4.4  Special warnings and precautions for use

Priapism:
Prolonged erections and priapism have been reported with alpha-1 blockers including doxazosin in post marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, it could result in penile tissue damage and permanent loss of potency could result, therefore the patient should seek immediate medical assistance.

4.5  Interaction with other medicinal products and other forms of interaction

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 doxazosin prolonged release formulations.

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 medicinal products tested (digoxin, warfarin, phenytoin or indometacin). However, the theoretical potential for interaction with other protein bound medicinal products 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).

4.6  Fertility, pregnancy and lactation

Pregnancy
As there are no adequate and well controlled studies in pregnant women, the safety of doxazosin during pregnancy has not yet been established. Accordingly, during pregnancy, doxazosin 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.

Breast-feeding
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 riskDoxazosin is contraindicated during lactation as animal studies have shown that doxazosin accumulates in milk of lactating rats, and there is no information about the excretion of doxazosin into the milk of lactating women. The clinical safety of doxazosin during lactation has not been established, consequently this medicinal product is contra-indicated in nursing mothers.

Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (see section 5.3).

5.2  Pharmacokinetic properties

Biotransformation / Elimination:
The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basis for once daily dosing. Doxazosin is extensively metabolised with <5% excreted as unchanged product.

Pharmacokinetic studies with doxazosin immediate release tablets in patients with renal impairment did not show any significant alterations compared to patients with normal renal function.

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 patients with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 30% (see section 4.4).

Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is primarily metabolised by O-demethylation and hydroxylation.

Doxazosin is extensively metabolised in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent.

5.3  Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional animal studies of safety in pharmacology, repeated dose toxicity, genotoxicity and, carcinogenicity and gastrointestinal tolerance.

Although no teratogenic effects were seen in animal testing, reduced foetal survival was observed in animals at doses approximately 300 times greater than the maximum human recommended dose.

Studies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum of concentration about 20 times greater than the maternal plasma concentration.

For further information see section 4.6.

 

4.1  Therapeutic Indications

Essential h Hypertension.:
Doxacar is indicated for the treatment of hypertension and can be used as a sole agent to control blood pressure in hypertensive patients.

In patients inadequately controlled on single antihypertensive therapy, Doxacar may be used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent, calcium antagonist or an angiotensin-converting enzyme inhibitor.

4.2  Posology and method of administration

Posology:

Adults:
The initial dose of Doxacar is 4 mg once daily. A significant number of patients will be controlled on this dose. If necessary, the dosage may be increased to 8 mg once daily according to patient response.

The maximum recommended dose is 8 mg doxazosin once daily.

Adults:
Most patients treated with Doxacar 4 mg once daily achieve control of blood pressure. It may take up to four weeks to reach optimal effect. If necessary, the dose can thereafter be increased to 8 mg once daily depending on the clinical response.

Doxacar can be used as monotherapy or in combination with another medicinal product e.g. a thiazide diuretic, a beta­adrenoceptor blocking agent, a calcium antagonist or an ACE-inhibitor if either of them alone does not provide sufficient effect.

Elderly:
Same dosage recommendations as for adults. In common with other medicinal products of this class, the dosage should be kept as low as possible and increments made under close supervision.

Patients with r Renal impairment:
Since there is no change in pharmacokinetics of doxazosin are unchanged in patients with impaired renal function insufficiency, and since there are is no signs evidence that doxazosin aggravates existing renal impairment dysfunction, the normal usual dosages e can generallymay be used in these patients. Doxacar is not dialysable.

Patients with h Hepatic 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)Doxazosin should be administered with caution in patients with signs of minor to moderate hepatic impairment. As with any medicinal product metabolised wholly by the liver, Doxacar should be used with care in patients with significant existing hepatic dysfunction Since no clinical experience from patients with severe hepatic insufficiency exists, use in these patients is not recommended (see sections 4.4 and 5.2).

Paediatric population:
The safety and efficacy of doxazosin in children below 18 years and adolescents of age has have not yet been established.

Method of administration

Doxacar prolonged-release tablets can be taken with or without food.

