had a negative prostate puncture biopsy in the previous 6 months. These subjects were randomized to placebo (n=4126) or 0.5 mg of dutasteride daily (n=4105) for 4 years. The mean age of these subjects was 63 years and 91% of them were Caucasian. These subjects underwent prostate puncture biopsies at years 2 and 4 as required by the protocol or, if clinically indicated, no protocol-arranged tissue biopsy. The treatment group (1.0%) had a higher risk of having prostate cancer with a Gleason score of 8 to 10 compared to the placebo group (0.5%) (see [Caution]). In a 7-year controlled trial with another 5a-reductase inhibitor (finasteride 5 mg) as placebo, similar prostate cancers with a Gleason score of 8 to 10 also occurred. (1.8% in the finasteride group and 1.1% in the placebo group)
There was no clinical benefit for patients with prostate cancer who were taking dutasteride.
Diseases of the reproductive system and breast: In 3 placebo-controlled clinical trials of dutasteride for the treatment of BPH lasting 4 years, no evidence was found that prolonging the treatment period increased adverse effects of reproductive (impotence, decreased libido, and ejaculatory disorders) or breast disease. In each of the 3 trials, 1 case of breast cancer was reported in the treatment and placebo groups. No breast cancer was reported in the treatment group in either the 4-year CombAT trial or the 4-year REDUCE trial.
The association between long-term dutasteride treatment and male breast tumors is not known.
Combination alpha antagonist therapy: In a 4-year double-blind clinical trial, more than 4800 male subjects with BPH were randomized to 0.5 mg dutasteride daily, 0.4 mg tamsulosin daily, or a combination (0.5 mg dutasteride and 0.4 mg tamsulosin daily), with 1623 subjects receiving dutasteride monotherapy and 1611 subjects receiving 1623 subjects received dutasteride monotherapy, 1611 subjects received tamsulosin monotherapy, and 1610 subjects received combination therapy. Reports of higher incidence of adverse reactions in combination therapy with an incidence ≥ 1% than in dutasteride or tamsulosin alone are summarized in Table 2.
Table 2. Reports of higher incidence of adverse reactions in combination therapy with an incidence ≥ 1% than in treatment with dutasteride or tamsulosin alone (pooled randomized, double-blind, placebo-controlled trials)
Adverse reactions Time to adverse reaction 1 year 0-June 7-December 2 years 3 years 4 years Combination an=1610n=1527n=1428n=1283n=1200 Dutasteride n=1623n=1548n=1464n=1325n=1200 Tamsulosin n=1611n=1545n=1468n=1281n= 1112 Ejaculatory disordersb,c Coadministration 7.8%1.6%1.0%0.5%<0.1% Dutasteride 1.0%0.5%0.5%0.2%0.3% Tamsulosin 2.2%0.5%0.5%0.2%0.3% Impotencec,d Coadministration 5.4%1.1%1.8%0.9%0.4% Dutasteride 4.0%1.1% 1.6%0.6%0.3%Tamsulosin2.6%0.8%1.0%0.6%1.1%Decreased libidoc,e Coadministration4.5%0.9%0.8%0.2%0.0%Dutasteride3.1%0.7%1.0%0.2%0.0%Tamsulosin2.0%0.6%0.7%0.2%<0.1%Mastopathyf Coadministration 1.1%1.1%0.8%0.9%0.6%Dutasteride0.9%0.9%1.2%0.5%0.7%Tamsulosin0.4%0.4%0.4%0.2%0.0%Dizziness Combination1.1%0.4%0.1%<0.1%0.2%Dutasteride0.5%0.3%0.1%<0.1%<0.1% Tamsulosin 0.9%0.5%0.4%<0.1%0.0%a Combination therapy: dutasteride 0.5 mg daily plus tamsulosin 0.4 mg daily.
b Includes frigidity, retrograde ejaculation, decreased semen volume, decreased orgasm, paradoxical orgasm, delayed ejaculation, ejaculatory disorders, ejaculatory failure, and premature ejaculation.
c These adverse reactions in sexual function have been associated with dutasteride therapy (both monotherapy and in combination with tamsulosin). These adverse reactions will persist after treatment has been discontinued. The role of dutasteride in this persistence has not been clarified.
d Includes erectile dysfunction and sexual urge dysregulation.
e Includes decreased libido, sexual desire disorder, loss of libido, sexual dysfunction, and male sexual dysfunction.
f Includes breast enlargement, male female-pattern breasts, breast swelling, breast pain, breast tenderness, nipple pain and swelling.
Heart Failure.
