DETRUSITOL SR 2 MG

Israel - English - Ministry of Health

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Active ingredient:
TOLTERODINE L-TARTRATE
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
G04BD07
Pharmaceutical form:
CAPSULES SLOW RELEASE
Composition:
TOLTERODINE L-TARTRATE 2 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
PFIZER ITALIA S.R.L, ITALY
Therapeutic group:
TOLTERODINE
Therapeutic area:
TOLTERODINE
Therapeutic indications:
For the treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency or urge incontinence.
Authorization number:
125 56 30466 00
Authorization date:
2012-05-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

20-01-2021

Patient Information leaflet Patient Information leaflet - Arabic

19-02-2017

Patient Information leaflet Patient Information leaflet - Hebrew

16-06-2020

PATIENT PACKAGE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The dispensing of this medicine

requires a doctor’s prescription

Read this package insert carefully

in its entirety before using this medicine

The format of this leaflet was determined by the

Ministry of Health and its content

was checked and approved

Detrusitol

®

SR

Detrusitol

®

SR

2 mg

4 mg

Capsules

Capsules

Composition:

Each capsule contains:

Each capsule contains:

Tolterodine tartrate 2 mg

Tolterodine tartrate 4 mg

Inactive ingredients:

Sugar spheres, hydroxypropyl methylcellulose,

ethylcellulose, ammonium hydroxide, medium chain

triglycerides, oleic acid, gelatin, FD&C Blue#2,

shellac glaze, titanium dioxide, propylene glycol,

simethicone.

The 2 mg capsules also contain yellow iron oxide.

Each 2 mg capsule contains 67.23 mg sugar spheres.

Each 4 mg capsule contains 134.5 mg sugar spheres.

Therapeutic group: Muscarinic receptor antagonist.

Therapeutic

activity:

preparation

with

anti-muscarinic activity intended for the treatment

of overactive bladder with symptoms of urinary

frequency, urgency or urge incontinence.

When should the preparation not be used?

Do not use this medicine if you are breastfeeding.

Do not use this medicine if you are sensitive to any

of its ingredients.

Do not use this medicine in patients afflicted with

urinary retention, gastrointestinal obstruction,

uncontrolled narrow-angle glaucoma.

Do not take this medicine without consulting a

doctor before starting treatment in the following

cases:

If you are pregnant.

If you are suffering, or have suffered in the past, from

impaired function of the eyes (e.g. glaucoma), the liver,

the kidney/urinary tract - in cases of bladder outflow

obstruction, risk of urinary retention and kidney

diseases, the digestive system - gastrointestinal

disturbances or obstructive disorders such as pyloric

stenosis.

If you are suffering, or have suffered in the past,

from arrhythmias or if you are taking medicines for

regulating heart rate.

If you are suffering, or have suffered in the past, from

severe muscle weakness (myasthenia gravis).

How will this medicine affect your daily life?

Use of this medicine may cause blurred vision and

influence reaction time, and therefore caution should

be exercised when engaging in activities such as

driving a car and operating dangerous machinery.

Warnings: Use of this medicine may cause blurred

vision.

If you are sensitive to any type of food or medicine,

inform your doctor before commencing treatment with

this medicine.

Avoid pregnancy during treatment with this

medicine.

Consult with your doctor regarding appropriate

contraceptive measures.

The capsules contain sugar.

Drug interactions: If you are taking another drug

concomitantly, including non-prescription medicines

and food supplements, or if you have just finished

treatment with another medicine, inform the attending

doctor in order to prevent hazards or lack of efficacy

arising from drug interactions. This is especially

important for medicines belonging to the following

groups: anticholinergic medicines or medicines with

anticholinergic activity (such as preparations for

treating stomach convulsions); antibiotic medicines:

erythromycin and clarithromycin; antifungal medicines:

ketoconazole, itraconazole and miconazole;

cyclosporin; vinblastine.

Side effects: In addition to the desired effect of

the medicine, adverse reactions may occur during

the course of taking this medicine, for example: dry

mouth, headache, diarrhea, constipation, abdominal

pain, disturbances in the accommodation of vision,

dry eyes, allergic reaction, rapid pulse, edemas,

hallucinations, confusion, memory disturbances.

