Discovery Pharmaceuticals Ltd

4.3.      Contraindications

Doxazosin is contraindicated in:

·       patients with a known hypersensitivity to quinazolines  (e.g. prazosin, terazosin, doxazosin), 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 infection or bladder stones

·       during lactation (see section 4.6 Pregnancy and Lactation).

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

4.4.      Special warnings and precautions for use

Initiation of Therapy: in relation to the alpha-blocking properties of doxazosin, 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 doxazosin 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 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, doxazosin should be administered with particular caution to patients with evidence of impaired hepatic function. Since there is no clinical experiences in patients with severe hepatic impairment, use in these patients is not recommended.

Use with PDE-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 thermodynamically stabilised 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: 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.

Excipients: Doxadura tablets contain lactose. Therefore, they should not be administered to persons with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

The excipient E110 is known to cause allergic reactions, including asthma. Allergy is more common in persons who are allergic to aspirin. This excipient is only used in the 2mg and 4mg tablets.

4.5.      Interactions with other medicinal Products and other forms of interaction

Concomitant administration of doxazosin with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see section 4.4 Special Warnings and Special Precautions for Use). No studies have been conducted with doxazosin prolonged release formulations.

Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indometacin. Conventional doxazosin has been administered without any adverse drug interaction in clinical experience with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycaemic drugs, uricosuric agents and anticoagulants. However data from formal drug/drug interactions studies are not present.

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

In an open-label, randomised, placebo-controlled trial in 22 healthy male volunteers, the administration of a single 1mg dose of doxazosin on day 1 of a four-day regiment of oral cimetidine (400mg twice daily) resulted in a 10% increase in mean AUC of doxazosin and no statistically significant changes in mean Cmax 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 of doxazosin with placebo.

4.6.      Pregnancy and lactation

As there are no adequate and well controlled studies in pregnant women, the safety of doxazosin during pregnancy has not been established. Accordingly, during pregnancy, doxazosin should be used only if the potential benefit outweighs the risk. Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at high doses (see section 5.3 Preclinical Safety Data).

Doxazosin is contraindicated during lactation as the drug accumulates in milk of lactating rats and there is no information about the excretion of the drug into the milk of lactating women. Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (see section 5.3 Preclinical Safety Data).

4.7.      Effects on ability to drive and use machines

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

4.8.      Undesirable effects

Frequencies used are as follows: very common ³ 1/10, common ³ 1/100 and < 1/10, uncommon ³ 1/1,000 and < 1/100, rare ³ 1/10,000 and <1/1,000, very rare <1/10,000.

4.9.      Overdose

Should overdose 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 doxazosin is highly protein bound, dialysis is not indicated.

If this measure is inadequate, the patient should first be treated with volume expanders. If necessary, vasopressor should then be used. Renal function should be monitored and supported as needed.

·          Change name of MA holder (SPUK to Genus Pharmaceuticals Ltd) 03/02/05

·          Change of address for MAH (Benham Valence to Park View House) 15/01/2008

·          Update to SmPC re PhVWP wording 22/07/09