In the CombAT trial, after a 4-year treatment period, the incidence of heart failure was greater with combination therapy (12/1610; 0.7%) than with monotherapy: dutasteride 2/1623 (0.1%) and tamsulosin 9/1611 (0.6%). When heart failure was assessed in a 4-year placebo-controlled trial alone evaluating the progression of prostate cancer in patients taking dutasteride, the incidence of heart failure was 0.6% in subjects taking dutasteride (26/4105) and 0.4% in subjects taking placebo (15/4126). The majority of subjects with heart failure in the 2 trials had complications associated with an increased risk of heart failure. Therefore, the clinical significance of the uneven heart failure data is unclear. No causal relationship was established between dutasteride alone and in combination with tamsulosin and resulting heart failure. No imbalance in the incidence of cardiovascular adverse events was found in any of the trials.
Postmarketing Experience
The following adverse reactions were identified with postmarketing use of dutasteride. Because these adverse reactions were reported in volunteer subjects from an uncertain population, it is not possible to accurately estimate the incidence of adverse reactions or with establish a causal relationship with the amount of drug exposure. The following adverse reactions were identified considering a combination of severity, frequency of reporting, or potential correlation with dutasteride.
Immune system disorders: allergic reactions, including rash, pruritus, urticaria, localized puffiness, severe skin reactions, and angioedema.
Malignancies: male breast cancer.
Mental disorders: emotional depression.
Reproductive and breast disorders: testicular pain and testicular swelling.
Skin and subcutaneous tissue disorders: hair loss (mainly body hair loss), hirsutism.
Contraindications
The use of this product is prohibited in the following groups.
1. people who are hypersensitive to any of the ingredients in this product, other 5α-reductase inhibitors or any of the excipients.
2. Pregnant women. In reproductive and developmental toxicity studies in animals, this product was shown to prevent the development of reproductive organs in male fetuses. Therefore, the use of this product by pregnant women can lead to fetal damage. If this product is used in a patient who is pregnant or preparing to become pregnant, the patient should be informed of the potential risk to the fetus (see [Precautions], [Use in Pregnant and Lactating Women]).
3. Women (see [Precautions], [Use in Pregnant and Lactating Women]).
4. Children and adolescents (see [Pediatric Use]).
5. Severe hepatic impairment (see [Pharmacokinetics]).
[Precautions].
Capsule leakage
Dutasteride is absorbed through the skin, so women, children and adolescents must avoid contact with leaking capsules (see [Pregnancy and Lactation]). In case of accidental contact with leaking capsules, the contact area should be washed immediately with soap and water.
Liver Injury
Dutasteride has not been clinically studied in patients with hepatic disease, but due to the extensive metabolic pathway of dutasteride and its three- to five-week half-life, it should be used with caution in patients with mild to moderate hepatic impairment (see [Dosage]/[Contraindications]/[Pharmacokinetics]).
Effects on prostate-specific antigen (PSA) and the role of PSA in the detection of prostate cancer
Serum prostate-specific antigen (PSA) concentration is an important indicator for the detection of prostate cancer. In clinical studies, serum PSA concentrations were reduced by approximately 50% in patients with benign prostatic hyperplasia and even in patients with prostate cancer after 3-6 months of treatment with this product. Although individual differences exist, an approximately 50% reduction in PSΑ is expected across the entire range of baseline PSΑ values (1.5-10ng/ml). This product may also lead to a reduction in serum PSΑ in patients with prostate cancer. To interpret PSΑ in men taking dutasteride, a new PSΑ baseline should be established at least 3 months after initiation of treatment, followed by periodic monitoring of PSΑ. Any confirmed elevation in the self-minimal PSA level during treatment with this product may be a sign of the presence of prostate cancer or poor compliance with this treatment and must be evaluated with caution, even if these values remain within the normal range for men not receiving a 5α-reductase inhibitor. For patients taking this product, it is important to compare PSA values with previous PSA values when interpreting PSA values. Not taking this product may also affect PSΑ test results. Therefore, when interpreting isolated PSΑ values in patients receiving this product for 3 months or longer, the PSΑ value should be doubled and then compared to the normal range of values in patients not taking the drug. The application of this treatment does not affect the use of PSA as an adjunctive diagnostic tool for prostate cancer after a new baseline value has been established. The ratio of free PSΑ to total PSΑ remains stable despite the effects of this product. If a clinician chooses to use the free PSΑ percentage as an adjunct to monitor for the development of prostate cancer in patients treated with this product, there is no need to check the PSΑ value. The combination of dutasteride and tamsulosin produced similar serum PSΑ results as dutasteride alone. Rectal examinations and other tests for prostate cancer must be performed before starting treatment with this product in patients with benign prostatic hyperplasia (BPH) and at regular intervals after treatment.
