Pfizer Inc.
Composition of the medicinal product:
Pharmacological properties
Pharmacodynamics. Doxazosin is a potent and selective antagonist of postsynaptic α 1 -adrenoreceptors. Blockade of these receptors leads to a decrease in systemic blood pressure. Cardura is intended for oral administration once daily in patients with hypertension.
Cardura has been shown to have no adverse metabolic effects and can be used in patients with diabetes, gout, or insulin resistance.
Cardura can also be prescribed to patients with asthma, left ventricular hypertrophy and the elderly. The use of the drug helps to reduce left ventricular hypertrophy, inhibits platelet aggregation and enhances the activity of tissue plasminogen activator. In addition, the use of Cardura increases insulin sensitivity in those patients in whom such sensitivity is impaired.
Also, long-term studies have demonstrated that, in addition to its antihypertensive effect, the use of Cardura causes a moderate decrease in the concentration of total cholesterol, LDL, and TG in blood plasma, and therefore this drug may be particularly useful for patients with hypertension and hyperlipidemia.
The use of Cardura in patients with benign prostatic hyperplasia (BPH) leads to a significant improvement in urodynamics and a decrease in the severity of symptoms. It is believed that the effect of the drug in BPH is achieved by selective blockade of α 1 -adrenoreceptors located in the muscular stroma and capsule of the prostate gland, as well as in the bladder neck.
Pharmacokinetics
Absorption: When administered orally to humans (young males or elderly individuals of either sex), doxazosin is rapidly absorbed with a bioavailability of approximately ⅔ of the dose.
Biotransformation/Elimination: Approximately 98% of doxazosin is bound to plasma proteins. Doxazosin has been shown to be extensively metabolized in humans and in experimental animals and is excreted primarily in the feces.
The average T ½ of the drug from blood plasma is 22 hours, which allows taking the drug once a day.
When Cardura is administered orally, the plasma concentrations of its metabolites are low. The plasma concentration of the most active metabolite, 6'-hydroxydoxazosin, in humans is 40 times lower than the plasma concentration of the parent compound, indicating that the antihypertensive effect of the drug is primarily due to doxazosin.
To date, there are only limited data on the use of the drug in patients with impaired liver function and on the effect of drugs that can alter hepatic metabolism (e.g. cimetidine). In a clinical study involving 12 patients with moderate hepatic dysfunction, a single dose of doxazosin resulted in a 43% increase in AUC and a 40% decrease in apparent oral clearance. As with other drugs that are completely metabolized by the liver, Cardura should be used with caution in patients with evidence of impaired liver function.
Indication
AG
The drug is indicated for the treatment of hypertension and can be used as monotherapy for the control of blood pressure in most patients. In case of ineffectiveness of monotherapy for the treatment of patients with hypertension, the drug can be used in combination with thiazide diuretics, β-adrenoceptor blockers, calcium channel blockers and ACE inhibitors.
BPH
The drug is indicated for the treatment of urinary tract obstruction, as well as symptoms associated with BPH. The drug can be prescribed to patients with BPH both in the presence of hypertension and with normal blood pressure levels.
Cardura can be taken both in the morning and in the evening.
AG
The drug should be used once a day. The initial dose is 1 mg to minimize the risk of orthostatic hypotension and/or syncope. After 1-2 weeks of initial therapy, the dose can be increased to 2 mg, and then, if necessary, to 4 mg. In most patients, the response to therapy is observed when using the drug in a dose of ≤4 mg. If necessary, the dose of the drug can be increased to 8 mg or to the maximum recommended dose of 16 mg.
BPH
The recommended initial dose of Cardura is 1 mg once daily to minimize the risk of orthostatic hypotension and/or syncope. Depending on the individual patient's urodynamics and symptoms of BPH, the dose may be increased to 2 mg, then to 4 mg and to the maximum recommended dose of 8 mg. The recommended dose adjustment interval is 1-2 weeks. The usual recommended dose is 2-4 mg/day.
Elderly patients should use the usual adult doses.
