Alfadil BPH

- 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 Alfadil BPH once daily.

Essential hypertension:

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

Alfadil BPH 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 Alfadil BPH once daily. If necessary, the dosage may be increased to 8 mg Alfadil BPH once daily.

Alfadil BPH 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 Alfadil BPH aggravates existing renal impairment, the usual dose can be used in these patients.

Patients with hepatic impairment: Alfadil BPH 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 Alfadil BPH is not recommended..

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

Alfadil BPH is contraindicated in

- Patients with a known hypersensitivity to quinazolines (e.g. prazosin, terazosin, Alfadil BPH), 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

Alfadil BPH 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 Alfadil BPH 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 Alfadil BPH the clinical significance of this is unclear.

Initiation of Therapy: In relation with the alpha-blocking properties of Alfadil BPH, 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 Alfadil BPH 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 Alfadil BPH 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, Alfadil BPH 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 Alfadil BPH 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 Alfadil BPH. No studies have been conducted with Alfadil BPH 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 Alfadil BPH 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 Alfadil BPH is highly protein bound, dialysis is not indicated.

Pharmacotherapeutic group: Alpha-adrenoceptor antagonists

ATC code: C02CA04

Hypertension:

Administration of Alfadil BPH 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 Alfadil BPH. In patients with hypertension, the decrease in blood pressure during treatment with Alfadil BPH was similar in both the sitting and standing position.

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

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

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

Alfadil BPH 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 Alfadil BPH 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.

Alfadil BPH 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, Alfadil BPH has only a minor or no effect on blood pressure in normotensive benign prostatic hyperplasia (BPH) patients.

Absorption:

After oral administration of therapeutic doses, Alfadil BPH 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 Alfadil BPH tablets. Trough levels at 24 hours are, however, similar. The pharmacokinetic properties of Alfadil BPH lead to a minor variation in plasma levels. Peak/trough ratio of Alfadil BPH prolonged-release is less than half that of immediate release Alfadil BPH tablets.

At steady-state, the relative bioavailability of Alfadil BPH from Alfadil BPH 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 Alfadil BPH is protein-bound in plasma.

Biotransformation:

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

Alfadil BPH 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 Alfadil BPH in the elderly have shown no significant alterations compared to younger patients.

Renal impairment:

Pharmacokinetic studies with Alfadil BPH 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 Alfadil BPH resulted in an increase of AUC of 43% and a decrease in oral clearance of app. 40%. Alfadil BPH 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 Alfadil BPH 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 Alfadil BPH to pregnant rats

Not applicable

No special requirements.