Side effects that require special attention:

Urinary retention: stop treatment and consult your

doctor.

In the event that you experience side effects not

mentioned in this leaflet, or if there is a change in your

general health, consult your doctor immediately.

Dosage: Dosage is according to doctor’s instructions

only. Do not exceed the recommended dosage.

This medicine is not usually intended for children.

This medicine is to be taken at specific time intervals

as determined by the attending doctor. If you forget

to take this medicine at the specified time, take the

dose as soon as you remember, but never take a

double dose!

Directions for use: Do not chew! Swallow this

medicine with a half glass of water. The medicine

can be taken before or after a meal. Do not halve or

crush the capsule.

How can you contribute to the success of the

treatment?

Complete the full course of treatment as instructed

by the doctor. Even if there is an improvement in your

health, do not discontinue use of this medicine without

consulting your doctor.

Avoid poisoning! This medicine, and all other

medicines, must be stored in a safe place out of the

reach of children and/or infants, to avoid poisoning.

If you have taken an overdose, or if a child has

accidentally swallowed the medicine, proceed

immediately to a hospital emergency room and bring

the package of the medicine with you. Do not induce

vomiting unless explicitly instructed to do so by a

doctor! This medicine has been prescribed for the

treatment of your illness; in another patient it may

cause harm. Do not give this medicine to your

relatives, neighbours or acquaintances.

Do not take medicines in the dark! Check the label

and the dose each time you take your medicine. Wear

glasses if you need them.

Storage: At a temperature not exceeding 25

Even if kept in their original container and stored as

recommended, medicines may be kept for a limited

period only. Please note the expiry date of the

medicine! In case of doubt, consult the pharmacist

who dispensed the medicine to you.

Do not store different medications in the same

package.

License number:

Detrusitol

SR 2 mg: 125.56.30466

Detrusitol

SR 4 mg: 125.55.30467

Manufacturer: Pfizer Italia S.R.L, Ascoli Piceno,

Italy.

Registration owner: Pfizer PFE Pharmaceuticals

Israel Ltd., 9 Shenkar St., Herzeliya Pituach 46725.

Detrusitol SR LPD CC 17052020

SR 2MG

®

DETRUSITOL

SR 4MG

RUSITOL

DET

NAME OF THE MEDICINAL PRODUCT

Detrusitol

2 mg

Detrusitol

4 mg

QUALITATIVE AND QUANTATIVE COMPOSITION

Each capsule contains 2 mg or 4mg of tolterodine L-tartrate.

Excipients with known effect:

Each capsule contains sugar spheres.

For the full list of excipients, see section Description (9) in this leaflet.

PHARMACEUTICAL FORM

Capsules slow release

1

INDICATIONS AND USAGE

For the treatment of patients with an overactive bladder with symptoms of urinary frequency,

urgency, or urge incontinence.

2

DOSAGE AND ADMINISTRATION

The recommended dose of DETRUSITOL

SR Capsules are 4 mg daily. DETRUSITOL

should be taken

once daily with liquids and swallowed whole. The dose may be lowered to 2 mg daily based on individual

response and tolerability, however, limited efficacy data is available for DETRUSITOL

SR 2 mg (see

CLINICAL STUDIES).

For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are

potent inhibitors of CYP3A4, the recommended dose of DETRUSITOL

is 2 mg daily (see CLINICAL

PHARMACOLOGY and PRECAUTIONS, Drug Interactions).

3

CONTRAINDICATIONS

DETRUSITOL

SR is contraindicated in patients with urinary retention, gastric retention, or uncontrolled

narrow-angle glaucoma. DETRUSITOL

SR is also contraindicated in patients with known hypersensitivity to

the active substance or to any of the excipients listed in section 9,, or to fesoterodine fumarate extended-release

tablets which, like DETRUSITOL

SR, are metabolized to 5-hydroxymethyl tolterodine

[see WARNINGS

AND PRECAUTIONS (4.2) (4.3) (4.4)].