The tablets should be swallowed whole with a sufficient amount of liquid. The patient They should not be cut, chew, divide or crush ed or chewed the tablet (see section 4.4).

Doxacar prolonged-release tablets can be taken with or without food.

4.3  Contraindications

Doxacar prolonged-release tablets are contraindicated in:

• patients Patients with known hypersensitivity to the active substance, other types of quinazolines (e.g. prazosin, terazosin, doxazosin), or to any of the excipients listed in section 6.1.
• patients Patients with a history of orthostatic hypotension.
• patients Patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.
• patients Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary tract, chronic urinary tract infections or bladder stones.
• during During lactation (see section 4.6).

4.4  Special warnings and precautions for use

Information to be given to the patient:

Patients should be informed that Doxacar prolonged-release tablets should be swallowed whole. Patients should not chew, divide or crush the tablets (see section 4.2).

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

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 right-sided heart failure due to pulmonary embolism, or pericardial effusion,
- left ventricular heart failure with low filling pressure.

Use in patients with hepatically impairment impaired patients:
As with any medicinal products wholly metabolised by the liver, doxazosin should be administered with particular caution to in 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 with phosphodiesterase PDE-5 inhibitors:
Concomitant administration of doxazosin with phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, and vardenafil) should be done with caution as both medicinal products 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 tablet formulations.

Use in patients undergoing cataract surgery:
Intraoperative Floppy Iris Syndrome
The "Intraoperative intraoperative Floppy floppy Iris iris Syndrome 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- I1 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- I1 blockers should be made known to the ophthalmic surgeon in advance of surgery.

4.5  Interaction with other medicinal products and other forms of interaction

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 doxazosin prolonged release formulations.

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

Conventional doxazosin has been administered without any adverse interactions in clinical experience with thiazide diuretics, furosemide, beta-blockers blocking agents, non-steroidal anti-inflammatories inflammatory drugs, antibiotics, oral hypoglycaemic medicinal products, uricosuric agents, and 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, randomised, 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 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 for doxazosin with placebo.

Non-steroidal anti rheumatics or oestrogens may reduce the antihypertensive effect of doxazosin.

Sympathomimetics may reduce the antihypertensive effect of doxazosin; doxazosin may reduce blood pressure and vascular reactions to dopamine, ephedrine, epinephrine, metaraminol, methoxamine and phenylephrine.

There are no studies available concerning interactions with agents influencing hepatic metabolism.
Doxazosin may influence the plasma renin activity and urinary excretion of vanillylmandelic acid. This should be considered when analysing laboratory data.

4.6  Fertility, pregnancy and lactation

Pregnancy
As there are no adequate and well controlled studies in pregnant women, the safety of doxazosin during pregnancy has not yet been established. Accordingly, during pregnancy, doxazosin should be used only if 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.

Breast-feeding
Doxazosin is contraindicated during lactation as animal studies have shown that doxazosin accumulates in milk of lactating rats. , and There there is no information about the excretion of doxazosin into the milk of lactating women. The clinical safety of doxazosin during lactation has not been established, consequently this medicinal product is contra-indicated in nursing mothers.

Alternatively, mothers should stop breast-feeding when treatment with doxazosin is necessary (see section 5.3).

4.7  Effects on ability to drive and use machines

The ability to handle machines and drive a carengage in activities such as operating machinery or operating a motor vehicle may be impaired, especially at the beginning ofwhen initiating therapy. The medicinal product may also induce drowsiness. Patients should not drive or operate machinery unless it has been shown not to affect their alertness or dexterity.

4.8  Undesirable effects

In clinical trials, the most common reactions associated with doxazosin were of a postural type (rarely associated with fainting) or non-specific.
The undesirable effects for prolonged release tablets were are similar to those with immediate release tablets.
The following undesirable effects have been observed and reported during treatment with doxazosin with the following frequencies: 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); not known (frequency cannot be estimated from the available data).