Increased risk of high-grade prostate cancer
In a 4-year study involving subjects aged 50-75 years with negative prostate cancer tissue biopsy prior to enrollment and baseline PSA values between 2.5ng/ml and 10ng/ml (REDUCE study). The incidence of prostate cancer with a Gleason score of 8-10 was higher in the group treated with this product (1%) compared to the placebo group (0.5%) (see [Adverse Reactions]). In contrast, the incidence of prostate cancer with Gleason score 5-6 or 7-10 was not increased. A causal relationship between dutasteride and high-grade prostate cancer has not been confirmed. The clinical significance of the imbalance in values between groups is unknown. Patients taking this product should be evaluated regularly for risk of prostate cancer, including a PSA test.
In the supplemental 2-year follow-up study of patients originally enrolled in the Dutasteride Chemoprevention Study (REDUCE), the rate of new prostate cancer diagnoses was low (dutasteride group [n=14, 1.2%], placebo group [n=7, 0.7%]) and there were no new cases of prostate cancer with a Gleason score of 8-10.
In patients taking another 5a-reductase inhibitor (finasteride 5 mg) in a 7-year placebo-controlled clinical trial, the incidence of prostate cancer with a Gleason score of 8-10 was also increased (1.8% in the finasteride group and 1.1% in the placebo group). Long-term follow-up (up to 18 years) showed no statistically significant differences between the finasteride and placebo groups in overall survival (risk ratio, 1.02; 95% confidence interval: 0.97-1.08) or survival after prostate cancer diagnosis (risk ratio, 1.01, 95% confidence interval, 0.85-1.20).
5α-reductase inhibitors may increase the risk of progression of high-grade prostate cancer. It is not clear whether the effect of 5α-reductase inhibitors on reducing prostate volume or trial-related factors affects the outcome of these trials.
Cardiovascular Adverse Events
In two 4-year clinical studies (the CombAT study and the REDUCE study), the incidence of heart failure (a composite of reported events, primarily heart failure and congestive heart failure) was higher in subjects who combined this product with an alpha-receptor antagonist (primarily tamsulosin) than in subjects who did not combine the drugs. In both studies, the incidence of heart failure was low (≤1%) and differed between studies. No between-group imbalance in cardiovascular adverse events was observed in either study. A causal relationship between this product (either alone or in combination with an alpha-receptor antagonist) and heart failure has not been confirmed.
In a meta-analysis of 12 randomized, placebo or controlled drug-controlled clinical studies (n=18, 802), the risk of cardiovascular adverse events during dutasteride administration was evaluated (by comparison with controls) and found heart failure (RR 1.05; 95% confidence interval: 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% confidence interval: 0.77, 1.30) and stroke (RR 1.20; 95% confidence interval: 0.88, 1.64) did not show statistically significant elevations in these cardiovascular adverse events.
Breast Cancer
Reports of breast cancer events in men received during clinical trials and post-marketing were relatively rare. However, epidemiologic studies suggest that there is no increased risk of male breast cancer with the use of 5α-reductase inhibitors. Clinicians must instruct their patients to immediately report any changes in their breast tissue, such as lumps or nipple discharge.
Evaluation of Other Urologic Disorders
Other urologic disorders that may cause similar symptoms should be considered before initiating treatment with this product. In addition, BPH and prostate cancer may coexist.
Fetal Risks
Pregnant women should not be exposed to this product. Dutasteride is absorbed through the skin and may cause accidental fetal death. If a pregnant woman comes into contact with spilled product, wash the contact area immediately with soap and water (see [Pregnancy and Lactation] / [Pharmacokinetics]).
Blood Donation
Blood should not be donated for at least 6 months after the last dose of dutasteride. The purpose is to stop dutasteride remaining in the body during this extended period from affecting pregnant women by way of blood transfusion.
Effect of semen characteristics
The effect of daily doses of 0.5 mg dutasteride on semen characteristics was assessed in normal volunteers 18 to 52 years of age (n=27 dutasteride, n=23 placebo) through 52 weeks of treatment and at 24 weeks post-treatment follow-up. At 52 weeks, when corrected for baseline changes in the placebo group, the mean percentage reductions in total sperm count, semen volume and sperm motility at baseline in the dutasteride group were 23%, 26% and 18%, respectively. Sperm concentration and sperm morphology were unaffected. At 24-week post-treatment follow-up, the mean percentage change in total sperm count in the dutasteride group remained below 23% of baseline. The mean semen parameters remained within normal limits at all time points and did not meet the predetermined criteria for clinically significant change (30%), except for two subjects in the dutasteride group whose sperm counts decreased by more than 90% at 52 weeks and partially recovered at the 24-week follow-up. The clinical significance of the effect of dutasteride on the semen characteristics of fertility in individual patients is unknown.
Effects on the ability to drive and use machines
Based on the pharmacodynamic properties of dutasteride, treatment with dutasteride is not expected to affect the ability to drive or operate machinery.