4

WARNINGS AND PRECAUTIONS

4.1

Angioedema

Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with

the first or subsequent doses of DETRUSITOL

SR. In the event of difficulty in breathing, upper airway

2016-0018532, 2015-0013293

obstruction, or fall in blood pressure, DETRUSITOL

SR should be discontinued and appropriate therapy

promptly provided.

4.2

Urinary Retention

Administer

DETRUSITOL

SR Capsules with caution to patients with clinically significant bladder outflow

obstruction because of the risk of urinary retention

[see CONTRAINDICATIONS (3)]

4.3 Gastrointestinal Disorders

Administer DETRUSITOL

SR with caution in patients with gastrointestinal obstructive disorders because of

the risk of gastric retention.

DETRUSITOL

SR, like other antimuscarinic drugs, may decrease gastrointestinal motility and should be used

with caution in patients with conditions associated with decreased gastrointestinal motility (e.g., intestinal

atony)

[see CONTRAINDICATIONS (3)]

4.4

Controlled Narrow-Angle Glaucoma

Administer DETRUSITOL

SR with caution in patients being treated for narrow-angle glaucoma

[see

CONTRAINDICATIONS (3)]

4.5

Central Nervous System Effects

DETRUSITOL

SR is associated with anticholinergic central nervous system (CNS) effects [see Adverse

Reactions (5

.

2)] including dizziness and somnolence [see Adverse Reactions (5.1)]. Patients should be

monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose.

Advise patients not to drive or operate heavy machinery until the drug’s effects have been determined. If a

patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

4.6

Hepatic Impairment

The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients

than in the healthy volunteers. For patients with mild to moderate hepatic impairment (Child-Pugh Class A or

B), the recommended dose for DETRUSITOL

SR is 2 mg once daily. DETRUSITOL

SR is not

recommended for use in patients with severe hepatic impairment (Child-Pugh Class C)

[see DOSAGE AND

ADMINISTRATION (2.2) and USE IN SPECIFIC POPULATIONS (7.6)].

4.7

Renal Impairment

Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of

DETRUSITOL

SR should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10-

30 mL/min). Patients with CCr<10 mL/min have not been studied and use of DETRUSITOL

SR in this

population is not recommended

[see DOSAGE AND ADMINISTRATION (2) and USE IN SPECIFIC

POPULATIONS (7.5)

]

4.8

Myasthenia Gravis

Administer DETRUSITOL

SR with caution in patients with myasthenia gravis, a disease characterized by

decreased cholinergic activity at the neuromuscular junction.

2016-0018532, 2015-0013293

4.9

Use in Patients with Congenital or Acquired QT Prolongation

In a study of the effect of tolterodine immediate release tablets on the QT interval

[see CLINICAL

PHARMACOLOGY (10.2)]

, the effect on the QT interval appeared greater for 8 mg/day (two times the

therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than

extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not as large as that observed after four

days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped.

These observations should be considered in clinical decisions to prescribe DETRUSITOL

SR to patients with

a known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or

Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. There has been no association of Torsade de

Pointes in the international post-marketing experience with DETRUSITOL

or DETRUSITOL

4.10 Important information regarding some of the ingredients of the medicine

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-

isomaltase insufficiency should not take this medicine.

5

ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in practice.

5.1

Clinical Trials Experience

The efficacy and safety of DETRUSITOL

SR Capsules was evaluated in 1073 patients (537 assigned to

DETRUSITOL

SR ; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months.

These included a total of 1012 patients (505 randomized to DETRUSITOL

SR 4 mg once daily and 507

randomized to placebo) enrolled in a randomized, placebo-controlled, double-blind, 12-week clinical efficacy

and safety study.

Adverse events were reported in 52% (n=263) of patients receiving DETRUSITOL

SR and in 49% (n=247) of

patients receiving placebo. The most common adverse events reported by patients receiving DETRUSITOL

SR were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported

adverse event for patients treated with DETRUSITOL

SR, occurring in 23.4% of patients treated with

DETRUSITOL

SR and 7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision

(accommodation abnormalities), urinary retention, and dry eyes are expected side effects of antimuscarinic

agents. A serious adverse event was reported by 1.4% (n=7) of patients receiving SETRUSITOL

SR and by

3.6% (n=18) of patients receiving placebo.