System Organ Class	Common	Uncommon	Rare	Very Rare	Not known
Infections and infestations	Respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders				Leucopenia, thrombocytopenia
Immune system disorders		Allergic drug reaction
Metabolism and nutrition disorders		Anorexia, gout, increased appetite
Psychiatric disorders		Anxiety, depression, insomnia		Agitation, nervousness
Nervous system disorders	Dizziness, headache, somnolence	Cerebrovascular accident, hypoesthesia, syncope, tremor		Dizziness postural, paraesthesia
Eye disorders				Blurred vision	Intraoperative floppy iris syndrome (see section 4.4)
Ear and labyrinth disorders	Vertigo	Tinnitus
Cardiac disorders	Palpitation, tachycardia	Angina pectoris, myocardial infarction		Bradycardia, cardiac arrhythmias
Vascular disorders	Hypotension, postural hypotension			Hot Flushflushes
Respiratory, thoracic and mediastinal disorders	Bronchitis, cough, dyspnoea, rhinitis	Epistaxis		Bronchospasm
Gastrointestinal disorders	Abdominal pain, dyspepsia, dry mouth, nausea	Constipation, diarrhoea, flatulence, vomiting, gastroenteritis	Gastrointestinal obstruction
Hepatobiliary disorders		Abnormal liver function tests		Cholestasis, hepatitis, jaundice, icterus, increased liver transaminases
Skin and subcutaneous tissue disorders	Pruritus	Skin rash		Alopecia, purpura, urticaria
Musculoskeletal, and connective tissue disorders	Back pain, myalgia	Arthralgia		Muscle cramps, muscle weakness
Renal and urinary disorders	Cystitis, urinary incontinence	Dysuria, haematuria, micturition frequency		Micturition disorder, nocturia, polyuria, increased diuresis
Reproductive system and breast disorders		Impotence		Gynecomastia, priapism	Retrograde ejaculation
General disorders and administration site conditions	Asthenia, chest pain, influenza-like symptoms, peripheral oedema	Pain, facial oedema		Fatigue, malaise
Investigations		Weight increase

4.9  Overdose

Toxicity
There is limited data on the effect of overdoses. Syncope occurred in a fasting adult who had taken doxazosin 16 mg. A 13-year-old experienced moderate intoxication following a maximum dose of doxazosin 40 mg.

Symptoms:
Headache, dizziness, unconsciousness, syncope, dyspnoea, hypotension, palpitations, tachycardia, arrhythmia, nausea, vomiting, possibly hypoglycaemia and hypokalaemia.

Treatment:
Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Other supportive measures should may be performed if thought appropriate in individual cases.

Since doxazosin is strongly highly bound to proteins protein-bound dialysis is not indicated.

5 PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists
ATC code: C02CA04 (Hypertension)

Mode of action
Doxazosin is a potent and selective post-junctional alpha 1-adrenoceptor antagonist.

Administration of doxazosin to 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 1-adrenoreceptors 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. In patients with hypertension, blood pressure during treatment with doxazosin prolonged-release tablets was similar in both the supine and standing position.

Responder data from the 2 primary hypertension efficacy studies (including a total of 630 doxazosin treated patients) indicate that those patients controlled on 1 mg, 2 mg or 4 mg doxazosin immediate release tablets would be equally well controlled on 4 mg doxazosin prolonged-release tablets.

Pharmacodynamic effects
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with coexistent diabetes mellitus, gout and insulin resistance.

Doxazosin is suitable for use in patients with coexistent asthma, left ventricular hypertrophy and in elderly patients. Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Additionally, doxazosin improves insulin sensitivity in patients with impairment.

Doxazosin produces favourable effects on blood lipids, with a significant increase in the high-density lipoprotein HDL/total cholesterol ratio and trends to a favourable reduction in total triglycerides. It therefore confers an advantage over diuretics and beta adrenoceptor blocking agents which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favourable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in risk of developing coronary heart disease.

5.2  Pharmacokinetic properties

Absorption:
After oral administration of therapeutic doses, doxazosin prolonged-release tablets are well absorbed with peak blood levels gradually reached at 8 to 9 hours after dosing. Peak plasma levels are approximately one third of those of the level obtained after administration same dose of immediate release doxazosin tablets. Trough levels at 24 hours are, however, similar. for both formulations.

The pharmacokinetic properties characteristics of doxazosin in prolonged-release tablets will lead to a minor variation in smoother plasma levels profile.

