Carzin Xl 4 mg Prolonged-release, FC tablet.

CARZIN XL is indicated for:

• treatment of mild to moderate hypertension
• the treatment of symptoms in benign prostatic hyperplasia (BPH) and for reduced urinary flow associated with BPH. CARZIN XL may be used in patients with BPH who are either hypertensive or normotensive

The orthostatic hypotension effect of CARZIN XL following the initial dose can be avoided by starting treatment with a low dose, preferably at night. The initial dose of CARZIN XL in patients with hypertension and/or BPH is 4 mg once daily in the morning with food. Depending on the patientu2019s symptomatic response and tolerability, the dose may be increased to 8 mg, the maximum recommended dose. Should CARZIN XL be discontinued for several days, therapy should be restarted using a 4 mg once daily dose.

Hypertension
The usual dose is one CARZIN XL 4 mg tablet once daily; (the majority of patients will be controlled on 4 mg daily). If necessary, the dosage may be increased to 8 mg once daily according to the patientu2019s response. In patients not adequately controlled on a single antihypertensive medicine, CARZIN XL may be used in combination with a thiazide diuretic or a beta-blocking medicine.

Benign Prostatic Hyperplasia
The usual dose is one CARZIN XL 4 mg tablet once daily. Depending on the individual patientu2019s urodynamics and BPH symptomatology, dosage may then be increased to 8 mg once daily. The recommended titration interval is 3-4 weeks. Blood pressure should be evaluated routinely in these patients.

Special populations

Use in elderly
Normal adult dosage is recommended. Due to an enhanced propensity to orthostasis in the elderly, or to an increased sensitivity to vasodilator medicines in the elderly, caution should be exercised in prescribing CARZIN XL to elderly patients, especially those who are u2265 70 years of age (see section 5.2).

Use in renally impaired patients
Since the pharmacokinetics of doxazosin is unchanged in patients with renal insufficiency, and there is no evidence that CARZIN XL aggravates existing renal dysfunction, the usual dosages may be used in these patients.

Use in hepatically impaired patients
CARZIN XL is wholly metabolised by the liver and should be administered with caution to patients with evidence of impaired hepatic function. Use in patients with severe hepatic impairment is not recommended.

Paediatric population
No experience is available on usage of CARZIN XL in children.

Method of administration
Oral use. CARZIN XL can be taken with or without food. The tablets should be swallowed whole with a sufficient amount of liquid. Patients should not chew, divide, or crush the tablets.

CARZIN XL is contraindicated in:

• hypersensitivity to doxazosin, other quinazolines or to any of the ingredients of CARZIN XL
• patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract
• pregnancy and lactation (see section 4.6)
• 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
• patients with hypotension (for benign prostatic hyperplasia indication only)

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

Postural hypotension
There is a potential for dizziness, weakness, and syncope after an initial dose or after an increase in dosage strength when CARZIN XL is administered to patients with symptomatic hypotension (see sections 4.2, 4.5 and 4.8). Upon initiation of therapy, the patient should be advised on how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. Patients should be warned about this and should be cautioned to avoid situations where injury could result, should dizziness or weakness occur during the initiation of CARZIN XL therapy.

Concomitant use with phosphodiesterase-5 (PDE-5) inhibitors
Concomitant administration of CARZIN XL with a PDE-5 inhibitor should be used with caution as it may lead to symptomatic hypotension in some patients. No studies have been conducted with doxazosin Gastrointestinal Therapeutic System (GITS).

Hepatic impairment
Care should be taken when CARZIN XL is administered to patients with mild or moderately impaired hepatic or renal function. These conditions may increase exposure to CARZIN XL and may increase the hypotensive effect. Use in patients with severe hepatic impairment is not recommended.

Coronary insufficiency
Caution should be used when CARZIN XL is administered to patients with coronary insufficiency. If symptoms of angina pectoris should newly appear or worsen, CARZIN XL should be discontinued.

