Overdose
There is no experience with CARDURA XL overdosage.
Overdosage experience with the doxazosin IR is limited. Two adolescents who
each intentionally ingested 40 mg doxazosin IR with diclofenac or paracetamol
were treated with gastric lavage with activated charcoal and made full
recoveries. A two-year-old child who accidentally ingested 4 mg doxazosin IR
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 doxazosin IR and was reported to have been drowsy. A
32-year-old female with chronic renal failure, epilepsy, and depression
intentionally ingested 60 mg doxazosin IR (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
doxazosin IR, alcohol, and Dalmane® (flurazepam) developed hypotension which
responded to fluid therapy. The most likely manifestation of overdosage would
be hypotension, for which the usual treatment would be intravenous infusion of
fluid, keeping the patient in the supine position, and in certain
circumstances, the administration of vasopressors. As doxazosin is highly
protein bound, dialysis would not be indicated.
Undesirable effects
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice.
The incidence of adverse reactions was derived from two
controlled efficacy and safety trials involving 1473 BPH patients. In Study 1,
CARDURA XL (n=317) was compared to doxazosin IR tablets (n=322) and to placebo
(n=156). In Study 2, CARDURA XL (n=350) was compared just to doxazosin IR
tablets (n=330). In both of these studies, CARDURA XL was initiated at a dose
of 4 mg, which could be increased by the investigator to 8 mg after seven weeks
if an adequate response was not seen. Similarly,
doxazosin IR was begun at a dose of 1 mg, which was increased in all patients
to 2 mg after 1 week, followed by the option to increase to 4 mg after 4 weeks,
and 8 mg after 7 weeks.
The most commonly reported adverse reactions leading to
discontinuation in the CARDURA XL group were: dizziness, dyspnea, asthenia,
headache, hypotension, postural hypotension, and somnolence. The rates of
discontinuation for adverse reactions were 6%, 7% and 3% in the CARDURA XL,
doxazosin IR, and placebo groups, respectively.
Table 1 lists the incidence rates of adverse reactions
derived from all reported adverse events in the two controlled studies (Studies
1 and 2) combined, at a rate greater than placebo and in 1% or more of patients
treated with CARDURA XL.
TABLE 1 : Adverse Reactions, Derived from All
Adverse Events Exceeding Placebo Rate and Occurring in ≥ 1% of BPH
Patients Treated with CARDURA XL
| Body System |
CARDURA XL
(N = 666) |
Doxazosin IR
(N = 651) |
Placebo
(N = 156) |
| BODY AS A WHOLE |
| Abdominal Pain |
1.8% |
2.3% |
0.6% |
| Asthenia |
3.9% |
6.9% |
1.3% |
| Headache |
6.0% |
5.1% |
4.5% |
| CARDIOVASCULAR |
| Hypotension |
1.7% |
1.8% |
0.0% |
| Postural Hypotension |
1.2% |
2.2% |
0.6% |
| DIGESTIVE |
| Dyspepsia |
1.4% |
1.2% |
0.0% |
| Nausea |
1.2% |
2.3% |
0.6% |
| MUSCULOSKELETAL |
| Myalgia |
1.4% |
0.5% |
0.0% |
| NERVOUS |
| Dizziness |
5.3% |
9.1% |
1.9% |
| Somnolence |
1.5% |
1.2% |
0.0% |
| Vertigo |
1.5% |
4.1% |
0.6% |
| RESPIRATORY |
| Dyspnea |
1.2% |
1.2% |
0.0% |
| Respiratory Tract Infection |
4.8% |
4.5% |
1.9% |
| UROGENITAL |
| Urinary Tract Infection |
1.4% |
0.8% |
0.6% |
Additional adverse events
reported with CARDURA XL, reported by less than 1% of patients, and those of
clinical interest include: Cardiovascular System: angina pectoris,
syncope, tachycardia, chest pain, palpitations; Digestive System: diarrhea;
Musculoskeletal System: arthralgia; Nervous System: libido
decreased; Urogenital System: impotence, dysuria.
In general, the adverse events
reported in the open-label safety extension, in approximately 295 BPH patients
treated for up to 37 weeks, were similar in type and frequency to the events
described above in the controlled trials.
