Doxalfa

- Essential hypertension

- Symptomatic treatment of benign prostatic hyperplasia.

The tablets can be taken with or without food. The tablets must be swallowed whole with a sufficient amount of liquid. The tablets should not be chewed, divided or crushed.

The maximum recommended dose is 8 mg Doxalfa once daily.

Essential hypertension:

Adults: Usually 4 mg Doxalfa once daily. If necessary, the dosage may be increased to 8 mg Doxalfa once daily.

Doxalfa can be used as sole agent or in combination with another medicinal product e.g. a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an ACE-inhibitor.

Symptomatic treatment of prostatic hyperplasia:

Adults: Usually 4 mg Doxalfa once daily. If necessary, the dosage may be increased to 8 mg Doxalfa once daily.

Doxalfa may be used in benign prostatic hyperplasia (BPH) patients who are either hypertensive or normotensive, as the blood pressure changes in normotensive patients are clinically insignificant. In hypertensive patients both conditions are treated concomitantly.

Elderly: Same dosage as for adults.

Patients with renal impairment: Since there is no change in pharmacokinetics in patients with impaired renal function, and since there are no signs that Doxalfa aggravates existing renal impairment, the usual dose can be used in these patients.

Patients with hepatic impairment: Doxalfa should be given with particular caution to patients with evidence of impaired liver function. In patients with severe hepatic impairment clinical experience is lacking and therefore the use of Doxalfa is not recommended..

Children and adolescents: Doxalfa is not recommended for patients under the age of 18 years.

Doxalfa is contraindicated in

- Patients with a known hypersensitivity to quinazolines (e.g. prazosin, terazosin, Doxalfa), or any of the excipients

- Patients with a history of orthostatic hypotension

- Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infections or bladder stones

- Patients with a history of gastrointestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastrointestinal tract¹

- During lactation ²

- Patients with hypotension³

Doxalfa is contraindicated as monotherapy in patients with either overflow bladder or anuria or without progressive renal insufficiency.

¹ For patients taking the sustained release tablets only.

² For the hypertension indication only

³ For the benign prostatic hyperplasia indication only

Information to be given to the Patient: Patients should be informed that Doxalfa tablets should be swallowed whole. Patients should not chew, divide or crush the tablets.

In Cardozo XL the active compound is surrounded by an inert, non absorbable coating that is designed to control the release of the drug over a prolonged period. After transit through the gastrointestinal tract, the empty tablet shell is excreted. Patients should be advised not to be concerned if they occasionally observe remains in their stools that look like a tablet

Abnormally short transit times through the gastrointestinal tract (e.g. following surgical resection) could result in incomplete absorption. In view of the long half life of Doxalfa the clinical significance of this is unclear.

Initiation of Therapy: In relation with the alpha-blocking properties of Doxalfa, patients may experience postural hypotension evidenced by dizziness and weakness, or rarely loss of consciousness (syncope), particularly with the commencement of therapy. Therefore, it is prudent medical practice to monitor blood pressure on initiation of therapy to minimise the potential for postural effects. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of Doxalfa therapy.

Use in Patients with Acute Cardiac Conditions:

As with any other vasodilatory anti-hypertensive agent it is prudent medical practice to advise caution when administering Doxalfa to patients with the following acute cardiac conditions:

- pulmonary oedema due to aortic or mitral stenosis

- heart failure at high output

- right-sided heart failure due to pulmonary embolism or pericardial effusion

- left ventricular heart failure with low filling pressure.

Use in Hepatically Impaired Patients:

As with any drug wholly metabolised by the liver, Doxalfa should be administered with particular caution to patients with evidence of impaired hepatic function. Since there is no clinical experience in patients with severe hepatic impairment use in these patients is not recommended.

Use with PDE-5 inhibitors:

Concomitant administration of Doxalfa with phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, and vardenafil) should be done with caution as both drugs have vasodilating effects and may lead to symptomatic hypotension in some patients. To reduce the risk of orthostatic hypotension it is recommended to initiate the treatment with phosphodiesterase-5-inhibitors only if the patient is hemodynamically stabilized on alpha-blocker therapy. Furthermore, it is recommended to initiate phosphodiesterase-5-inhibitor treatment with the lowest possible dose and to respect a 6-hour time interval from intake of Doxalfa. No studies have been conducted with Doxalfa prolonged release formulations.