Table 1 lists the adverse events, regardless of causality, that were reported in the randomized, double-blind,

placebo-controlled 12-week study at an incidence greater than placebo and in greater than or equal to 1% of

patients treated with DETRUSITOL® SR 4 mg once daily.

2016-0018532, 2015-0013293

Table 1. Incidence

*

(%) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients

Treated with DETRUSITOL

SR (4 mg daily) in a 12-week, Phase 3 Clinical Trial

Body System

Adverse Event

% DETRUSITOL

n=505

% Placebo

n=507

Autonomic Nervous

dry mouth

General

headache

fatigue

Central/Peripheral

Nervous

dizziness

Gastrointestinal

constipation

abdominal pain

dyspepsia

Vision

xerophthalmia

vision abnormal

Psychiatric

somnolence

anxiety

Respiratory

sinusitis

Urinary

dysuria

in nearest integer.

The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment.

Similar percentages of patients treated with DETRUSITOL

SR or placebo discontinued treatment due to

adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among

patients receiving DETRUSITOL

SR [n=12 (2.4%) vs. placebo n=6 (1.2%)].

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/.

5.2

Post-marketing Experience

The following events have been reported in association with tolterodine use in worldwide post-marketing

experience:

General:

anaphylaxis and angioedema;

Cardiovascular:

tachycardia, palpitations, peripheral edema;

Gastrointestinal:

diarrhea

;

Central/Peripheral Nervous:

confusion, disorientation, memory impairment,

hallucinations.

Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported

after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.

Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency

of events and the role of tolterodine in their causation cannot be reliably determined.

6

DRUG INTERACTIONS

6.1

Potent CYP2D6 Inhibitors

2016-0018532, 2015-0013293

Fluoxetine, a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine

immediate release in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC.

There was a 52% decrease in C

and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the

pharmacologically active metabolite of tolterodine

[see CLINICAL PHARMACOLOGY (10.1)]

. The sums of

unbound serum concentrations of tolterodine and 5-HMT are only 25% higher during the interaction. No dose

adjustment is required when tolterodine and fluoxetine are co-administered

[see CLINICAL

PHARMACOLOGY (10.3)].

6.2

Potent CYP3A4 Inhibitors

Ketoconazole (200 mg daily), a potent CYP3A4 inhibitor, increased the mean C

and AUC of tolterodine by

2- and 2.5-fold, respectively, in CYP2D6 poor metabolizers.

For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, clarithromycin, or

ritonavir, the recommended dose of DETRUSITOL

SR is 2 mg once daily

[see DOSAGE AND

ADMINISTRATION(2) and CLINICAL PHARMACOLOGY (10.3)]

6.3

Other Interactions

No clinically relevant interactions have been observed when tolterodine was co-administered with warfarin,

with a combined oral contraceptive drug containing ethinyl estradiol and levonorgestrel, or with diuretics

[see

CLINICAL PHARMACOLOGY (10.3)].

6.4

Other Drugs Metabolized by Cytochrome P450 Isoenzymes

In vivo

drug-interaction data show that tolterodine immediate release does not result in clinically relevant

inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine,

debrisoquine, S-warfarin, and omeprazole

[see CLINICAL PHARMACOLOGY (10.3)].

6.5

Drug-Laboratory-Test Interactions

Interactions between tolterodine and laboratory tests have not been studied.

6.6

Other Anticholinergics

The concomitant use DETRUSITOL

SR with other anticholinergic (antimuscarinic) agents may increase the

frequency and/or severity of dry mouth, constipation, blurred vision, somnolence, and other anticholinergic

pharmacological effects.

7

USE IN SPECIFIC POPULATIONS

7.1

Pregnancy

Risk Summary

There are no available data with DETRUSITOL

SR use in pregnant women to inform drug-associated risks.