For Pregnant and Lactating Women]
Pregnancy Level X. This product is contraindicated in women who are pregnant or planning to become pregnant. This product is contraindicated in women.
Fertility
The effect of dutasteride 0.5 mg/day on semen characteristics was evaluated in normal volunteers aged 18 to 52 years (dutasteride n=27, placebo n=23) during 52 weeks of treatment and at 24 weeks of post-treatment follow-up. At 52 weeks, the mean percentage reductions from baseline (when adjusted for change from baseline in the placebo group) in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively. Sperm concentration and sperm morphology were not affected. After a 24-week follow-up period, the mean percentage change in total sperm count in the dutasteride group was maintained at 23% below baseline values. Although the mean values of all semen parameters remained within the normal range at all time points and did not meet the pre-defined condition of clinically significant change (30%), two subjects in the dutasteride group had a sperm count reduction of more than 90% from baseline at week 52 that partially recovered during the 24-week follow-up period. The clinical significance of the effect of dutasteride on semen characteristics in terms of individual patient fertility is unclear.
Pregnant women
Dutasteride has not been studied in women.
This product is a 5a-reductase inhibitor that blocks the reduction of testosterone to dihydrotestosterone (DHT), a sex hormone necessary for normal male genital development. In reproductive and developmental toxicity tests in animals, dutasteride prevented the normal development of the genital organs in male fetuses. Therefore, when used on pregnant women this product can cause fetal toxicity. If this product is used during pregnancy or in preparation for pregnancy, the fetus should be informed of the potential hazards to the fetus. As with other 5α-reductase inhibitors, patients should be advised to use condoms to avoid exposure of their spouse to semen when the patient’s spouse is pregnant or has the potential to become pregnant.
Because 5a-reductase inhibitors physiologically inhibit the conversion of testosterone to dihydrotestosterone DHT, they can cause genital malformations in male infants. Symptoms are similar to those seen in fetuses of males with 5a-reductase genetic defects. Dutasteride is absorbed transdermally. To avoid potential fetal exposure, women who are pregnant or preparing to become pregnant should not be exposed to this product. In case of contact with leaking softgels, the contact area should be washed immediately with soap and water (see [Precautions]). Dutasteride is secreted in semen. In men treated with dutasteride, the highest concentration in semen was 14 ng/ml, which corresponds to a concentration of 0.0175 ng/ml detected in a 50 kg female after daily intercourse with a dutasteride-treated man who received 5 ml of semen (assuming 100% uptake). In animal studies, this concentration is 100 times higher than the minimum concentration that causes genital malformations in males. Dutasteride is highly bound to proteins in human semen (>96%). This may reduce the amount of dutasteride absorbed vaginally.
Lactating Women
This product is contraindicated in women of childbearing potential, including women who are breastfeeding. It is not known whether dutasteride is excreted in human breast milk.
Pediatric Use
This product is contraindicated in children and adolescents.
Geriatric use
In three clinical trials of 2167 male patients treated with dutasteride, 60% of them were aged 65 or older.
In three clinical trials of 2167 male patients treated with dutasteride, 60% were 65 years of age or older and 15% were 75 years of age or older. In terms of safety and efficacy, there was no significant difference between these subjects and those younger than them, but it cannot be ruled out that older subjects had a greater sensitivity. No dose adjustment is required in the elderly (see [Pharmacokinetics]).
Drug Interactions]
Cytochrome P450 3Α inhibitor
In vitro drug metabolism studies have shown that dutasteride is metabolized by the human cytochrome P450 isoenzyme CYP3A4. Therefore, the blood concentration of dutasteride may increase in the presence of CYP3A4 inhibitors. The effect of potent CYP3Α4 inhibitors on dutasteride has not been studied. Use this product with caution in patients taking potent chronic CYP3Α4 enzyme inhibitors due to drug interactions.
No formal drug interaction studies have been conducted with this product and potent inhibitors of CYP3Α4. The long-term combination of dutasteride with drugs that are potent inhibitors of the CYP3Α4 enzyme (e.g., oral ritonavir, indinavir, nefazodone, itraconazole, and ketoconazole) may increase blood levels of dutasteride. Clinical drug interaction trials have not been conducted to assess the effect of CYP3Α enzyme inhibitors on dutasteride pharmacokinetics.
Because of the wide safety margin (up to 10 times the recommended dose given to patients over a maximum of six months), the reduction in clearance in the presence of CYP3A4 inhibitors and the resulting increase in dutasteride exposure is unlikely to be clinically significant and therefore no dose adjustment is required.
In in vitro studies, dutasteride was not metabolized by the human cytochrome P450 isozymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6, and CYP2D6.
Dutasteride did not inhibit human cytochrome P450 drug metabolizing enzymes in in vitro studies, nor did it induce cytochrome P450 isozymes CYP1A, CYP2B and CYP3A in in vivo studies in rats and dogs.
