CADEX 4 MG

Israel - English - Ministry of Health

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Active ingredient:
DOXAZOSIN AS MESYLATE
Available from:
DEXCEL LTD, ISRAEL
ATC code:
C02CA04
Pharmaceutical form:
CAPLETS
Composition:
DOXAZOSIN AS MESYLATE 4 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
DEXCEL LTD, ISRAEL
Therapeutic group:
DOXAZOSIN
Therapeutic area:
DOXAZOSIN
Therapeutic indications:
Antihypertensive agent. For the treatment of benign prostatic hyperthropy.
Authorization number:
113 80 29602 00
Authorization date:
2014-02-28

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

21-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

04-10-2020

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Cadex 1 mg, Cadex 2 mg, Cadex 4 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Cadex 1mg: each tablet contains Doxazosin 1mg (as mesylate).

Excipient with known effect:

Each tablet contains approximately 38mg Lactose.

Cadex 2mg: each caplet contains Doxazosin 2mg (as mesylate).

Excipient with known effect:

Each caplet contains approximately 77mg Lactose.

Cadex 4mg: each caplet contains Doxazosin 4mg (as mesylate).

Excipient with known effect:

Each caplet contains approximately 154mg Lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Cadex 1 mg: White to off-white, round, biconvex tablets, scored on one side.

Cadex 2 mg: White to off-white, biconvex caplets, scored on one side.

Cadex 4 mg: White to off-white, biconvex caplets, scored on both sides and marked "D4" on

one side.

The tablets/caplets can be divided into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Antihypertensive agent.

For the treatment of benign prostatic hypertrophy.

4.2 Posology and method of administration

Posology

Cadex may be administered in the morning or the evening.

Hypertension: Cadex is used in a once daily regimen: the initial dose is 1mg, to minimise the

potential for postural hypotension and/or syncope (see section 4.4: Special warnings and

precautions for use). Dosage may then be increased to 2mg after an additional one or two weeks

of therapy and thereafter, if necessary to 4mg. The majority of patients who respond to Cadex

will do so at a dose of 4mg or less. Dosage can be further increased if necessary to 8mg or the

maximum recommended dose of 16mg.

Benign prostatic hyperplasia: The recommended initial dosage of Cadex is 1mg given once

daily to minimise the potential for postural hypotension and/or syncope (see section 4.4).

Depending on the individual patient's urodynamics and BPH symptomatology dosage may then

be increased to 2mg and thereafter to 4mg and up to the maximum recommended dose of 8mg.

The recommended titration interval is 1-2 weeks. The usual recommended dose is 2-4mg daily.

Paediatric population: The safety and efficacy of doxazosin in children and adolescents have

not been established.

Elderly patients: Normal adult dosage.

Hepatic/Renal impairment

Patients with renal impairment: Since there is no change in pharmacokinetics in patients with

impaired renal function, the usual adult dose of doxazosin is recommended.

Doxazosin is not dialysable.

Patients with hepatic impairment: There are only limited data in patients with liver impairment

and on the effect of drugs known to influence hepatic metabolism (e.g. cimetidine). As with any

drug wholly metabolised by the liver, doxazosin should be administered with caution to patients

with evidence of impaired liver function (see section 4.4: Special warnings and precautions for

use and section 5.2: Pharmacokinetic properties).

Method of administration

Oral administration

4.3 Contraindications

Doxazosin is contraindicated in:

1) Hypersensitivity to the active substance or other types of quinazolines (e.g. prazosin,

terazosin), or to any of the excipients listed in section 6.1.

2) Patients with a history of orthostatic hypotension.

3) Patients with benign prostatic hyperplasia and concomitant congestion of the upper urinary

tract, chronic urinary tract infection or bladder stones.

4) Patients with hypotension (for benign prostatic hyperplasia indication only).

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

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 (see section 4.2:

Posology and method of administration). 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.

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

- high-output cardiac failure

- 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 (see section 4.2:

Posology and method of administration). 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 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:

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.

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.

Screening for Prostate Cancer:

Carcinoma of the prostate causes many of the symptoms associated with BPH and two disorders

can co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing

therapy with doxazosin for treatment of BPH symptoms.

Cadex contains lactose. Patients with rare hereditary problems of galactose intolerance, total

lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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

Concomitant administration of doxazosin with a PDE-5 inhibitor may lead to symptomatic

hypotension in some patients (see section 4.4: Special warnings and precautions for use). 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 drugs tested (digoxin, phenytoin, warfarin

or indometacin).