Patients with renal impairment should use the usual adult doses, as the pharmacokinetic parameters of the drug do not change in renal impairment.
Cardura is not removed from the body by hemodialysis.
Patients with hepatic impairment. To date, information on the use of the drug in patients with hepatic impairment and on the effects of drugs that can alter hepatic metabolism (e.g. cimetidine) is limited. As with other drugs that are completely metabolized by the liver, the drug should be administered with caution to patients with signs of hepatic impairment.
Contraindication:
The use of Cardura is contraindicated in the following categories of patients:
with hypersensitivity to quinazoline derivatives (e.g. prazosin, terazosin, doxazosin) or to any of the excipients of the drug; with a history of orthostatic hypotension; with BPH and concomitant upper urinary tract obstruction, chronic urinary tract infections and the presence of bladder stones; with arterial hypotension (applies only to patients with BPH).
Doxazosin as monotherapy is contraindicated in patients with bladder overactivity or anuria with or without progressive renal insufficiency.
SIDE EFFECTS:
AG
In clinical studies involving patients with hypertension, the most frequently observed adverse reactions were postural (which in some cases were accompanied by loss of consciousness) or nonspecific adverse reactions.
BPH
According to controlled clinical studies, patients with BPH had the same adverse reaction profile as patients with hypertension.
The following classification is used to assess the frequency of side effects: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and frequency unknown (cannot be estimated from the available data).
MedDRA System Organ Class frequency adverse reactions
| Infections and infestations | often | Respiratory tract infections, urinary tract infections |
| Blood and lymphatic system disorders | Very rare | Leukopenia, thrombocytopenia |
| Immune system disorders | Not often | allergic reactions |
| Metabolic and nutritional disorders | Not often | Gout, increased or lack of appetite |
| mental disorders | Not often | Disorders, depression, anxiety, insomnia, nervousness |
| Nervous system disorders | often | Drowsiness, dizziness, headache |
| Not often | Stroke, hypoesthesia, syncope, tremor |
| Very rare | Orthostatic dizziness, paresthesia |
| Disorders of the organ of vision | Very rare | blurred vision |
frequency
unknown | Intraoperative atonic iris syndrome |
| Hearing and balance disorders | often | vertigo |
| Not often | Tinnitus |
| Heart disorders | often | Increased heartbeat, tachycardia |
| Not often | Angina pectoris, myocardial infarction |
| Very rare | Bradycardia, cardiac arrhythmia |
| Vascular disorders | often | Arterial hypotension, orthostatic hypotension |
| Very rare | tides |
| Respiratory, thoracic and mediastinal disorders | often | Bronchitis, cough, shortness of breath, rhinitis |
| Not often | Nosebleed |
| Very rare | Exacerbation of existing bronchospasm |
| Gastrointestinal disorders | often | Abdominal pain, dyspepsia, dry mouth, nausea |
| Not often | Constipation, flatulence, vomiting, gastroenteritis, diarrhea |
| Hepatobiliary disorders | Not often | Abnormal liver function tests |
| Very rare | Cholestasis, hepatitis, jaundice |
| Skin and subcutaneous tissue disorders | often | itch |
| Not often | skin rash |
| Very rare | Urticaria, alopecia, purpura |
| often | Back pain, muscle pain |
| Not often | arthralgia |
| rarely | Muscle spasms, muscle weakness |
| Kidney and urinary tract disorders | often | Cystitis, urinary incontinence |
| Not often | Dysuria, frequent urination, hematuria |
| rarely | polyuria |
| Very rare | Increased diuresis, urination disorders, nocturia |
| Reproductive system and mammary gland disorders | Not often | impotence |
| Very rare | Gynecomastia, priapism |
| frequency unknown | retrograde ejaculation |
| General disorders and administration site conditions | often | Asthenia, chest pain, influenza-like symptoms, peripheral edema |
| Not often | Body pain, facial swelling |
| Very rare | Increased fatigue, general malaise |
| Research results | Not often | Weight gain |
|
SPECIAL INSTRUCTIONS:
Use in liver dysfunction
As with other drugs that are completely metabolized by the liver, Cardura should be administered with caution to patients with signs of impaired liver function. Due to the lack of clinical experience with the drug in patients with severe hepatic insufficiency, the drug is not recommended for use in this category of patients.