Alpha-adrenoceptor antagonist
Co-administration of this product with tamsulosin or terazosin had no effect on the steady-state pharmacokinetics of the alpha-adrenergic antagonists. The effect of tamsulosin or terazosin administration on dutasteride pharmacokinetic parameters has not been evaluated.
Calcium channel antagonists
Co-administration of verapamil or diltiazem decreased dutasteride clearance and resulted in increased dutasteride exposure. The increase in dutasteride exposure is not considered clinically significant and dose adjustment is not recommended. In a population pharmacokinetic analysis, reduced dutasteride clearance was found when co-administered with the CYP3Α4 inhibitors verapamil (-37%, n=6) and diltiazem (-44%, n=5). In contrast, when amlodipine, another calcium channel antagonist that is not a CYP3Α4 inhibitor, was co-administered with dutasteride (+7%, n=4), there was no reduction in clearance.
Caurethanide.
Administration of a single dose of 5 mg dutasteride softgels followed 1 hour later by 12 g of colesevelam did not affect the relative bioavailability of dutasteride.
Digoxin
The daily administration of 0.5 mg of this product in combination with digoxin for 3 weeks did not alter the steady-state pharmacokinetics of digoxin.
Warfarin
Daily administration of 0.5 mg of this product in combination with warfarin for 3 weeks does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time.
Other
In vitro studies have demonstrated that dutasteride does not displace acenocoumarol, phenylpropionic coumarin, diazepam, or phenytoin from plasma proteins, nor do these model compounds displace dutasteride. Compounds that have been studied in men for drug interactions include warfarin and digoxin, and no clinically significant pharmacokinetic or pharmacodynamic interactions have been observed.
Although no specific interaction studies have been conducted using other compounds, approximately 90% of subjects receiving dutasteride in large phase III studies were taking other drugs concomitantly. In clinical trials, no clinically significant adverse interactions were observed when dutasteride was administered concomitantly with antihyperlipidemic agents, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blockers, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase type V inhibitors, and quinolone antibiotics.
[Drug overdose].
In volunteer trials, dutasteride was administered at single daily doses of up to 40 mg/day (80 times the therapeutic dose) for 7 consecutive days without significant safety concerns. In clinical trials, subjects taking 5 mg of dutasteride daily for 6 months did not experience additional adverse effects compared to taking a therapeutic dose of 0.5 mg. Since there is no specific antidote for dutasteride, appropriate symptomatic and supportive treatment should be given when symptoms of suspected drug overdose occur.
Pharmacology and Toxicology
Pharmacological effects
Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). As an androgen, DHT plays a role in the initial development and subsequent enlargement of the prostate. Testosterone is converted to DHT by the enzyme 5α-reductase, which has two isoenzymes, type I and type II. Type II isoenzymes are mainly found in reproductive tissues, while type I isoenzymes also have a role in the conversion of testosterone in the skin and liver.
Dutasteride is a specific competitive inhibitor of 5α-reductase type I and II isozymes and forms a stable enzyme complex with 5α-reductase. In vivo and in vitro dissociation assays of the enzyme complex showed very low dissociation. Dutasteride does not bind to the human androgen receptor.
Toxicological studies
CNS Toxicity: Repeated oral administration of dutasteride to rats and dogs at 425 and 315 times the normal clinical exposure of the prodrug resulted in non-specific, reversible CNS toxicity in some animals, but no significant histopathological changes were observed.
Genotoxicity.
The Ames test for dutasteride, the CHO cell chromosome aberration test and the rat micronucleus test were all negative. The Ames test or simplified Ames test for the two major human metabolites was negative.
Reproductive toxicity.
Oral administration of dutasteride to sexually mature male rats for 31 weeks at doses of 0.05, 10, 50 and 500 mg/kg/day (prodrug concentrations equivalent to 0.1 to 110 times the normal clinical exposure dose) resulted in a dose- and time-dependent decrease in animal fertility; in the 50 and 500 mg/kg/day groups, the absolute number of spermatozoa in the cauda epididymis decreased, but sperm concentration in the semen In the 50 and 500 mg/kg/day groups, a decrease in the absolute number of epididymal tail spermatozoa was observed, but no significant decrease in sperm concentration in the seminal fluid; a reduction in the weight of the epididymis, prostate and seminal vesicles; and microscopic changes in the male reproductive system. The effects of dutasteride on fertility were reversible, with gradual recovery in all dose groups after 6 weeks of discontinuation and normalization of sperm counts after week 14. 5α-reductase treatment-related changes included vacuolar degeneration of epididymal duct epithelial cells and reduced cytoplasmic content of epithelial cells, consistent with reduced secretory activity in the prostate and seminal vesicles. After 14 weeks of drug withdrawal, the microscopic changes disappeared in the low-dose group and partially recovered in the remaining dose groups. Low levels of dutasteride (0.6-17 ng/mL) were detected in the serum of male rats given dutasteride 10, 50 or 500 mg/kg/day orally for 29-30 weeks after mating with unadministered female rats.