Postmarketing Experience
The following adverse events
have been identified during post-approval use of doxazosin. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Autonomic Nervous System: priapism; Cardiovascular
System: cerebrovascular accidents, dizziness postural, myocardial
infarction; Central and Peripheral Nervous System: hypoesthesia,
paresthesia; Endocrine System: gynecomastia; Gastrointestinal System:
gastrointestinal obstruction, vomiting; General Body System: fatigue,
hot flushes, malaise; Heart Rate/Rhythm: bradycardia, cardiac
arrhythmias; Hematopoietic: leukopenia, purpura, thrombocytopenia; Liver/Biliary
System: abnormal liver function tests, hepatitis, hepatitis cholestatic,
jaundice; Musculoskeletal System: muscle cramps, muscle weakness; Psychiatric:
agitation, anorexia, nervousness; Respiratory System: bronchospasm
aggravated; Skin Disorders: alopecia, urticaria, skin rash, pruritus; Special
Senses: blurred vision, Intraoperative Floppy Iris Syndrome ; Urinary System: hematuria, micturition disorder,
micturition frequency, nocturia, polyuria.
There have been rare reports of
gastrointestinal irritation and gastrointestinal bleeding with use of another
drug in this non-deformable sustained release formulation, although causal
relationship to the drug is uncertain.
Pharmacodynamic properties
Administration of CARDURA XL to
patients with symptomatic BPH resulted in a statistically significant
improvement in maximum urinary flow rate.
Pharmacokinetic properties
The pharmacokinetics of CARDURA
XL is different from that of doxazosin IR. CARDURA XL provides a controlled
release of doxazosin over a 24-hour period.
Absorption: Pharmacokinetic parameters describing absorption following
4 and 8 mg CARDURA XL daily doses are reported in Table 2 below. The relative
bioavailability of CARDURA XL compared with doxazosin IR was 54% at the 4 mg
dose and 59% for the 8 mg dose.
TABLE 2 : Mean (±SD) Plasma Concentration of
Doxazosin at Steady State in Healthy Volunteers: Pharmacokinetic Parameters
| Parameter |
CARDURA XL (4 mg) |
CARDURA XL (8 mg) |
| Cmax (ng/mL) |
10.1 ± 5.6 |
25.8 ± 12.1 |
| AUC (0 - ∞) |
183 ± 85.5 |
472 ± 170.8 |
| Tmax (h) |
8 ± 3.7 |
9 ± 4.7 |
Food Effect: As illustrated in Figure
1, the plasma C max and AUC were approximately 32% and 18% higher,
respectively, after CARDURA XL was administered in the fed state compared with
the fasted state. In order to provide the most consistent exposure, CARDURA XL
should be administered with breakfast.
Figure 1: Mean (+SD) Plasma
Concentration of Doxazosin Following Single Oral Doses of 8 mg CARDURA XL (Fed
and Fasted)
GI Retention Time Effect: Markedly reduced GI
retention times (e.g., short bowel syndrome) may influence the pharmacokinetics
of CARDURA XL and possibly result in lower plasma concentrations. Conversely,
markedly prolonged GI retention times (e.g., chronic constipation) can increase
systemic exposure to doxazosin and potentially result in increased adverse
reactions.
Distribution: At the plasma
concentrations achieved by therapeutic doses, approximately 98% of the
circulating drug is bound to plasma proteins.
Metabolism: Doxazosin is extensively
metabolized in the liver. In vitro studies suggest that the primary pathway for
elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways
also exist to a lesser extent. No in vivo drug interaction studies have been
performed with CARDURA XL. Although several active metabolites of doxazosin
have been identified, the pharmacokinetics of these metabolites has not been
characterized.
Excretion: In a study of two
subjects administered radiolabeled doxazosin IR 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.
The apparent elimination half-life of CARDURA XL is 15-19 hours.
Date of revision of the text
Feb 2017
Fertility, pregnancy and lactation
Risk Summary
CARDURA XL is not indicated for use in females and is not
indicated for the treatment of hypertension. The limited available data with
CARDURA XL in pregnant women are not sufficient to inform a drug-associated
risk for major birth defects and miscarriage. No adverse developmental outcomes
were observed in animal reproduction studies with oral administration of
doxazosin to pregnant rats and rabbits at doses of up to 10 and 4 times,
respectively, the 12 mg/day recommended dose. Postnatal development was delayed
in rats at a dose of 8 times the 12 mg/day recommended dose.
