Dutasteride

Dutasteride is a synthetic hormone or antiandrogenic agent belonging to the pharmacological class of 5-Alpha-Reductase Inhibitors.

Dutasteride is approved by the FDA to treat benign prostate hyperplasia (BPH)and androgenic alopecia (male pattern hair loss) in men.

Dutasteride undergoes hepatic metabolism by CYP3A4 and CYP3A5 isoenzymes after absorption from the GI tract. Plasma proteins bind to more than 99.5% of the drug. The primary routes of excretion are through faeces (40% as metabolites) and urine (<1% as unchanged drug).

Dutasteride is well tolerated and has only very mild sexual side effects such as mild sexual side effects such as low libido, trouble getting and maintaining an erection (impotence), and decreased sperm count.

Dutasteride is available in the form of oral capsules.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan and Brazil.

Dutasteride is an synthetic hormone or antiandrogenic agent belonging to the pharmacological class of 5-Alpha-Reductase Inhibitors.

The conversion of testosterone to DHT is inhibited by dutasteride. DHT is the androgen principally responsible for the prostate gland's initial growth and subsequent expansion. The enzyme five alpha-reductase, which comes in type 1 and 2 variants, converts testosterone to DHT. While the type 1 isoenzyme is also in charge of converting testosterone in the skin and liver, the type 2 isoenzyme is mainly active in the reproductive tissues.

Dutasteride forms a stable enzyme complex with type 1, type 2, and 5 alpha-reductase isoenzymes, with which it is a competitive and selective inhibitor. Dissociation from this complex is gradual and has been studied both in vitro and in vivo. There is no binding of dutasteride to the human androgen receptor.

Dutasteride is available in the form of oral capsules.

Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily; it can be taken with or without food as directed.

• Benign prostatic hyperplasia
• In combination with the alpha-adrenergic antagonist, tamsulosin, dutasteride treats symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate.

Limitations on Use: Prostate cancer prevention with dutasteride is not approved.

In Benign prostatic hyperplasia:

Benign prostatic hyperplasia (BPH) can be effectively managed with dutasteride. Prostate symptoms like urgency and frequency are effectively reduced by blocking the conversion of testosterone to dihydrotestosterone (DHT). Acute urinary retention risk and the requirement for surgery associated with BPH are also reduced with dutasteride. People with BPH can significantly improve their quality of life with an all-encompassing therapy, which targets both symptom relief and the underlying development of the problem.

• For men with an enlarged prostate, dutasteride may be prescribed to improve symptoms, reduce the risk of acute urinary retention, and lower the likelihood of needing surgery for benign prostatic hyperplasia (BPH).
• Dutasteride, in combination with the alpha-adrenergic antagonist tamsulosin, effectively treats symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate.

Orally: Dutasteride oral capsules are administered through the oral route. The typical dosage is one 0.5 mg capsule taken once daily, with or without food. Capsules should be swallowed whole, not crushed or opened, to avoid potential contact with the drug. It is best to adhere to the prescribed dosage and consult a physician before discontinuing or altering the treatment plan because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Capsule: 0.5 mg

Dutasteride is available in the form of oral capsules.

Dose Adjustment in Adult Patients:

Benign Prostatic Hyperplasia Cancer: 5 mg PO qDay; evaluate responses after 6 months to 12 weeks.

There aren't specific dietary restrictions for dutasteride. However, maintaining a balanced diet rich in nutrients supports general health, including hair health.

Also, limit the intake of alcohol, as it may exacerbate side effects like dizziness or drowsiness.

The dietary restriction should be individualized as per patient requirements.

Dutasteride may be contraindicated in the following conditions:-

•Anyone who has previously experienced hypersensitivity to any of the product's constituents.

•Pregnant women or those who may get pregnant.

•Paediatrics

• Pre-existing Urologic Conditions: Before initiating dutasteride treatment, thoroughly investigate and rule out other urologic conditions to ensure an accurate diagnosis.

• Obstructive Uropathy and Liver Disease: Exercise caution in patients with obstructive uropathy and liver disease, as dutasteride may have implications for these conditions.

• Blood Donation: Patients should refrain from donating blood for at least six months after the last dutasteride dose, as the drug's effects may impact blood composition.

• PSA Monitoring: Due to a significant reduction (40-50%) in serum PSA levels caused by dutasteride, establish a new baseline PSA after 3-6 months of treatment for accurate assessment.

• Cardiac Monitoring: Regularly monitor patients for cardiac changes or the development of cardiac failure during dutasteride therapy.

• Handling Precautions for Women: Women, especially those who are pregnant or may become pregnant, should avoid taking leaking dutasteride capsules. The drug can be readily absorbed through the skin, posing a risk to a male fetus. In case of contact, wash the affected area immediately with soap and water, based on findings from animal studies suggesting skin absorption.

It is unsafe to consume dutasteride with alcohol.

Avoid use during breastfeeding.

It is not recommended for use during pregnancy.

There are no specific food warnings.

The adverse reactions related to dutasteride can be categorized as

• Common Adverse Effects: Gynecomastia.
• Less Common Adverse Effects: Impotence, decreased libido, ejaculation disorder, breast disorders
• Rare Adverse Effects: Dizziness

Post-marketing experience:

Immune system disorders: Angioedema, localized oedema, severe skin responses, pruritus, urticaria, and hypersensitivity reactions

Neoplasms: Breast cancer in men

Mental health conditions: Depression

Breast diseases and the reproductive system: Testicular swelling and pain

The clinically relevant drug interactions of dutasteride are briefly summarized here.