In the female rat fertility test, animals were given dutasteride orally at 0.05, 2.5, 12.5 and 30 mg/kg/day, showing reduced litter size, increased embryo uptake and feminization of male litters (reduced distance between anus and reproductive orifice) in the ≥2.5 mg/kg/day group (prodromal drug concentration equivalent to 2-10 times the normal clinical exposure dose); ≥0.05 mg/kg/day (0.02 times the normal clinical exposure), a reduction in fetal weight was observed.
In pregnant rats, oral administration of dutasteride at doses less than 10 times the maximum recommended human dose (MRHD) (0.5 mg/dose) resulted in male fetuses with abnormal external genitalia (reduced anal-genital distance in the 0.05 mg/kg/day group), nipple development, hypospadias and distended prepuce glands (all dose groups including 0.05, 2.5, 12.5 and 30 mg/kg/day). An increase in the number of stillbirths was seen at doses equivalent to 111 times the MRHD, and a decrease in fetal weight was seen at doses approximately 15 times the MRHD (2.5 mg/kg/day). An increase in the incidence of skeletal variation was observed at a dose of approximately 56 times the MRHD (12.5 mg/kg/day).
In pregnant rabbits (gestation days 7-29, covering the late development of the external genitalia), dutasteride was administered orally at 28-93 times the MRHD (30, 100 and 200 mg/kg/day), and histological evaluation of the reproductive papillae of the fetuses showed evidence of feminization of male fetuses in the dose groups used. In the second rabbit embryo-fetal study, oral doses were administered at 0.3-53 times the expected clinical exposure (0.05, 0.4, 3.0, and 30 mg/kg/day), and evidence of external genital feminization was seen in male fetuses in all dose groups.
Pregnant macaques (12/group, days 20-100 of gestation) were given intravenous dutasteride at 400, 780, 1,325, or 2,010 ng/day, and dutasteride blood levels were equivalent to dutasteride concentrations in human semen. No significant abnormalities in the external genital development of male fetuses were observed. At the highest dose, a decrease in fetal adrenal weight, a decrease in fetal prostate weight, and a decrease in fetal ovarian and testicular weight were observed. Based on the highest dutasteride semen concentration measured in dutasteride-treated men (14 ng/mL), the above dose corresponds to 0.8-16 times the maximum possible dutasteride exposure level detected in a 50 kg female after daily intercourse with a dutasteride-treated male receiving 5 mL of semen exposure (assuming 100% absorption) (equivalent to 32-186 times the ng/kg daily (32-186 times the daily dose). Dutasteride is highly protein bound (> 96%) to male semen, which may reduce transvaginal absorption. It is not clear whether the metabolites in rabbits or rhesus monkeys are the same as those in humans.
For perinatal reproductive toxicity in rats, oral administration of dutasteride at 0.05, 2.5, 12.5, and 30 mg/kg/day showed that altered genital feminization (i.e., reduced anal-to-genital orifice distance, increased incidence of hypospadias, and nipple development) was seen in F1 generation male rats in the ≥22.5 mg/kg/day group (prodromal drug concentrations equivalent to 14-90 times the MRHD) . In the 0.05 mg/kg/day (prodrug concentration equivalent to 0.05 times the normal clinical exposure) group, evidence of feminization was seen in the form of a mild but statistically significant reduction in the distance between the anal and genital orifices. 2.5 to 30 mg/kg/day dose levels were associated with prolonged maternal gestation, reduced time to vaginal closure in offspring females, and reduced prostate and seminal vesicle weights in offspring males. The dose was reduced. The effect on neonatal startle reflex was observed in the ≥12.5 mg/kg/day group, and the stillbirth rate was increased in the 30 mg/kg/day group.
Carcinogenicity.
A 2-year carcinogenicity study was conducted in B6C3F1 mice administered at doses of 3, 35, 250 and 500 mg/kg/day in males and 3, 35 and 250 mg/kg/day in females, resulting in an increased incidence of benign hepatocellular adenomas in the 250 mg/kg/day (prodromal drug concentration equivalent to 290 times the normal clinical exposure dose) group in females. The incidence of benign hepatocellular adenomas was increased. Two of the three major metabolites of dutasteride in humans have been detected in mice. Exposure levels of some of these metabolites in mice are lower than those in humans, and there is a lack of empirical data on some of them.