In animal reproduction studies, oral administration of tolterodine and its 5-HMT metabolite to pregnant mice

during organogenesis did not produce adverse developmental outcomes at doses approximately 9 to 12 times

the clinical exposure at a dose of 20 mg/kg/day; however, higher doses produced adverse developmental

outcomes

(see Data)

2016-0018532, 2015-0013293

In the U.S. general population, the estimated background rate of major birth defects and miscarriage in

clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

No anomalies or malformations were observed after oral administration of tolterodine to pregnant mice during

organogenesis at approximately 9-12 times the clinical exposure to the pharmacologically active components of

DETRUSITOL

SR (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day).

At 14-18 times the clinical exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine was embryo-lethal,

caused reduced fetal weight, and increased the incidence of fetal abnormalities (cleft palate, digital

abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification).

Pregnant rabbits administered tolterodine subcutaneously at about 0.3-2.5 times the clinical exposure (dose of

0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity.

7.2

Lactation

Risk Summary

There is no information on the presence of tolterodine or its 5-HMT metabolite in human milk, the effects on

the breastfed infant, or the effects on milk production. Based on limited data, tolterodine is excreted into the

milk in mice in low amounts

(see Data)

. The development and health benefits of breastfeeding should be

considered along with the mother’s clinical need for DETRUSITOL

SR and any potential adverse effects on

the breastfed infant from DETRUSITOL

SR or from the underlying maternal condition.

Animal Data

The use of radiolabeled tolterodine in pregnant mice produced milk: plasma ratios that ranged between 0.0 and

0.7.

7.3

Pediatric Use

The effectiveness of DETRUSITOL

SR has not been established in pediatric patients.

Efficacy was not established in two randomized, placebo-controlled, double-blind, 12-week studies that

enrolled 710 pediatric patients (486 on DETRUSITOL

SR, 224 on placebo) aged 5–10 years with urinary

frequency and urge incontinence. The percentage of patients with urinary tract infections was higher in patients

treated with DETRUSITOL

SR (6.6%) compared to patients who received placebo (4.5%). Aggressive,

abnormal, and hyperactive behavior and attention disorders occurred in 2.9% of children treated with

DETRUSITOL

SR compared to 0.9% of children treated with placebo.

7.4

Geriatric Use

No overall differences in safety were observed between the older and younger patients treated with tolterodine.

In multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum

concentrations of tolterodine and of 5-HMT were similar in healthy elderly volunteers (aged 64 through 80

years) and healthy young volunteers (aged less than 40 years). In another clinical study, elderly volunteers (aged

2016-0018532, 2015-0013293

71 through 81 years) were given tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum

concentrations of tolterodine and 5-HMT in these elderly volunteers were approximately 20% and 50% higher,

respectively, than concentrations reported in young healthy volunteers. However, no overall differences were

observed in safety between older and younger patients on tolterodine in the Phase 3, 12-week, controlled

clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended.

7.5

Renal Impairment

Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In

a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine and 5-HMT

levels were approximately 2–3 fold higher in patients with renal impairment than in healthy volunteers.

Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid,

N

-dealkylated tolterodine acid,

N

dealkylated tolterodine, and

N

-dealkylated hydroxy tolterodine) were significantly higher (10–30 fold) in

renally impaired patients as compared to the healthy volunteers. The recommended dose for patients with severe

renal impairment (CCr: 10-30 mL/min) is DETRUSITOL

SR 2 mg daily. Patients with CCr<10 mL/min have

not been studied and use of DETRUSITOL

SR in this population is not recommended

[see DOSAGE AND

ADMINISTRATION (2)

WARNINGS AND PRECAUTIONS (4.7)].

DETRUSITOL

SR has not been

studied in patients with mild to moderate renal impairment [CCr 30-80 mL/min].

7.6

Hepatic Impairment

Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study of

tolterodine immediate release conducted in cirrhotic patients (Child-Pugh Class A and B), the elimination half-

life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young,

and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine immediate release

was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg).

The recommended dose for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) is

DETRUSITOL

SR 2 mg once daily. DETRUSITOL

SR is not recommended for use in patients with severe

hepatic impairment (Child-Pugh Class C)

[see DOSAGE AND ADMINISTRATION (2)

WARNINGS

AND PRECAUTIONS (4.6)].