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 interaction 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 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

For the hypertension indication:

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. Although no teratogenic effects were seen in animal testing, reduced foetal survival was

observed in animals at extremely high doses (see Section 5.3: Pre-clinical safety data).

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 risk

For the benign prostatic hyperplasia indication: This section is not applicable

4.7 Effects on ability to drive and use machines

The ability to drive or use machinery may be impaired, especially when initiating therapy.

4.8 Undesirable effects

Hypertension: In clinical trials involving patients with hypertension, the most common reactions

associated with doxazosin therapy were of a postural type (rarely associated with fainting) or

non-specific.

Benign prostatic hyperplasia: Experience in controlled clinical trials in BPH indicates a similar

adverse event profile to that seen in hypertension.

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).

System Organ

Class

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)

Unknown

Infections and

infestations

Respiratory

tract

infection,

urinary tract

infection

Blood and the

lymphatic system

disorders

Leukopenia,

thrombocytopenia

Immune system

disorders

Allergic drug

reaction

Metabolism and

nutrition

disorders

Gout, increased

appetite,

anorexia

Psychiatric

disorders

Agitation,

depression,

anxiety,

insomnia,

nervousness

Nervous system

disorders

Somnolence

dizziness,

headache

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

Hypotension,

Hot flushes

System Organ

Class

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)

Unknown

disorders

postural

hypotension

Respiratory,

thoracic and

mediastinal

disorders

Bronchitis,

cough,

dyspnoea,

rhinitis

Epistaxis,

Bronchospasm

Gastrointestinal

disorders

Abdominal

pain,

dyspepsia,

dry mouth,

nausea

Constipation,

flatulence,

vomiting,

gastroenteritis

diarrhoea

Hepato-biliary

disorders

Abnormal liver

function tests

Cholestasis,

hepatitis, jaundice

Skin and

subcutaneous

tissue disorders

Pruritus

Skin rash

Urticaria, alopecia,

purpura

Musculoskeletal,

connective tissue

and bone

disorders

Back pain,

myalgia

Arthralgia

Muscle

cramps,

muscle

weakness

Renal and

urinary disorders

Cystitis,

urinary

incontinence

Dysuria,

micturition

frequency,

haematuria

Polyuria

Increased diuresis,

micturition

disorder, nocturia

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

System Organ

Class

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)

Unknown

Investigations

Weight

increase

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.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

https://sideeffects.health.gov.il

4.9 Overdose

Should overdosage lead to hypotension, the patient should be immediately placed in a supine,

head down position. Other supportive measures may be appropriate in individual cases.

If this measure is inadequate, shock should first be treated with volume expanders. If necessary,

vasopressor should then be used. Renal function should be monitored and supported as needed.

Since doxazosin is highly protein bound, dialysis is not indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists, ATC code: C02CA04

Mechanism of action

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

results in a decrease in systemic blood pressure. Doxazosin is appropriate for oral administration

in a once daily regimen in patients with essential hypertension.

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 co-existent 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, in addition to its antihypertensive effect, has in long term studies produced a modest

reduction in plasma total cholesterol, LDL-cholesterol and triglyceride concentrations and

therefore may be of particular benefit to hypertensive patients with concomitant hyperlipidaemia.

Administration of doxazosin to patients with symptomatic BPH results in a significant

improvement in urodynamics and symptoms. The effect in BPH is thought to result from

selective blockade of the alpha-adrenoceptors located in the muscular stroma and capsule of the

prostate, and in the bladder neck.

5.2 Pharmacokinetic properties

Absorption: Following oral administration in humans (young male adults or the elderly of either

sex), doxazosin is well absorbed and approximately two thirds of the dose is bioavailable.

Biotransformation/Elimination: Approximately 98% of doxazosin is protein-bound in plasma.

Doxazosin is extensively metabolised in man and in the animal species tested, with the faeces

being the predominant route of excretion.

The mean plasma elimination half-life is 22 hours thus making the drug suitable for once daily

administration.

After oral administration of doxazosin the plasma concentrations of the metabolites are low. The

most active (6' hydroxy) metabolite is present in man at one fortieth of the plasma concentration

of the parent compound, which suggests that the antihypertensive activity is in the main due to

doxazosin.

There are only limited data in patients with liver impairment and on the effects of drugs known

to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 subjects 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 40%. As with any drug wholly

metabolised by the liver, doxazosin should be administered with caution to patients with

impaired liver function (see section 4.4).

