Doxazosin - Doxazosin Mesylate tablet

Doxazosin tablets are an alpha₁ adrenergic antagonist indicated for:

• Signs and symptoms of Benign Prostatic Hyperplasia (BPH)
• Treatment of Hypertension

• For the treatment of BPH: Initiate therapy at 1 mg once daily. Dose may be titrated at 1 to 2-week intervals, up to 8 mg once daily. (
  2.2 Benign Prostatic Hyperplasia

  The recommended initial dosage of doxazosin tablets is 1 mg given once daily either in the morning or evening.

  
  
  

  Depending on the individual patient’s urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2 mg, and thereafter to 4 mg and 8 mg once daily. The maximum recommended dose for BPH is 8 mg once daily.

  
  
  

  Routinely monitor blood pressure in these patients.
  )
• For the treatment hypertension: Initiate therapy at 1 mg once daily. Dose may be titrated as needed, up to 16 mg once daily. (
  2.3 Hypertension

  The initial dosage of doxazosin tablets is 1 mg given once daily. Daily dosage may be doubled up 16 mg once daily, as needed, to achieve the desired reduction in blood pressure.
  )

Doxazosin Tablets, USP are available containing doxazosin mesylate, USP equivalent to 1 mg, 2 mg, 4 mg or 8 mg of doxazosin as the free base.

• The 1 mg tablets are a white to off white, round, biconvex tablet debossed with ''D1" on one side and score on the other side of the tablet.
• The 2 mg tablets are a pink, round, biconvex tablet debossed with ''D2" on one side and score on the other side of the tablet.
• The 4 mg tablets are a blue, round, biconvex tablet debossed with ''D4" on one side and score on the other side of the tablet.
• The 8 mg tablets are a purple, round, biconvex tablet debossed with ''D8" on one side and score on the other side of the tablet.

• Hepatic Impairment: Monitor for hypotension. (
  8.6 Hepatic Impairment

  Doxazosin tablets are extensively metabolized in the liver. Hepatic impairment is expected to increase exposure to doxazosin. Use of doxazosin tablets in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. Monitor blood pressure and for symptoms of hypotension in patients with lesser degrees of hepatic impairment (Child-Pugh Class A and B)

  [see Clinical Pharmacology (12.3)]

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  12.3 Pharmacokinetics

  Absorption:

  After oral administration of therapeutic doses, peak plasma levels of doxazosin tablets occur at about 2-3 hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of doxazosin tablets was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration (C_max) and 12% in the area under the concentration-time curve (AUC) occurred when doxazosin tablets were administered with food. Neither of these differences is clinically significant.

  
  
  

  In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The AUC after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 vs. 3.5 hours).

  
  
  

  Distribution:

  At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.

  
  
  

  Metabolism:

  Doxazosin tablets are extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety.

  In vitro

  studies suggest that the primary pathway for elimination is via CYP3A4; however, CYP2D6 and CYP2C9 metabolic pathways are also involved to a lesser extent. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized.

  
  
  

  Excretion:

  Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2 to 16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first-dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations.

  
  
  

  In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug.

  
  
  

  Specific Populations:

  Geriatric:

  The pharmacokinetics of doxazosin tablets in young (< 65 years) and elderly (≥ 65 years) subjects were similar for plasma half-life values and oral clearance.

  
  
  

  Renal Impairment:

  Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function.

  
  
  

  Hepatic Impairment:

  Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. The impact of moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment on the pharmacokinetics of doxazosin is not known

  [see Use in Specific Populations (8.6)]

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  Drug Interactions:

  There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin (e.g., cimetidine).

  
  
  

  Cimetidine:

  In healthy volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and a slight but not significant increase in mean C_maxand mean half-life of doxazosin.

  
  
  

  In vitro

  data in human plasma indicate that doxazosin tablets have no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.
  )

• Postural hypotension with or without syncope may occur. (
  5.1 Postural Hypotension

  Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of doxazosin tablets. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing. As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength. Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop.

  
  
  

  Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.
  )
• Risk of Intraoperative Floppy Iris Syndrome during cataract surgery. (
  5.2 Cataract Surgery

  Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha₁blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha₁blocker therapy prior to cataract surgery.
  )
• Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards. (
  5.3 Prostate Cancer

  Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin tablets for the treatment of BPH.
  )