8

OVERDOSAGE

Overdosage with DETRUSITOL

Capsules can potentially result in severe central anticholinergic effects and

should be treated accordingly.

ECG monitoring is recommended in the event of overdosage. In dogs, changes in the QT interval (slight

prolongation of 10% to 20%) were observed at a suprapharmacologic dose of 4.5 mg/kg, which is about 68

times higher than the recommended human dose. In clinical trials of normal volunteers and patients, QT interval

prolongation was observed with tolterodine immediate release at doses up to 8 mg (4 mg bid) and higher doses

were not evaluated

[see WARNINGS AND PRECAUTIONS (4.

9) and CLINICAL PHARMACOLOGY

(10.2)]

A 27-month-old child who ingested 5 to 7 tolterodine immediate release 2 mg tablets was treated with a

suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully

recovered.

9

DESCRIPTION

DETRUSITOL

SR Capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic

2016-0018532, 2015-0013293

receptor antagonist. The chemical name of tolterodine tartrate is (R)-N,N-diisopropyl-3-(2-hydroxy-5-

methylphenyl)-3-phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is

. Its structure is:

Tolterodine tartrate is a white, crystalline powder with a molecular weight of 475.6. The pK

value is 9.87 and

the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically

insoluble in toluene. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3.

DETRUSITOL

SR 4 mg capsule for oral administration contains 4 mg of tolterodine tartrate. Inactive

ingredients are sugar spheres, ethylcellulose, medium chain triglycerides, oleic acid , ammonium hydroxide,

purified water, hydroxypropyl methylcellulose, , , , gelatin, titanium dioxide and FD&C Blue #2.

DETRUSITOL

SR 2 mg capsule for oral administration contains 2 mg of tolterodine tartrate, and the

following inactive ingredients: sugar spheres, ethylcellulose, medium chain triglycerides, oleic acid ,

ammonium hydroxide, purified water, hydroxypropyl methylcellulose, gelatin, yellow iron oxide, titanium

dioxide and FD&C Blue #2.

10

CLINICAL PHARMACOLOGY

10.1

Mechanism of Action

Tolterodine acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors. Both

urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.

After oral administration, tolterodine is metabolized in the liver, resulting in the formation of 5-hydroxymethyl

tolterodine (5-HMT), the major pharmacologically active metabolite. 5-HMT, which exhibits an antimuscarinic

activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and 5-

HMT exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other

neurotransmitter receptors and other potential cellular targets, such as calcium channels.

10.2

Pharmacodynamics

Tolterodine has a pronounced effect on bladder function. Effects on urodynamic parameters before and 1 and 5

hours after a single 6.4 mg dose of tolterodine immediate release were determined in healthy volunteers. The

main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete

emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an

antimuscarinic action on the lower urinary tract.

Cardiac Electrophysiology

The effect of 2 mg BID and 4 mg BID of DETRUSITOL

immediate release (tolterodine IR) tablets on the QT

interval was evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg

QD) study in healthy male (N=25) and female (N=23) volunteers aged 18–55 years. Study subjects

[approximately equal representation of CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs)]

completed sequential 4-day periods of dosing with moxifloxacin 400 mg QD, tolterodine 2 mg BID, tolterodine

2016-0018532, 2015-0013293

4 mg BID, and placebo. The 4 mg BID dose of tolterodine IR (two times the highest recommended dose) was

chosen because this dose results in tolterodine exposure similar to that observed upon coadministration of

tolterodine 2 mg BID with potent CYP3A4 inhibitors in patients who are CYP2D6 poor metabolizers

[see

DRUG INTERACTIONS

(6.2)]

. QT interval was measured over a 12-hour period following dosing, including

the time of peak plasma concentration (T

) of tolterodine and at steady state (Day 4 of dosing).