Doxazosin is extensively metabolized 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 in

safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

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 radioactive doxazosin indicate that doxazosin

accumulates in rat milk with a maximum of concentration about 20 times greater than the

maternal plasma concentration.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, magnesium stearate,

silica colloidal anhydrous, sodium laurilsulfate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The expiry date of the product is indicated on the packaging materials

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Blister

Pack sizes: 10, 28, 30, 90 Tablets / Caplets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Dexcel Ltd.

1 Dexcel Street, Or Akiva, 3060000, Israel

8. MARKETING AUTHORISATION NUMBER

Cadex 1mg: 113 78 29600 00

Cadex 2mg: 113 79 29601 00

Cadex 4mg: 113 80 29602 00

Revised in March 2020

ץרמ

2020

Cadex 1 mg, tablets

Cadex 2 mg, caplets

Cadex 4 mg, caplets

,דבכנ יאופר תווצ

ןוכדע לע םכעידוהל תשקבמ מ"עב לסקד תרבח םינולעב

ו אפורל רישכתה לש ןכרצל םי

סקדק

1

סקדק ,ג"מ

2

,ג"מ סקדק

4

ג"מ

העדוהב וז םינוכדעה םיטרופמ דבלב יתוחיטבה עדימב הרמחה םיווהמה

ןייעל שי ,אלמ עדימל םינולעב

ןכרצלו אפורל םינולעה

חלשנ

ופורתה רגאמב םוסרפל לבקל ןתינו תואירבה דרשמ רתאבש ת

ספדומ םי

י"ע :םושירה לעבל היינפ

לסקד מ"עב לסקד 'חר ,

אביקע רוא ,

3060000

:'לט ,לארשי

04-6364000

רישכתה בכרה םי

:

Each tablet/caplet contains doxazosin (as mesylate) 1mg, 2mg or 4mg respectively.

יוותה תו

רשואמ

ו

Antihypertensive agent.

For the treatment of benign prostatic hypertrophy.

ןולעה

אפורל

ןכדוע

ךיראתב ץרמ

2020

םינוכדעה ןלהל . יתוחיטבה עדימב הרמחה םיווהמה

םינמוסמ)

םודא

:

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. 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:

Carcinoma of the prostate causes many of the symptoms associated with BPH and two

disorders can co-exist. Carcinoma of the prostate should therefore be ruled out prior to

commencing therapy with doxazosin for treatment of BPH symptoms.

4.5 Interaction with other medicinal products and other forms of interaction

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).

5.2 Pharmacokinetic properties

Biotransformation/Elimination:

Doxazosin is extensively metabolized 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

Studies in lactating rats given a single oral dose of radioactive doxazosin indicate that

doxazosin accumulates in rat milk with a maximum of concentration about 20 times greater

than the maternal plasma concentration.

ןולעה

ןכרצל

ןכדוע

ב

ךיראת ץרמ

2020

יתוחיטבה עדימב הרמחה םיווהמה םינוכדעה ןלהל . םינמוסמ)

םודא

:

2

.

הפורתב שומישה ינפל

...

הפורתב שומישל תועגונה תודחוימ תורהזא

...

ב לופיטה תלחתה ינפל סקדק ןטרס ןוגכ םירחא םיבצמ לולשל תנמ לע תוקידב עצבי ךלש אפורהש ןכתיי , .תינומרעה לש הריפש רתי תלדגהב ומכ םיהז םינימסתל םורגל לולעה ,תינומרעה

תופקז

.דיימ אפורל תונפל שי ,הזכ הרקמב .דואמ תורידנ םיתיעל שחרתהל תולולע תובאוכו תוכשמתמ

...

תויתפורת ןיב תובוגת

,הנורחאל תחקל םא ,חקול התא םא תחקל יושע התא םא וא

םשרמ אלל תופורת ללוכ תורחא תופורת חקורל וא אפורל ךכ לע רפס ,הנוזת יפסותו

םע תויתפורת ןיב תובוגת תויהל תולולע תופורתהמ קלחל סקדק ,שומישה ינפל חקורה וא אפורה תא לאש . לש העפשהה תא תונשל תולולע ןהש תויה ,תואבה תופורתהמ רתוי וא תחא חקול התא םא סקדק

...

,לוזנוקרטיא ,ןיצימורתירלק ןוגכ םייתיירטפ וא םייקדייח םימוהיזב לופיטל תופורת ,לוזנוקוטק .לוזנוקירוו ,ןיצימורתילט

ב לופיטל תופורת

.ריבניווקס ,ריבנוטיר ,ריבניפלנ ,ריבנידניא ןוגכ

.ןואכידב לופיטל הפורת ,ןודוזפנ

...

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