Avodart

Avodart Uses, Dosage, Side Effects, Food Interaction and all others data.

Avodart is a dual inhibitor of 5α-reductase. It inhibits both type 1 and type 2, 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.

Avodart is a synthetic 4-azasteroid compound that selectively inhibits both the type I and type II isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT). Avodart works by reducing the levels of circulating DHT. It was also shown to reduce the size of the prostate gland, improve urinary flow, and symptoms of benign prostatic hyperplasia alone or in combination with tamsulosin. The effect of the reduction of DHT by dutasteride is dose-dependent, with the maximum effect observed within 1-2 weeks following initial administration.

After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. The serum concentrations of DHT were maintained to be decreased by more than 90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. As evident from the clinical studies, dutasteride may also cause decreases in serum PSA in the presence of prostate cancer.

Trade Name Avodart
Availability Prescription only
Generic Dutasteride
Dutasteride Other Names Dutasterida, Dutasteride
Related Drugs tamsulosin, finasteride, Flomax, prazosin, tadalafil, Cialis
Weight 0.5mg,
Type Capsule, Capsule*, Oral Capsule
Formula C27H30F6N2O2
Weight Average: 528.5297
Monoisotopic: 528.221147444
Protein binding

Dutasteride is about 99% bound to albumin and 96.6% bound to α-1 acid glycoprotein in the serum.

Groups Approved, Investigational
Therapeutic Class BPH/ Urinary retention/ Urinary incontinence
Manufacturer Glaxosmithkline, Glaxosmithkline Uk, Glaxo Saudi Arabia
Available Country Pakistan, United Kingdom, Canada, Australia, Saudi Arabia, United States, Netherlands, Switzerland,
Last Updated: September 19, 2023 at 7:00 am
Avodart
Avodart

Uses

Avodart is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

  • Improve symptoms
  • Reduce the risk of acute urinary retention
  • Reduce the risk of the need for BPH-related surgery

Avodart is also used to associated treatment for these conditions: Benign Prostatic Hyperplasia (BPH), Symptomatic Benign Prostatic Hyperplasia

How Avodart works

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

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

Dosage

Avodart dosage

The recommended dose is Avodart 0.5 mgorally once daily. The capsules should be swallowed whole. Avodart may be administered with or without food.

Side Effects

  • Sexual problems (such as decreased sexual interest/ ability, decrease in the amount of semen/ sperm released during sex)
  • Impotence (trouble getting or keeping an erection)
  • Testicle pain or swelling
  • Increased breast size
  • Breast tenderness.

Toxicity

LD50 values

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

Overdose

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

Nonclinical Toxicology

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

Pregnancy and Lactation

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

Precaution

Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with Avodart. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5 a-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy. Blood Donation: Men being treated with Avodart should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of Avodart to a pregnant female transfusion recipient.

Interaction

Care should be taken when administering Avodart to patients taking potent, chronic CYP3A4 inhibitors. Avodart does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/ml, 25 times greater than steady-state serum concentrations in humans. In vitro studies demonstrate that Avodart does not displace Warfarin, Diazepam, or Phenytoin from plasma protein binding sites, nor do these model compounds displace Avodart.

Food Interaction

  • Take with or without food. The absorption is unaffected by food.

Avodart Disease Interaction

Moderate: liver disease

Volume of Distribution

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

Elimination Route

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

Half Life

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

Clearance

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

Elimination Route

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

Pregnancy & Breastfeeding use

Pregnancy Category X. Avodart is contraindicated for use in women.

Contraindication

Avodart is contra-indicated for use in women and children and for patients with known hypersensitivity to Avodart, and other 5 a-reductase inhibitors. Warnings: Exposure of women-risk to male fetus: Avodart is absorbed through the skin. Therefore, women who are pregnant or may be pregnant should not handle Avodart capsules because of the possibility of absorption of Avodart and the potential risk of a fetal anomaly to a male fetus. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Special Warning

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

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

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

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

Acute Overdose

In volunteer studies, single doses of Avodart up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical study, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for Avodart. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of Avodart into consideration.

Storage Condition

Store in a cool and dry place, protected from light

Innovators Monograph

You find simplified version here Avodart

Avodart contains Dutasteride see full prescribing information from innovator Avodart Monograph, Avodart MSDS, Avodart FDA label

*** Taking medicines without doctor's advice can cause long-term problems.
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