Data
Animal Data
Radioactivity was found to cross the placenta following
oral administration of labeled doxazosin to pregnant rats. Studies in pregnant
rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively
(plasma drug concentrations of 10 and 4 times, respectively, the human AUC
exposures with a 12 mg/day therapeutic dose), during organogenesis have
revealed no evidence of adverse developmental effects. A dosage regimen of 82
mg/kg/day in the rabbit was associated with reduced fetal survival. In peri-and
postnatal studies in rats, postnatal development at maternal doses of 40 or 50
mg/kg/day of doxazosin (about 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.
Special warnings and precautions for use
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Postural Hypotension
Postural hypotension with or without symptoms (e.g.,
dizziness) may develop within a few hours following administration of CARDURA
XL. 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. Patients should be warned of the possible
occurrence of such events and should avoid situations where injury could result
should syncope occur. Care should be taken when CARDURA XL is administered to
patients with symptomatic hypotension or patients who have had a hypotensive
response to other medications.
Cataract Surgery
Intraoperative Floppy Iris Syndrome (IFIS) has been
observed during cataract surgery in some patients on or previously treated with
alpha 1 blockers. 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 from stopping alpha 1 blocker therapy
prior to cataract surgery.
Gastrointestinal Disorders
As with any other non-deformable material, caution should
be used when administering CARDURA XL to patients with preexisting severe
gastrointestinal narrowing (pathologic or iatrogenic). There have been rare
reports of obstructive symptoms in patients with known strictures in
association with the ingestion of another drug in this non-deformable extended
release formulation. Markedly increased GI retention times, as may occur in
patients with chronic constipation, can increase systemic exposure to doxazosin
and thereby potentially increase adverse reactions.
Prostate Cancer
Carcinoma of the prostate causes many of the same
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 XL.
PDE-5 Inhibitors
Concomitant administration of CARDURA XL with a PDE-5
inhibitor can result in additive blood pressure lowering effects and
symptomatic hypotension. Pharmacodynamic interactions between CARDURA XL and
antihypertensive medications or other vasodilating agents have not been
determined.
Patients With Hepatic Impairment
CARDURA XL is not recommended for patients with severe
hepatic impairment and should be administered with caution to patients with
mild or moderate hepatic impairment.
Patients With Coronary Insufficiency
Patients with congestive heart failure, angina pectoris,
or acute myocardial infarction within the last 6 months were excluded from the
Phase 3 studies. If symptoms of angina pectoris should newly appear or worsen,
CARDURA XL should be discontinued.
CYP 3A4 Inhibitors
Caution should be exercised when concomitantly
administering CARDURA XL with a strong CYP 3A4 inhibitor, such as atanazavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, or voriconazole.
Priapism
Rarely (probably less frequently than once in every
several thousand patients), alpha-1 antagonists, including 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.
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION)
Postural Hypotension
Patients should be told about
the possible occurrence of symptoms related to postural hypotension, such as
dizziness or syncope, when beginning therapy or when increasing dosage strength
of CARDURA XL. Patients should be cautioned about driving, operating machinery,
or performing hazardous tasks during this period, until the drug's effect has
been determined.
Priapism
Inform the patient about the
possibility of priapism as a result of treatment with CARDURA XL extended
release tablets and other similar medications. Patients should be informed that
this reaction is extremely rare, but if not brought to immediate medical
attention, can lead to permanent erectile dysfunction.
Tablet Administration
Patients should be informed
that CARDURA XL extended release tablets should be swallowed whole. Patients
should not chew, divide, cut, or crush tablets.
Dosing Interval
CARDURA XL should be taken each
day with breakfast.
Tablet Elimination
Patients should not be
concerned if they occasionally notice in their stool something that looks like
a tablet. In the CARDURA XL extended release tablet, the medication is
contained within a nonabsorbable shell designed to release the drug at a
controlled rate. When this process is completed, the empty tablet is eliminated
from the body.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis And Mutagenesis
Doxazosin mesylate was not carcinogenic to rats or mice
when administered daily for 2 years at doses up to 40 mg/kg/day or 120
mg/kg/day, respectively. Systemic drug exposures, as measured by AUC, were
approximately 34fold in rats and 16-fold in mice above the exposures at the
maximum human recommended dose (MHRD) of 8 mg CARDURA XL.