• Cytochrome P450 3A Inhibitors: In humans, cytochrome P450 (CYP)3A4 and CYP3A5 isoenzymes catalyze the extensive metabolism of dutasteride. There is no research on the impact of strong CYP3A4 inhibitors on dutasteride. Give patients potent, long-term CYP3A4 enzyme inhibitors (such as ritonavir) caution while prescribing dutasteride due to the possibility of drug-drug interactions.
• Adrenergic Antagonists: The steady-state pharmacokinetics of either alpha-adrenergic antagonist are unaffected by the coadministration of dutasteride and tamsulosin or terazosin. It has yet to be determined how tamsulosin or terazosin administration affects the pharmacokinetic characteristics of dutasteride.
• Calcium Channel Antagonists: Dutasteride exposure is enhanced when verapamil or diltiazem are used together because they reduce dutasteride clearance. It is not thought that the variation in dutasteride exposure is clinically significant. It is not advised to change the dosage.
• Cholestyramine: The relative bioavailability of dutasteride is unaffected by administering a 5-mg drug dose, followed by 12 g one hour later.
• Digoxin: When taken concurrently with dutasteride at a dose of 0.5 mg/day for three weeks, there is no change in the steady-state pharmacokinetics of digoxin.
• Warfarin: The steady-state pharmacokinetics of the S- or R-warfarin isomers, as well as the impact of warfarin on prothrombin time, remain unchanged when dutasteride 0.5 mg/day is administered concurrently with warfarin for three weeks.

The most common side effects of dutasteride include:

• Decreased sperm count
• Impotence
• Low sexual desire
• Ejaculation disorder
• Breast enlargement in male
• Breast tenderness in male

• Pregnancy

Pregnancy Category X (FDA): The risks outweigh the potential benefits. Safer alternatives exist.

Not recommended for use in women and in pregnant women as it may cause potential harm to the male fetus.

The medication, a five alpha-reductase inhibitor, stops testosterone from being converted to dihydrotestosterone (DHT), a hormone required for the normal development of male genitalia. Abnormalities in the genitalia of male fetuses are a physiological consequence of this inhibition, and these results are comparable to those seen in male infants who have a genetic five alpha-reductase deficiency.

• Nursing Mothers

It is not recommended for usage in females.

It is unknown if human milk contains Dutasteride excretion.

• Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

Studies on the clinical efficacy of dutasteride only involved participants older than 65. Dutasteride dosage adjustments for older patients are not required, according to the pharmacokinetics of Dutasteride 5 mg. Nevertheless, the effectiveness of dutasteride in older adults has yet to be established.

Dose Adjustment in Kidney Impairment Patients:

Renal impairment: No dosage adjustment is necessary.

Dose Adjustment in Hepatic Impairment Patients:

Hepatic impairment: No dosage adjustment is necessary.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of dutasteride.

Overconsumption of Dutasteride is unknown. There is no specific antidote or treatment for excessive intake of dutasteride. However, immediate medical attention is essential. Dutasteride should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Single-day dosages of dutasteride up to 40 mg (eighty times the therapeutic dose) have been given in volunteer trials without causing any serious safety issues. Over six months, 60 participants in a clinical experiment received daily doses of 5 mg (10 times the therapeutic dose), with no extra side effects beyond those observed at therapeutic levels of 0.5 mg.

Pharmacodynamics:

Effect on 5 Alpha-Dihydrotestosterone and Testosterone

Dihydrotestosterone (DHT) is reduced dose-dependent by daily dosages of dutasteride, which reaches optimum effectiveness in one to two weeks. The median serum DHT concentrations declined by 85% and 90% after taking dutasteride 0.5 mg daily for one and two weeks, respectively. The median drop in blood DHT in individuals with benign prostatic hyperplasia (BPH) treated for four years was 94% at one year, 93% at two years, and 95% at three and four years. The dutasteride group had considerably greater mean prostatic tissue testosterone concentrations than the placebo group. Reduced DHT levels stop BPH development in adult guys with type 2 5 alpha-reductase impairment.

Effects on Other Hormones

Using dutasteride 0.5 mg/day for 52 weeks in a group of healthy volunteers did not result in any significant changes to the levels of follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, estradiol, thyroxine (free T4), dehydroepiandrosterone, or luteinizing hormone when compared to placebo. Thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P <0.05) and total testosterone at 8 weeks (97.1 ng/dL, P <0.003) showed statistically significant baseline-adjusted mean increases compared to placebo. In patients with relevant data, levels of thyroid-stimulating hormone and testosterone reverted to baseline following a 24-week cessation of dutasteride treatment.

Pharmacokinetics:

• Absorption: Dutasteride is absorbed from the gastrointestinal tract, exhibiting an approximate bioavailability of 60%. The time to reach peak plasma concentration is 1-3 hours after administration.

• Distribution: The drug demonstrates high plasma protein binding, exceeding 99.5%, contributing to its efficient distribution throughout the body.

• Metabolism: Dutasteride undergoes hepatic metabolism, primarily mediated by the CYP3A4 and CYP3A5 isoenzymes. This metabolic process is crucial for converting the drug into its metabolites.

• Excretion: The elimination of dutasteride occurs predominantly through the faeces, with 40% excreted as metabolites and approximately 5% as an unchanged drug. Urinary excretion is minimal, constituting less than 1% of unchanged drugs. Dutasteride has a prolonged elimination half-life, lasting approximately 3-5 weeks.

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