Use with PDE-5 inhibitors
Doxazosin should be used with caution in combination with PDE5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) as these medicinal products cause vasodilation and may therefore cause symptomatic hypotension in some patients. To reduce the risk of orthostatic hypotension, it is recommended to start treatment with phosphodiesterase-5 inhibitors only if the patient is haemodynamically stable on α-adrenoceptor blockers. It is also recommended to start treatment with phosphodiesterase-5 inhibitors at the lowest possible dose and to maintain a 6-hour interval between the administration of doxazosin and phosphodiesterase-5 inhibitors. Doxazosin has not been studied in prolonged-release formulations.
Use in patients undergoing cataract surgery
Some patients who received tamsulosin during or before cataract surgery developed intraoperative atonic iris syndrome (IFIS, a variant of small pupil syndrome) during the procedure. Isolated cases of this side effect have also been reported with other α1-adrenergic blockers, so the possibility of this effect with other drugs of this class cannot be excluded. Since IFIS may lead to an increased incidence of procedural complications during surgery, ophthalmic surgeons should be informed in preparation for surgery whether the patient is taking or has taken α1-adrenergic blockers.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency and glucose-galactose malabsorption should not take this medicine.
Use during pregnancy and breastfeeding
Patients with hypertension
Due to the lack of adequate and well-controlled studies in pregnant women, the safety of Cardura during pregnancy remains unknown. Therefore, the drug should be used only if the potential benefit justifies the potential risk in the physician's judgment. Although the drug was not teratogenic in animal studies, its use at very high doses, approximately 300 times the maximum recommended human dose, resulted in reduced fetal survival.
Doxazosin is contraindicated during breastfeeding, as animal studies have shown that doxazosin accumulates in the milk of lactating rats, and as there are no data on the excretion of doxazosin into milk during lactation in humans. If doxazosin is necessary, breastfeeding should be discontinued.
Children: There is no experience with the use of Cardura in children.
Ability to influence the reaction rate when driving vehicles or operating machinery. The ability to drive a car and operate potentially dangerous machinery may be reduced, especially at the beginning of treatment with doxazosin.
Interaction with other drugs
Use with PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil)
Concomitant use of doxazosin with PDE-5 inhibitors may cause symptomatic hypotension in some patients. Doxazosin prolonged-release formulations have not been studied.
Doxazosin is highly bound to plasma proteins (98%). In vitro studies using human plasma indicate that the drug does not affect the protein binding of the test drugs (digoxin, phenytoin, warfarin or indomethacin).
No adverse interactions have been observed with the concomitant use of doxazosin and thiazide diuretics, furosemide, β-adrenergic blockers, nonsteroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs, uricosuric drugs, and anticoagulants. However, there are no formal drug interaction studies.
Doxazosin potentiates the hypotensive effect of other α-adrenergic blockers, as well as other antihypertensive drugs.
In an open-label, randomized, placebo-controlled clinical study in 22 healthy male volunteers, a single dose of 1 mg doxazosin on day 1 (4 days) of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean doxazosin AUC and no statistically significant changes in mean Cmax or mean T½ of doxazosin. This 10% increase in mean doxazosin AUC with cimetidine is within the range of interindividual variability (27%) in mean doxazosin AUC compared to placebo.
If an overdose causes hypotension, the patient should be immediately placed in the supine position with the head down. Other symptomatic measures may be taken if necessary.
If symptomatic therapy is not sufficient, shock should be treated primarily with plasma substitutes. Then, if necessary, vasoconstrictors should be used. Renal function should be monitored and supportive therapy should be used if necessary.
Hemodialysis is not indicated because Cardura is extensively bound to plasma proteins.
STORAGE CONDITIONS:
at temperatures up to 30 °C.