Doxazosin base was not mutagenic in the in vitro bacterial
Ames assays, the chromosomal aberration assay in human lymphocytes, or the
mouse lymphoma assay. Doxazosin was not clastogenic in the in vivo mouse
micronucleus assay. Doxazosin mesylate has not been evaluated for genotoxicity.
Fertility In Males
Studies in rats after oral administration of doxazosin
base showed reduced fertility in males, which was reversible after two weeks of
treatment termination at doxazosin base exposure of 13-fold above the human
exposure (AUC) at the MHRD of 8 mg CARDURA XL. There have been no reports of
any effects of doxazosin on male fertility in humans.
Use In Specific Populations
Pregnancy
Risk Summary
CARDURA XL is not indicated for use in females and is not
indicated for the treatment of hypertension. The limited available data with
CARDURA XL in pregnant women are not sufficient to inform a drug-associated
risk for major birth defects and miscarriage. No adverse developmental outcomes
were observed in animal reproduction studies with oral administration of
doxazosin to pregnant rats and rabbits at doses of up to 10 and 4 times,
respectively, the 12 mg/day recommended dose. Postnatal development was delayed
in rats at a dose of 8 times the 12 mg/day recommended dose.
Data
Animal Data
Radioactivity was found to cross the placenta following
oral administration of labeled doxazosin to pregnant rats. Studies in pregnant
rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively
(plasma drug concentrations of 10 and 4 times, respectively, the human AUC
exposures with a 12 mg/day therapeutic dose), during organogenesis have
revealed no evidence of adverse developmental effects. A dosage regimen of 82
mg/kg/day in the rabbit was associated with reduced fetal survival. In peri-and
postnatal studies in rats, postnatal development at maternal doses of 40 or 50
mg/kg/day of doxazosin (about 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.
Lactation
Risk Summary
CARDURA XL is not indicated for use in females and is not
indicated for the treatment of hypertension. Doxazosin is present in human milk.
There is no information on the effects of CARDURA XL on the breastfeed infant
or the effects on milk production.
Pediatric Use
The safety and effectiveness of CARDURA XL in pediatric
patients have not been established.
Geriatric Use
The incidence of hypotension with CARDURA XL use appears
to be age related and more prevalent in patients 70 years or older. At steady
state, increases of 27% in maximum plasma concentrations (C max ) and 34% in
the area under the concentration-time curve (AUC) were seen in the elderly
( > 65 years old) compared to the young.
Of the 666 patients with BPH who received CARDURA XL in
the two controlled clinical efficacy and safety studies, 325 patients (49%) were
65 years of age or older. One hundred thirty-six patients treated with CARDURA
XL (20%) were > 70 years of age. In these two studies, the cumulative
incidence of hypotension appeared to be age related. The reason for an
increased incidence of hypotension in patients older than 70 years of age may
be related to a modest increase in systemic exposure to doxazosin , to an increased propensity to orthostasis in the elderly, or
to an enhanced sensitivity to vasodilatory agents in the elderly. The incidence
of hypotension reported as an adverse reaction was higher in patients 70 years
of age and older (4/136; 2.9%) as compared to patients < 70 years of age
(7/530; 1.3%).
Hepatic Impairment
Since there is no clinical experience in patients with
severe hepatic impairment, use in these patients is not recommended. CARDURA XL
should be administered with caution to patients with mild or moderate hepatic
impairment.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice.
The incidence of adverse reactions was derived from two
controlled efficacy and safety trials involving 1473 BPH patients. In Study 1,
CARDURA XL (n=317) was compared to doxazosin IR tablets (n=322) and to placebo
(n=156). In Study 2, CARDURA XL (n=350) was compared just to doxazosin IR
tablets (n=330). In both of these studies, CARDURA XL was initiated at a dose
of 4 mg, which could be increased by the investigator to 8 mg after seven weeks
if an adequate response was not seen. Similarly,
doxazosin IR was begun at a dose of 1 mg, which was increased in all patients
to 2 mg after 1 week, followed by the option to increase to 4 mg after 4 weeks,
and 8 mg after 7 weeks.
The most commonly reported adverse reactions leading to
discontinuation in the CARDURA XL group were: dizziness, dyspnea, asthenia,
headache, hypotension, postural hypotension, and somnolence. The rates of
discontinuation for adverse reactions were 6%, 7% and 3% in the CARDURA XL,
doxazosin IR, and placebo groups, respectively.