Table 2 summarizes the mean change from baseline to steady state in corrected QT interval (QT

) relative to

placebo at the time of peak tolterodine (1 hour) and moxifloxacin (2 hour) concentrations. Both Fridericia’s

F) and a population-specific (QT

P) method were used to correct QT interval for heart rate. No single QT

correction method is known to be more valid than others. QT interval was measured manually and by machine,

and data from both are presented. The mean increase of heart rate associated with a 4 mg/day dose of

tolterodine in this study was 2.0 beats/minute and 6.3 beats/minute with 8 mg/day tolterodine. The change in

heart rate with moxifloxacin was 0.5 beats/minute.

Table 2. Mean (CI) change in QT

from baseline to steady state (Day 4 of dosing)

at T

max

(relative to placebo)

Drug/Dose

N

QT

F

(msec)

(manual)

QT

F

(msec)

(machine)

QT

P

(msec)

(manual)

QT

P

(msec)

(machine)

Tolterodine

2 mg BID

*

5.01

(0.28, 9.74)

1.16

(-2.99, 5.30)

4.45

(-0.37, 9.26)

2.00

(-1.81, 5.81)

Tolterodine

4 mg BID

*

11.84

(7.11, 16.58)

5.63

(1.48, 9.77)

10.31

(5.49, 15.12)

8.34

(4.53, 12.15)

Moxifloxaci

n 400 mg

19.26

(15.49, 23.03)

8.90

(4.77, 13.03)

19.10

(15.32, 22.89)

9.29

(5.34, 13.24)

*

At T

of 1 hr; 95% Confidence Interval.

At T

of 2 hr; 90% Confidence Interval.

The effect on QT interval with 4 days of moxifloxacin dosing in this QT trial may be greater than typically

observed in QT trials of other drugs.

The reason for the difference between machine and manual read of QT interval is unclear.

The QT effect of tolterodine immediate release tablets appeared greater for 8 mg/day (two times the therapeutic

dose) compared to 4 mg/day. The effect of tolterodine 8 mg/day was not as large as that observed after four

days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped.

Tolterodine’s effect on QT interval was found to correlate with plasma concentration of tolterodine. There

appeared to be a greater QT

interval increase in CYP2D6 poor metabolizers than in CYP2D6 extensive

metabolizers after tolterodine treatment in this study.

This study was not designed to make direct statistical comparisons between drugs or dose levels. There has been

no association of Torsade de Pointes in the international post-marketing experience with DETRUSITOL

DETRUSITOL

[

WARNINGS AND PRECAUTIONS (4.9)]

10.3

Pharmacokinetics

Absorption:

In a study with

C-tolterodine solution in healthy volunteers who received a 5 mg oral dose, at

least 77% of the radiolabeled dose was absorbed. C

and area under the concentration-time curve (AUC)

2016-0018532, 2015-0013293

determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg.

Based on the sum of unbound serum concentrations of tolterodine and 5-HMT (“active moiety”), the AUC of

tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). C

levels of tolterodine extended release are about 75% and 150% of tolterodine immediate release,

respectively. Maximum serum concentrations of tolterodine extended release are observed 2 to 6 hours after

dose administration.

Effect of Food:

There is no effect of food on the pharmacokinetics of tolterodine extended release.

Distribution:

Tolterodine is highly bound to plasma proteins, primarily α

-acid glycoprotein. Unbound

concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. 5-

HMT is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood

to serum ratio of tolterodine and 5-HMT averages 0.6 and 0.8, respectively, indicating that these compounds do

not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration

of a 1.28 mg intravenous dose is 113 ± 26.7 L.

Metabolism:

Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic

route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and

leads to the formation of a pharmacologically active metabolite, 5-HMT. Further metabolism leads to formation

of the 5-carboxylic acid and

N

-dealkylated 5-carboxylic acid metabolites, which account for 51% ± 14% and

29% ± 6.3% of the metabolites recovered in the urine, respectively.

Variability in Metabolism: A subset of individuals (approximately 7% of Caucasians and approximately 2% of

African Americans) are poor metabolizers for CYP2D6, the enzyme responsible for the formation of 5-HMT

from tolterodine. The identified pathway of metabolism for these individuals (“poor metabolizers”) is

dealkylation via cytochrome P450 3A4 (CYP3A4) to

N

-dealkylated tolterodine. The remainder of the

population is referred to as “extensive metabolizers.” Pharmacokinetic studies revealed that tolterodine is

metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly

higher serum concentrations of tolterodine and in negligible concentrations of 5-HMT.