Acute cardiac conditions
As with any other vasodilatory anti-hypertensive medicine, it is prudent medical practice to advise caution when administering CARZIN XL to patients with the following acute cardiac conditions:

• pulmonary oedema due to aortic or mitral stenosis
• high-output cardiac failure
• right-sided heart failure due to pulmonary embolism or pericardial effusion
• left ventricular heart failure with low filling pressure

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 alpha-1 blockers, therefore the possibility of a class effect cannot be excluded. This variant of small pupil syndrome is characterised by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilatation with standard mydriatic medicines, and potential prolapse of the iris toward the phacoemulsification incisions. The patientu2019s surgeon should be prepared for possible modifications to their surgical technique, such as the utilisation of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 adrenoreceptor blocker therapy prior to cataract surgery.

Priapism
Post marketing experience indicates prolonged erections and priapism have been reported with alpha-1 blockers including CARZIN XL. 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.

Screening for prostate cancer
Prostate cancer should be ruled out prior to commencing CARZIN XL therapy.

General
Orthostatic hypotension (which may be preceded by tachycardia and followed by syncope) can be avoided by starting treatment with a low dose, preferably at night (see section 4.2). Hypotensive effects may be increased by alcohol ingestion, exercise, and heat.

Information on excipients of CARZIN XL
CARZIN XL contains lactose. Patients with the rare hereditary conditions of galactose intolerance, e.g., galactosaemia, total lactase deficiency or glucose-galactose malabsorption should not take CARZIN XL. CARZIN XL contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus.

Concomitant administration of CARZIN XL with a PDE-5 inhibitors may lead to symptomatic hypotension in some patients (see section 4.4). No studies have been conducted with doxazosin prolonged-release formulations. The hypotensive effects of CARZIN XL may be enhanced by use with diuretics and other anti-hypertensives, and by alcohol and other medicines that cause hypotension. The risk of first-dose hypotension may be increased in patients receiving beta-blockers or calcium-channel blockers. In vitro studies suggest that doxazosin is a substrate of cytochrome P450 3A4 (CYP 3A4). Caution should be exercised when administering CARZIN XL concomitantly with a strong CYP 3A4 inhibitor, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole (see section 5.2).

Concomitant administration of antidepressants or antipsychotics may enhance the hypotensive effects of CARZIN XL. No adverse interaction has been noted in clinical experience to date with thiazide diuretics, furosemide, beta-adrenoceptor blocking medicines, antibiotics, oral hypoglycaemic medicines, non-steroidal anti-inflammatory drugs (NSAIDs), uricosuric products or anticoagulants. Administration of CARZIN XL may reduce serum concentrations of triglycerides, total and LDL-cholesterol and increase HDL-cholesterol. These potentially favourable effects on lipids persist when a thiazide-like diuretic is given concurrently. The long-term consequences of these medicine-induced changes in lipids are not known. Doxazosin is highly bound to plasma proteins (98 %). In vitro data in human plasma indicates that CARZIN XL has no effect on protein binding of digoxin, phenytoin, warfarin, or indomethacin.

Pregnancy
Safety in pregnancy has not been established (see section 4.3).

Breastfeeding
Safety in lactation has not been established (see section 4.3). Doxazosin is known to transfer into breast milk and to cross the placental barrier. A risk to the new-born or infant cannot be excluded.

Fertility
Fertility in males: Studies in rats after oral administration of doxazosin base showed reduced fertility in males. This was reversible after two weeks of treatment termination at doxazosin base exposure of 13-fold above the human exposure (AUC) at the MHRD of 8 mg CARZIN XL. There have been no reports of any effects of doxazosin on male fertility in humans.

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

a) Summary of the safety profile
The adverse event profile in elderly (> 65 years) patients with BPH showed no difference from the profile in the younger population. The most common reactions associated with CARZIN XL are of a postural type, (rarely associated with fainting) or non-specific.

b) Tabulated summary of adverse reactions

Post-marketing studies

Management of overdose:
Should overdosage lead to hypotension, the patient should be immediately placed in a supine, head down position. Doxazosin is highly protein bound; therefore, it is not removed by dialysis. Treatment is symptomatic and supportive.