CARDURA® (doxazosin mesylate) is a quinazoline compound that is a selective inhibitor of the alpha 1 subtype of alpha adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C 23 H 25 N 5 O 5 · CH 4 O 3 S and the molecular weight is 547.6. It has the following structure:
CARDURA® (doxazosin mesylate) is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. CARDURA® is available as colored tablets for oral use and contains 1 mg (white), 2 mg (yellow), 4 mg (orange) and 8 mg (green) of doxazosin as the free base.
The inactive ingredients for all tablets are: microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate and sodium lauryl sulfate. The 2 mg tablet contains D & C yellow 10 and FD & C yellow 6; the 4 mg tablet contains FD & C yellow 6; the 8 mg tablet contains FD & C blue 10 and D & C yellow 10.
After oral administration of therapeutic doses, peak plasma levels of CARDURA® (doxazosin mesylate) 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 CARDURA® was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when CARDURA® was administered with food. Neither of these differences was statistically or clinically significant.
CARDURA® is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. 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. At the plasma concentrations achieved by therapeutic doses approximately 98% of the circulating drug is bound to plasma proteins.
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 2-16 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 crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve 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 hr vs. 3.5 hr).
The pharmacokinetics of CARDURA® (doxazosin mesylate) in young (<65 years) and elderly (>/=65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin [e.g., cimetidine (see PRECAUTIONS )]. As with any drug wholly metabolized by the liver, use of CARDURA® in patients with altered liver function should be undertaken with caution.
In two placebo-controlled studies, of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of CARDURA® were similar in the two populations. Linear kinetics and dose proportionality were observed.
CARDURA® is contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin).
Syncope and "First-dose" Effect: Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and 8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATION section) with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agents should be added with caution.
Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night.
In an early investigational study of the safety and tolerance of increasing daily doses of doxazosin in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. In this study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosin dosing at 1 mg/day resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope.
In multiple dose clinical trials in hypertension involving over 1500 hypertensive patients with dose titration every one to two weeks, syncope was reported in 0.7% of patients. None of these events occurred at the starting dose of 1 mg and 1.2% (8/664) occurred at 16 mg/day.
In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients were taking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient was taking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced syncope.
If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.
Priapism Rarely (probably less frequently than once in every several thousand patients), alpha 1 antagonists such as doxazosin have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS : Information for Patients ).
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 CARDURA®.
Orthostatic Hypotension: While syncope is the most severe orthostatic effect of CARDURA®, other symptoms of lowered blood pressure, such as dizziness, lightheadedness, or vertigo can occur, especially at initiation of therapy or at the time of dose increases.
Information for Patients (See Patient Package Insert): Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur during initiation of doxazosin therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered. Patients should also be told that drowsiness or somnolence can occur with CARDURA® (doxazosin mesylate) or any selective alpha 1 adrenoceptor antagonist, requiring caution in people who must drive or operate heavy machinery.
Patients should be advised about the possibility of priapism as a result of treatment with alpha 1 antagonists. Patients should know that this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for if not treated promptly it can lead to permanent erectile dysfunction (impotence).
Drug/Laboratory Test Interactions: CARDURA® does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. Both doxazosin, an alpha 1 inhibitor, and finasteride, a 5-alpha reductase inhibitor, are highly protein bound and hepatically metabolized. There is no definitive controlled clinical experience on the concomitant use of alpha 1 inhibitors and 5-alpha reductase inhibitors at this time.
Impaired Liver Function: CARDURA® should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism (see ).
Leukopenia/Neutropenia: Analysis of hematologic data from hypertensive patients receiving CARDURA® in controlled hypertension clinical trials showed that the mean WBC (N=474) and mean neutrophil counts (N=419) were decreased by 2.4% and 1.0%, respectively, compared to placebo, a phenomenon seen with other alpha blocking drugs. In BPH patients the incidence of clinically significant WBC abnormalities was 0.4% (2/459) with CARDURA® and 0% (0/147) with placebo, with no statistically significant difference between the two treatment groups. A search through a data base of 2400 hypertensive patients and 665 BPH patients revealed 4 hypertensives in which drug-related neutropenia could not be ruled out and one BPH patient in which drug related leukopenia could not be ruled out. Two hypertensives had a single low value on the last day of treatment. Two hypertensives had stable, non-progressive neutrophil counts in the 1000/mm 3 range over periods of 20 and 40 weeks. One BPH patient had a decrease from a WBC count of 4800/mm 3 to 2700/mm 3 at the end of the study; there was no evidence of clinical impairment. In cases where follow-up was available the WBCs and neutrophil counts returned to normal after discontinuation of CARDURA®. No patients became symptomatic as a result of the low WBC or neutrophil counts.
Drug Interactions: Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that CARDURA® has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding. CARDURA® has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal 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 (p=0.006), and a slight but not statistically significant increase in mean C max and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown.
In clinical trials, CARDURA® tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. CARDURA® tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies.
Cardiac Toxicity in Animals: An increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated to provide 80 mg doxazosin/kg/day and after 12 months of dietary administration at concentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times the human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human C max exposure in mice). No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species. These lesions were not observed after 12 months of oral dosing in dogs at maximum doses of 20 mg/kg/day [maximum plasma concentrations (C max ) in dogs 14 times the C max exposure in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day (C max exposures 15 times human C max exposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions occur in humans.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day.
Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.
Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
Pregnancy Teratogenic Effects, Pregnancy Category C. Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4 times human C max and AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of harm to the fetus. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CARDURA® should be used during pregnancy only if clearly needed.
Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.
Nonteratogenic Effects. In peri-postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes.
Nursing Mothers: Studies in lactating rats given a single oral dose of 1 mg/kg of [2- 14 C]-CARDURA® indicate that doxazosin accumulates in rat breast milk with a maximum concentration about 20 times greater than the maternal plasma concentration. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CARDURA® is administered to a nursing mother.
Pediatric Use: The safety and effectiveness of CARDURA® as an antihypertensive agent have not been established in children.
Use in Elderly: The safety and effectiveness profile of CARDURA® in BPH was similar in the elderly (age >/=65 years) and younger (age <65 years) patients.
Experience with CARDURA® overdosage is limited. Two adolescents who each intentionally ingested 40 mg CARDURA® with diclofenac or paracetamol, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidently ingested 4 mg CARDURA® was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of CARDURA® and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy and depression intentionally ingested 60 mg CARDURA® (blood level 0.9 µg/mL; normal values in hypertensives=0.02 µg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg CARDURA®, alcohol and Dalmane® (flurazepam) developed hypotension which responded to fluid therapy.
The oral LD 50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated.
DOSAGE MUST BE INDIVIDUALIZED. The initial dosage of CARDURA® in patients with hypertension and/or BPH is 1 mg given once daily in the a.m. or p.m. This starting dose is intended to minimize the frequency of postural hypotension and first dose syncope associated with CARDURA®. Postural effects are most likely to occur between 2 and 6 hours after a dose. Therefore blood pressure measurements should be taken during this time period after the first dose and with each increase in dose. If CARDURA® administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.
CARDURA® (doxazosin mesylate) is available as colored tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 1 mg (white), 2 mg (yellow), 4 mg (orange) or 8 mg (green) of the active constituent, doxazosin.
CARDURA® TABLETS (doxazosin mesylate) are available as 1 mg (white), 2 mg (yellow), 4 mg (orange) and 8 mg (green) scored tablets.
Bottles of 100: 1 mg (NDC 0049-2750-66)
2 mg (NDC 0049-2760-66)
4 mg (NDC 0049-2770-66)
8 mg (NDC 0049-2780-66)
Unit Dose Packages of 100: 1 mg (NDC 0049-2750-41)
2 mg (NDC 0049-2760-41)
4 mg (NDC 0049-2770-41)
8 mg (NDC 0049-2780-41)
Recommended Storage: Store below 86°F (30°C).
CAUTION: Federal law prohibits dispensing without prescription.
©1997 PFIZER INC
70-4538-00-6 Revised June 1997
FOR BENIGN PROSTATIC HYPERPLASIA (BPH)
Read this leaflet:
You and your doctor should discuss this treatment and your BPH symptoms before you start taking CARDURA® and at your regular checkups. This leaflet does NOT take the place of discussions with your doctor.
CARDURA® is used to treat both benign prostatic hyperplasia (BPH) and high blood pressure (hypertension). This leaflet describes CARDURA® as treatment for BPH (although you may be taking CARDURA® for both your BPH and high blood pressure).
BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine from the bladder. The symptoms of BPH can be caused by a tensing of the enlarged muscle in the prostate gland which blocks the passage of urine. This can lead to such symptoms as:
The four main treatment options for BPH are:
CARDURA® works on a specific type of muscle found in the prostate, causing it to relax. This in turn decreases the pressure within the prostate, thus improving the flow of urine and your symptoms.
CARDURA® Can Cause a Sudden Drop in Blood Pressure After the VERY FIRST DOSE. You may feel dizzy, faint or "light-headed," especially after you stand up from a lying or sitting position. This is more likely to occur after you've taken the first few doses or if you increase your dose, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then restart treatment. If you feel very dizzy, faint or "light-headed" you should contact your doctor. Your doctor will discuss with you how often you need to visit and how often your blood pressure should be checked.
Your blood pressure should be checked when you start taking CARDURA® even if you do not have high blood pressure (hypertension). Your doctor will discuss with you the details of how blood pressure is measured.
Blood Pressure Measurement: Whatever equipment is used, it is usual for your blood pressure to be measured in the following way: measure your blood pressure after lying quietly on your back for five minutes. Then, after standing for two minutes measure your blood pressure again. Your doctor will discuss with you what other times during the day your blood pressure should be taken, such as two to six hours after a dose, before bedtime or after waking up in the morning. Note that moderate to high-intensity exercise can, over a period of time, lower your average blood pressure.
You can take CARDURA® either in the morning or at bedtime and it will be equally effective. If you take CARDURA® at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medication affects you. It is important to get up slowly from a chair or bed at any time until you learn how you react to CARDURA®. You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better.
FOR MORE INFORMATION ABOUT CARDURA® AND BPH TALK WITH YOUR DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER.
©1997 PFIZER INC
Revised May 1997