KAMIREN Prolonged-release tablet Ref.[49837] Active ingredients: Doxazosin

Information to be given to the patient

Patients should be informed that Kamiren prolonged-release tablets should be swallowed whole. Patients should not chew, divide or crush the tablets.

In Kamiren the active compound is surrounded by an inert a non-absorbable shell that has been specially designed to control the release of the drug over a prolonged period. After transit through the gastrointestinal tract, when this process is completed the empty tablet shell is excreted. Patients should be advised that they should not 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 doxazosin the clinical significance of this is unclear.

Postural Hypotension / Syncope

Initiation of therapy – As with all alpha-blockers, a very small percentage of patients have experienced 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.

When instituting therapy with any effective alpha-blocker, the patient should be advised how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. The patient should be cautioned to avoid situations where injury could result should dizziness or weakness occur during the initiation of Kamiren prolonged-release tablets therapy, such as driving or operating machinery.

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 doxazosin 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, Kamiren prolonged-release tablets should be administered with particular caution to patients with evidence of impaired hepatic function (see sections 4.2 and 5.2). Since there is no clinical experience in patients with severe hepatic impairment use in these patients is not recommended.

Use in Patients with Impaired Renal Function

There is no evidence that Kamiren prolonged-release tablets aggravates renal dysfunction. However, Kamiren prolonged-release tablets dosage introduction and adjustments should be carried out with great care.

Use with Phosphodiesterase Type-5 Inhibitors

Concomitant administration of doxazosin 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 doxazosin. No studies have been conducted with doxazosin prolonged release formulations.

Use in patients undergoing Cataract Surgery

Intraoperative Floppy Iris Syndrome

The ‘introoperative 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.

Priapism

Prolonged erections and priapism have been reported with alpha-1 blockers including doxazosin in post marketing experience. If priapism is not treated immediately, it could result in penile tissue damage and permanent loss of potency, therefore the patient should seek immediate medical assistance.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Phosphodiesterase Type-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil) Concomitant administration of an alpha blocker with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see section 4.4). No studies have been conducted with Kamiren prolonged-release tablets.

Doxazosin is highly bound to plasma proteins (98%). In vitro data in human plasma indicates that doxazosin has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin). However, the theoretical potential for interaction with other protein bound drugs should be borne in mind.

In vitro studies suggest that doxazosin is a substrate of cytochrome P450 3A4 (CYP 3A4). Caution should be exercised when concomitantly administering doxazosin with a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole (see section 5.2).

Conventional doxazosin has been administered without any adverse drug interactions in clinical experience with thiazide diuretics, furosemide, beta-blocking agents, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents, or anticoagulants. However, data from formal drug/drug interaction studies are not present.

Doxazosin potentiates the blood pressure lowering activity of other alpha-blockers and other antihypertensives.

In an open-label, randomized, placebo-controlled trial in 22 healthy male 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, and no statistically significant changes in mean C_max and mean half-life of doxazosin.

The 10% increase in the mean AUC for doxazosin with cimetidine is within intersubject variation (27%) of the mean AUC for doxazosin with placebo.

For the hypertension indication

Pregnancy

As there are no adequate and well-controlled studies in pregnant women, the safety of Kamiren prolonged-release tablets during pregnancy has not yet been established. Accordingly, during pregnancy, Kamiren prolonged-release tablets should be used only when, in the opinion of the physician, the potential benefit outweighs the potential risk.

Doxazosin crosses the placenta. Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at extremely high doses (see section 5.3). These doses were approximately 300 times the maximum recommended human dose.

Lactation

The excretion of doxazosin in breast milk was demonstrated to be very low (with the relative infant dose less than 1%) however human data is very limited. A risk to the newborn or infant cannot be excluded and therefore doxazosin should be used only when in the opinion of the physician, the potential benefit outweighs the potential risk.

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating therapy. The drug may also induce drowsiness. Patients should not drive or operate machinery unless it has been shown not to affect their alertness or dexterity.

In clinical trials, the most common reactions associated with Kamiren prolonged-release tablets were of a postural type (rarely associated with fainting) or non-specific.

The undesirable effects for doxazosin prolonged-release tablets are similar to those with immediate release doxazosin tablets.

The following undesirable effects have been observed and reported during treatment with doxazosin prolonged-release tablets with the following: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Earlsfort Terrace IRL – Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail: medsafety@hpra.ie.

Not applicable.