Use in Patients Undergoing Cataract Surgery:

The 'Intraoperative Floppy Iris Syndrome' (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. Isolated reports have also been received with other alpha-1 blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha-1 blockers should be made known to the ophthalmic surgeon in advance of surgery.

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating therapy.

The following undesirable effects have been observed and reported during treatment with Doxalfa with the following frequencies: Very common >1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000

Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Other supportive measures should be performed if thought appropriate in individual cases. Since Doxalfa is highly protein bound, dialysis is not indicated.

Pharmacotherapeutic group: Alpha-adrenoceptor antagonists

ATC code: C02CA04

Hypertension:

Administration of Doxalfa in hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24-hours post dose. The majority of patients are controlled on the initial dose of 4 mg Doxalfa. In patients with hypertension, the decrease in blood pressure during treatment with Doxalfa was similar in both the sitting and standing position.

Patients treated with immediate release Doxalfa tablets against hypertension can be transferred to Doxalfa prolonged-release and the dose titrated upwards as needed, while maintaining effect and tolerability.

Habituation has not been observed during long-term treatment with Doxalfa. Increase in plasma renin activity and tachycardia have rarely been seen during long-term treatment.

Doxalfa has a beneficial effect on blood lipids with significant increase of HDL/total cholesterol ratio (app. 4-13% of base line values), and significant reduction in total glycerides and total cholesterol. The clinical relevance of these findings is still unknown.

Treatment with Doxalfa has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation as well as enhanced capacity of tissue plasminogen-activator. The clinical relevance of these findings is still uncertain.

Additionally, Doxalfa improves insulin sensitivity in patients with impaired sensitivity to insulin, but also concerning this finding the clinical relevance is still uncertain.

Doxalfa has shown to be free of metabolic adverse effects and is suitable for treatment of patients with coexistent asthma, diabetes, left ventricular dysfunction or gout.

Prostatic hyperplasia:

Administration of Doxalfa to patients with prostatic hyperplasia results in a significant improvement in urodynamics and symptoms as a result of a selective blockade of alpha-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck.

Most of the patients with prostatic hyperplasia are controlled with the initial dose.

Doxalfa has shown to be an effective blocker of 1A subtype of alpha-adrenoceptors which make up more than 70% of the adrenergic subtypes in prostate.

Throughout the recommended dosage range, Doxalfa has only a minor or no effect on blood pressure in normotensive benign prostatic hyperplasia (BPH) patients.

Absorption:

After oral administration of therapeutic doses, Doxalfa in Cardozin XL 4mg Prolonged-release Tablets and associated names is well absorbed with peak blood levels gradually reached at 6 to 8 hours after dosing. Peak plasma levels are approximately one third of those of the same dose of immediate release Doxalfa tablets. Trough levels at 24 hours are, however, similar. The pharmacokinetic properties of Doxalfa lead to a minor variation in plasma levels. Peak/trough ratio of Doxalfa prolonged-release is less than half that of immediate release Doxalfa tablets.

At steady-state, the relative bioavailability of Doxalfa from Doxalfa prolonged-release compared to immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.

Distribution:

App. 98% of Doxalfa is protein-bound in plasma.

Biotransformation:

Doxalfa is extensively metabolised with <5% excreted as unchanged product.

Doxalfa is primarily metabolised by O-demethylation and hydroxylation.

Elimination:

The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basic for once daily dosing

Elderly:

Pharmacokinetic studies with Doxalfa in the elderly have shown no significant alterations compared to younger patients.

Renal impairment:

Pharmacokinetic studies with Doxalfa in patients with renal impairment also showed no significant alterations compared to patients with normal renal function.

Liver impairment:

There are only limited data in patients with liver impairment and on the effects of medicinal products known to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single dose administration of Doxalfa resulted in an increase of AUC of 43% and a decrease in oral clearance of app. 40%. Doxalfa therapy in patients with hepatic impairment should be performed with caution.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. Studies in pregnant rabbits and rats at daily doses resulting in plasma concentrations 4 and 10 times the human exposure (C_max and AUC), respectively, revealed no evidence of harm to the foetus. A dosage regime of 82 mg/kg/day (8 times the human exposure) was associated with reduced foetal survival.

Studies in lactating rats given a single oral dose of radioactive Doxalfa gave an accumulation in the breast milk with a maximum concentration of about 20 times greater than the maternal plasma concentration. Radioactivity was found to cross the placenta following oral administration of labelled Doxalfa to pregnant rats

Not applicable

No special requirements.