In a 2-year carcinogenicity study in Han Wistar rats administered at doses of 1.5, 7.5 and 53 mg/kg/day in males and 0.8, 6.3 and 15 mg/kg/day in females, an increased incidence of Leydig cell adenomas was seen in the male 53 mg/kg/day (prodrug concentration equivalent to 135 times the normal clinical exposure dose) group. The incidence of Leydig cell adenoma was increased in the 7.5 mg/kg/day (prodrug concentration equivalent to 52 times the normal clinical exposure dose) and 53 mg/kg/day groups in male rats, confirming that 5α-reductase inhibitor treatment was positively correlated with proliferative changes in Leydig cells and luteinizing hormone levels in the body circulation, which were associated with 5α-reductase being inhibited, consistent with the effect on the hypothalamic-pituitary-gonadal axis. At doses high enough to induce tumors, luteinizing hormone levels in rats were increased by 167%. In this study, the carcinogenicity of the major metabolites in human was also investigated in rats at approximately 1-3 times the clinical exposure level.
Pharmacokinetics]
The pharmacokinetics of dutasteride can be described as a primary absorption process and two parallel elimination pathways, one saturable (concentration-dependent) and the other non-saturable (concentration-independent).
Absorption
The time to peak concentration of dutasteride after oral administration of a single dose of 0.5 mg dutasteride softgels is 2 to 3 hours. Absolute bioavailability was approximately 60% (range: 40% to 94%) in 5 healthy subjects. When taken with food, the maximum plasma concentration is reduced by 10% to 15%, which is not clinically significant.
Distribution
Pharmacokinetic data from single and multiple oral doses indicate that dutasteride has a large volume of distribution (300-500 L) and high binding to plasma proteins (99.0%) and alpha-1 acidic glycoproteins (96.6%).
In a clinical trial with healthy subjects (n=26) taking dutasteride 0.5 mg daily for 12 months, the mean concentration of dutasteride in semen at 12 months was 3.4 ng/ml (range: 0.4-14 ng/ml) and it reached steady-state concentrations at month 6, which are similar to the data in blood. At month 12, 11.5% of the blood concentration of dutasteride was converted to semen.
Metabolism and clearance
Dutasteride is mostly metabolized in the human body. In vitro, dutasteride is metabolized by the cytochrome isozymes CYP3Α4 and CYP3Α5 to two monohydroxy metabolites (4′-hydroxydutasteride, 6-hydroxydutasteride) and one dihydroxy metabolite (6,4′-dihydroxydutasteride) in addition to a monohydroxy metabolite (15-hydroxydutasteride) that is also metabolized by CYP3Α4. In in vitro experiments, dutasteride was not metabolized by the cytochrome P450 isozymes CYP1Α2, CYP2Α6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Mass spectrometry of dutasteride given at a dose until it is in steady state in human serum allowed the detection of three major metabolites (4′-hydroxydutasteride, 6-hydroxydutasteride and 1,2-bishydroxydutasteride) and two minor metabolites (6,4′-bishydroxydutasteride and 15-hydroxydutasteride). The stereoselectivity of the hydroxylation reactions at the 6 and 15 positions is not yet known. In in vitro experiments, 4′-hydroxydutasteride and 1,2-bishydroxydutasteride were able to block both isoforms of human 5α-reductase more potently than dutasteride. 6β-hydroxydutasteride activity was similar to that of dutasteride.
The majority of dutasteride and its metabolites are excreted in the feces. Approximately 5% of the administered dose is excreted as dutasteride in its original form (1% to 15%) and approximately 40% is excreted as dutasteride metabolites (2% to 90%). In human urine, only trace amounts of dutasteride in its original form were detected (less than 0.1% of the administered dose). Thus, approximately 55% of dutasteride is excreted in an unknown manner on average (range: 5% to 97%).
The final elimination half-life for dutasteride to reach steady-state concentrations is approximately 5 weeks. The steady-state serum concentration of dutasteride 0.5 mg/day given for 1 year is 40 ng/ml. dutasteride given at daily doses reaches approximately 65% of the steady-state concentration in serum after 1 month of dosing and approximately 90% of the steady-state concentration in serum after 3 months of dosing. Due to the long half-life of dutasteride, serum concentrations (>0.1 ng/ml) are still detectable 4 to 6 months after discontinuation of treatment.
Special Populations
Pediatric patients.
Pharmacokinetic studies of dutasteride have not been performed in adolescents younger than 18 years of age.
Geriatric Patients.
No dose adjustment is required in the elderly. A single dose of 5 mg of dutasteride was administered to healthy male subjects aged 24 to 87 years and evaluated for pharmacokinetics and pharmacodynamics. In this single-dose trial, the half-life of dutasteride increased with age (approximately 170 hours between the ages of 20 and 49 years, approximately 260 hours between the ages of 50 and 69 years, and approximately 300 hours above the age of 70 years). In three trials totaling 2167 male patients treated with dutasteride, 60% of the patients were 65 years of age and older and 15% were 75 years of age and older. There were no major differences in safety and efficacy between these older and younger patients.