Peak/trough ratio of doxazosin prolonged-release tablets is less than half that of immediate release doxazosin tablets.

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

Pharmacokinetic studies with doxazosin prolonged-release tablets in the elderly have shown no significant alterations compared to younger patients.
Concomitant intake of food results in a somewhat higher degree of absorption, AUC is 14% higher and Cmax 23% higher compared with intake when fasting. Cmin is unaffected by concomitant food intake.

Distribution:
Approximately 98% of doxazosin is protein-bound in plasma. Volume of distribution: 1 litre/kg.

Biotransformation / Elimination:
The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basis for once daily dosing. Doxazosin is primarily metabolised by O-demethylation and hydroxylation. Doxazosin is extensively metabolised with <5% excreted as unchanged product.

Elimination:
Clearance of doxazosin is 1.3 ml/min/kg.

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

Elderly:
Pharmacokinetic studies with doxazosin prolonged-release tablets in older people have shown no significant alterations compared to younger patients.

Renal impairment:
Pharmacokinetic studies with doxazosin immediate release tablets in patients with renal impairment did not show any significant alterations compared to that of patients with normal renal function.

Liver impairment:
There are only limited data concerning in patients with liver impairment and on the effects of medicinal products known to influence hepatic metabolism (e.g. cimetidine). In a clinical study of in 12 subjects patients with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase of in AUC of 43% and a decrease in apparent oral clearance of approximately 30% (see section 4.4).

Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is primarily metabolised by O-demethylation and hydroxylation.

5.3  Preclinical safety data

Non-clinical Preclinical data reveal no special hazard for humans based on conventional animal studies of safety in pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity carcinogenic potential. For further information see section 4.6.

 

4.2 Posology and method of administration

Posology:

The maximum recommended dose is 8 mg doxazosin once daily.

Adults:

Most patients treated with Doxacar 4 mg once daily achieve control of blood pressure. It may take up to four weeks to reach optimal effect. If necessary, the dose can thereafter be increased to 8 mg once daily depending on the clinical response.

Doxacar can be used as monotherapy or in combination with another medicinal product e.g. a thiazide diuretic, a betaadrenoceptor blocking agent, a calcium antagonist or an ACE-inhibitor if either of them alone does not provide sufficient effect.

Elderly

 

 

Older people:

 

Same dosage recommendations as for adults.

 

In common with other medicinal products of this class, the dosage should be kept as low as possible and increments made under close supervision.

 

4.3 Contraindications

Doxacar prolonged-release tablets are contraindicated in:

- patients with known hypersensitivity to quinazolines (e.g. prazosin, terazosin, doxazosin) or to any of the excipients

 

listed in section 6.1.

 

- patients with a history of orthostatic hypotension.

- patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.

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

- during lactation (see section 4.6)

4.4 Special warnings and precautions for use

Information to be given to the patient:

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

For some prolonged-release formulations the active compound is surrounded by an inert, non-absorbable coating that is designed to control the release of the

 

active substance 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 doxazosin the clinical significance of this is unclear.

Postural hypotension/Syncope:

Initiation of therapy

 

-:

 

In relation with 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.

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 doxazosin therapy, such as driving or operating machinery.

 

Use in patients with hepatic impairment:

As with any

 

medicinal products drug wholly metabolised by the liver, doxazosin should be administered with particular caution in patients with evidence of impaired hepatic function (see section 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 doxazosin aggravates renal dysfunction. However, doxazosin dosage

 

introductioninstructions and adjustments should be carried out with great care.

 

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

 

medicinal productsdrugs 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 tablet formulations.

 

Priapism:

Prolonged erections and priapism have been reported with alpha-1 blockers including doxazosin in post marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

4.5 Interaction with other medicinal products and other forms of interaction

Phosphodiesterase-5-inhibitors (e.g. sildenafil, tadalafil, vardenafil).

Concomitant administration of

 

an alpha blockerdoxazosin with a PDE-5 inhibitor may lead to symptomatic hypotension in some patients (see section 4.4). 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. However, the theoretical potential for interaction with other protein bound medicinal productsdrugs should be borne in mind.