Table 1 lists the incidence rates of adverse reactions
derived from all reported adverse events in the two controlled studies (Studies
1 and 2) combined, at a rate greater than placebo and in 1% or more of patients
treated with CARDURA XL.
TABLE 1 : Adverse Reactions, Derived from All
Adverse Events Exceeding Placebo Rate and Occurring in ≥ 1% of BPH
Patients Treated with CARDURA XL
| Body System |
CARDURA XL
(N = 666) |
Doxazosin IR
(N = 651) |
Placebo
(N = 156) |
| BODY AS A WHOLE |
| Abdominal Pain |
1.8% |
2.3% |
0.6% |
| Asthenia |
3.9% |
6.9% |
1.3% |
| Headache |
6.0% |
5.1% |
4.5% |
| CARDIOVASCULAR |
| Hypotension |
1.7% |
1.8% |
0.0% |
| Postural Hypotension |
1.2% |
2.2% |
0.6% |
| DIGESTIVE |
| Dyspepsia |
1.4% |
1.2% |
0.0% |
| Nausea |
1.2% |
2.3% |
0.6% |
| MUSCULOSKELETAL |
| Myalgia |
1.4% |
0.5% |
0.0% |
| NERVOUS |
| Dizziness |
5.3% |
9.1% |
1.9% |
| Somnolence |
1.5% |
1.2% |
0.0% |
| Vertigo |
1.5% |
4.1% |
0.6% |
| RESPIRATORY |
| Dyspnea |
1.2% |
1.2% |
0.0% |
| Respiratory Tract Infection |
4.8% |
4.5% |
1.9% |
| UROGENITAL |
| Urinary Tract Infection |
1.4% |
0.8% |
0.6% |
Additional adverse events
reported with CARDURA XL, reported by less than 1% of patients, and those of
clinical interest include: Cardiovascular System: angina pectoris,
syncope, tachycardia, chest pain, palpitations; Digestive System: diarrhea;
Musculoskeletal System: arthralgia; Nervous System: libido
decreased; Urogenital System: impotence, dysuria.
In general, the adverse events
reported in the open-label safety extension, in approximately 295 BPH patients
treated for up to 37 weeks, were similar in type and frequency to the events
described above in the controlled trials.
Postmarketing Experience
The following adverse events
have been identified during post-approval use of doxazosin. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Autonomic Nervous System: priapism; Cardiovascular
System: cerebrovascular accidents, dizziness postural, myocardial
infarction; Central and Peripheral Nervous System: hypoesthesia,
paresthesia; Endocrine System: gynecomastia; Gastrointestinal System:
gastrointestinal obstruction, vomiting; General Body System: fatigue,
hot flushes, malaise; Heart Rate/Rhythm: bradycardia, cardiac
arrhythmias; Hematopoietic: leukopenia, purpura, thrombocytopenia; Liver/Biliary
System: abnormal liver function tests, hepatitis, hepatitis cholestatic,
jaundice; Musculoskeletal System: muscle cramps, muscle weakness; Psychiatric:
agitation, anorexia, nervousness; Respiratory System: bronchospasm
aggravated; Skin Disorders: alopecia, urticaria, skin rash, pruritus; Special
Senses: blurred vision, Intraoperative Floppy Iris Syndrome ; Urinary System: hematuria, micturition disorder,
micturition frequency, nocturia, polyuria.
There have been rare reports of
gastrointestinal irritation and gastrointestinal bleeding with use of another
drug in this non-deformable sustained release formulation, although causal
relationship to the drug is uncertain.
DRUG INTERACTIONS
CYP 3A4 Inhibitors
No in vivo drug interaction studies were conducted with
CARDURA XL.
In vitro studies suggest that doxazosin is a substrate of
CYP 3A4. Caution should be exercised when concomitantly administering CARDURA
XL with a strong CYP 3A4 inhibitor, such as atanazavir, clarithromycin,
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, telithromycin, or voriconazole.
Antihypertensive Medications
Pharmacodynamic interactions between CARDURA XL and
antihypertensive medications or other vasodilating agents have not been determined.
PDE-5 Inhibitors
Concomitant administration of CARDURA XL with a PDE-5
inhibitor can result in additive blood pressure lowering effects and
symptomatic hypotension.