Gender.
This product is contraindicated in women who are pregnant or about to become pregnant and should not be used in other women (see [Contraindications], [Precautions]). The pharmacokinetics of dutasteride in women have not been studied.
Race.
The effect of race on the pharmacokinetics of dutasteride has not been studied.
Renal Impairment.
The effect of renal impairment on the pharmacokinetics of dutasteride was not studied. However, concentrations measured in the urine of persons taking dutasteride 0.5 mg at steady-state concentrations were less than 0.1%; therefore, dutasteride does not require dose adjustment in patients with renal impairment (see [DOSAGE AND ADMINISTRATION]).
Hepatic Impairment.
The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Because dutasteride is primarily cleared by metabolism, it is expected that dutasteride plasma levels will be elevated in patients with hepatic impairment and that a prolonged half-life of dutasteride will occur (see [Dosage] and [Precautions]).
Drug Interactions
Cytochrome P450 inhibitors.
There are no clinical trials evaluating the drug-drug interactions of CYP3Α inhibitors on the pharmacokinetics of dutasteride. However, based on data from in vitro trials, coadministration with CYP3Α4/5 inhibitors such as ritonavir, ketoconazole, isoptin, diltiazem, metformin, vinblastine, and ciprofloxacin increased dutasteride blood levels.
In an in vitro model of metabolism, dutasteride at 1000 ng/ml did not inhibit the human cytochrome P450 enzyme family (CYP1Α2, CYP2C9, CYP2C19, CYP2D6, αnd CYP3Α4), a concentration that is 25-fold greater than steady-state serum concentrations in humans.
Alpha-adrenoceptor antagonists.
The combination of dutasteride softgels and tamsulosin or terazosin had no effect on the steady-state pharmacokinetics of either α-adrenoceptor antagonist in a single, crossover trial in healthy subjects. Although the effect of tamsulosin or terazosin use on dutasteride pharmacokinetic parameters has not been evaluated. Changes in DHT concentrations were similar when treated with dutasteride softgels alone and in combination.
Calcium channel antagonists.
In human pharmacokinetic studies, the combination of dutasteride softgels with CYP3Α4 inhibitors resulted in decreased clearance of dutasteride. The decrease was 37% (n=6) in combination with isoptin and 44% (n=5) in combination with diltiazem. In contrast, the combination of dutasteride softgels with other non-CYP3Α4 inhibitors of calcium channel antagonists, such as amlodipine, did not decrease dutasteride clearance (+7%, n=4).
In combination with isoptin and diltiazem, clearance of dutasteride was reduced and exposure increased; these effects were not clinically significant and no dose adjustment was required.
Kolaydenamide.
In 12 healthy subjects, a single dose of 5 mg of dutasteride softgels administered 1 hour after 12 g of koleenamide did not affect the relative bioavailability of dutasteride.
Digoxin.
In a trial involving 20 healthy volunteers, daily doses of dutasteride 0.5 mg administered in combination with digoxin for 3 weeks did not alter the steady-state pharmacokinetics of digoxin.
Warfarin.
In a trial of 23 healthy subjects, dutasteride 0.5 mg daily administered in combination with warfarin for 3 weeks did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time.
Other treatments.
Although no drug-drug interaction trials were conducted with other compounds, approximately 90% of subjects treated with dutasteride softgels were also taking other drugs concomitantly in a 3-group randomized, double-blind, placebo-controlled safety and efficacy trial. No clinically significant adverse drug interactions were observed when dutasteride softgels were combined with antihyperlipidemic agents, angiotensin-converting enzyme inhibitors, beta-receptor antagonists, calcium channel blockers, steroids, diuretics, NSAIDs, V-type phosphodiesterase inhibitors, and aldosterone antibiotics.
Storage
Seal and store below 30℃.
Package】
10 capsules/plate x 1 plate/bag x 1 bag/box.
Expiration date
24 months.
【Execution standard
YBBHXXXXXXXXXX
Approval number
State Drug Registration Number】 HXXXXXXXXXX
[Drug marketing license holder
Enterprise name: Sichuan Guowei Pharmaceutical Co.
Registered Address: New District, Meishan Economic Development Zone, Sichuan Province
Postal Code: 620000
Telephone number
Fax number: 028-85125108-815
【Manufacturer
Company name: Sichuan Guowei Pharmaceutical Co.
Production Address: Meishan Economic Development Zone New District
Postal code: 620000
Telephone number: 028-85319552 (sales) 028-38662609 (quality)
Fax number: 028-85125108-810
Website: http://www.cdgowell.com