 

Conventional doxazosin has been administered without any adverse

 

drug interactions in clinical experience with thiazide diuretics, furosemide, beta-blockers, non-steroidal anti-inflammatoriesy drugs, antibiotics, oral hypoglycaemic medicinal productsdrugs, uricosuric agents, and 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, randomi

 

szed, 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 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 for doxazosin with placebo.

 

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

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

 

sSection 5.3). These doses were approximately 300 times the maximum recommended human dose.

 

Breast-feeding

Doxazosin is contraindicated during lactation as

 

animal studies have shown that doxazosin the drug accumulates in milk of lactating rats. and Tthere is no information about the excretion of doxazosin the drug into the milk of lactating women.

 

4.7 Effects on ability to drive and use machines

The ability to handle machines and drive a car may be impaired, especially at the beginning of therapy. The

 

medicinal product drug may also induce drowsiness. Patients should not drive or operate machinery unless it has been shown not to affect their alertness or dexterity.

 

4.8 Undesirable effects

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

The undesirable effects for prolonged release tablets were similar to those with immediate release tablets.

 

 

 

5.2 Pharmacokinetic properties

 

Elderly:

 

Older people:

 

Pharmacokinetic studies with doxazosin prolonged-release tablets in older people have shown no significant alterations compared to younger patients.

Liver impairment:

There are only limited data concerning patients with liver impairment and on the effects of medicinal products known to influence hepatic metabolism (e.g. cimetidine). In a clinical study of 12 subjects with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase of AUC of 43% and a decrease in oral clearance of approximately 30% (see

also section 4.4).

 

Space was added to all heading titles according to new QRD guideline.

2. Prolonged-release added

4.4 - text added

Use in patients with impaired renal function:

There is no evidence that doxazosin aggravates renal dysfunction. However, doxazosin dosage instructions and adjustments should be carried out with great care.

4.6 - text added

Doxazosin crosses the placenta.

4.8 - Text added

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

deletion - muscle cramps

reporting of side effecrs - changed as per new HPRA guidelines

5.1 - text changed to

Administration of doxazosin to 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 adrenoreceptors 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. In patients with hypertension, blood pressure during treatment with doxazosin prolonged-release tablets was similar in both the supine and standing position.

 

Responder data from the 2 primary hypertension efficacy studies (including a total of 630 doxazosin treated patients) indicate that those patients controlled on 1mg, 2mg or 4mg doxazosin immediate release tablets would be equally well controlled on 4mg doxazosin prolonged-release tablets.

 

Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with coexistent diabetes mellitus, gout and insulin resistance.

 

Doxazosin is suitable for use in patients with coexistent asthma, left ventricular hypertrophy and in elderly patients. Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Additionally, doxazosin improves insulin sensitivity in patients with impairment.

 

Doxazosin produces favourable effects on blood lipids, with a significant increase in the HDL/total cholesterol ratio and trends to a favourable reduction in total triglycerides. It therefore confers an advantage over diuretics and beta adrenoceptor blocking agents which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favourable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in risk of developing coronary heart disease.

5.3 - Toxicity to reproduction - deleted

text added

For further information see section 4.6.

6.1 - Polythelene oxide changed to macrogol

6.6 - 'and other handling' removed from title

Safety updates to Sections 4$0$0$0$04.2$0$0Posology updated. dosage amount unchanged.$0$0Method of administration added$0$0Paediatric information updated.$0$0$0$0$04.3$0$0Contraindications updated.$0$0$0$0$04.4$0$0Special warnings and precautions updated.$0$0$0$0$04.5 $0$0Interaction with other medicinal products updated.$0$0$0$0$04.6$0$0Pregnancy and Breastfeeding information updated. Lactation added.$0$0$0$0$04.7$0$0Effects on ability to drive and use machines updated.$0$0$0$0$04.8$0$0List of side effects updated.$0$0Procedure for reporting of suspected adverse reactions added.$0$0$0$0$04.9$0$0Treatment for overdose updated.$0$0$0$0$010$0$0Date of revision of text changed to July 2013.$0$0$0$0$0$0$0$0$0$0$0(Internal Ref: IE/H/0215/IB/007)$0