Excretion:

Following administration of a 5 mg oral dose of

C-tolterodine solution to healthy volunteers, 77%

of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% (< 2.5% in poor

metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was

recovered as 5-HMT.

A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine extended release and 5-

HMT in extensive (EM) and poor (PM) metabolizers is provided in Table 3. These data were obtained

following single and multiple doses of tolterodine extended release administered daily to 17 healthy male

volunteers (13 EM, 4 PM).

2016-0018532, 2015-0013293

Table 3. Summary of Mean (±SD) Pharmacokinetic Parameters of Tolterodine Extended Release and its

Active Metabolite (5-Hydroxymethyl Tolterodine) in Healthy Volunteers

Tolterodine

5-Hydroxymethyl Tolterodine

(µg/L)

(µg/L)

(µg/L)

(µg/L)

Single dose

4 mg

4(2–6)

1.3(0.8)

0.8(0.57)

8.4(3.2)

4(3–6)

1.6(0.5)

1.0(0.32)

8.8(5.9)

Multiple

dose 4 mg

4(2–6)

4(3–6)

3.4(4.9)

19(16)

1.7(2.8)

13(11)

6.9(3.5)

18(16)

4(2–6)

2.7(0.90)

1.4(0.6)

9.9(4.0)

= Maximum serum concentration; t

= Time of occurrence of C

= Average serum concentration; t

= Terminal elimination half-life.

*Data presented as median (range).

†Parameter dose-normalized from 8 to 4 mg for the single-dose data.

‡ = not applicable.

Drug Interactions:

Potent CYP2D6 inhibitors:

Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of

CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate

release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine

immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a

52% decrease in C

and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT, the

pharmacologically active metabolite of tolterodine). Fluoxetine thus alters the pharmacokinetics in patients who

would otherwise be CYP2D6 extensive metabolizers of tolterodine immediate release to resemble the

pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine

immediate release and 5-HMT are only 25% higher during the interaction. No dose adjustment is required when

tolterodine and fluoxetine are co-administered.

Potent CYP3A4 inhibitors:

The effect of a 200 mg daily dose of ketoconazole on the pharmacokinetics of

tolterodine immediate release was studied in 8 healthy volunteers, all of whom were CYP2D6 poor

metabolizers. In the presence of ketoconazole, the mean C

and AUC of tolterodine increased by 2- and 2.5-

fold, respectively. Based on these findings, other potent CYP3A4 inhibitors may also lead to increases of

tolterodine plasma concentrations.

For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, miconazole,

clarithromycin, ritonavir, the recommended dose of DETRUSITOL

SR is 2 mg daily

[see DOSAGE AND

ADMINISTRATION(2)]

Warfarin:

In healthy volunteers, coadministration of tolterodine immediate release 4 mg (2 mg bid) for 7 days

and a single dose of warfarin 25 mg on day 4 had no effect on prothrombin time, Factor VII suppression, or on

the pharmacokinetics of warfarin.

2016-0018532, 2015-0013293

Oral Contraceptives

:

Tolterodine immediate release 4 mg (2 mg bid) had no effect on the pharmacokinetics of

an oral contraceptive (ethinyl estradiol 30 µg/levo-norgestrel 150 µg) as evidenced by the monitoring of ethinyl

estradiol and levo-norgestrel over a 2-month period in healthy female volunteers.

Diuretics:

Coadministration of tolterodine immediate release up to 8 mg (4 mg bid) for up to 12 weeks with

diuretic agents, such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide,

methylchlorothiazide, or furosemide, did not cause any adverse electrocardiographic (ECG) effects.

Effect of tolterodine on other drugs metabolized by Cytochrome P450 enzymes: Tolterodine immediate release

does not cause clinically significant interactions with other drugs metabolized by the major drug-metabolizing

CYP enzymes.

In vivo

drug-interaction data show that tolterodine immediate release does not result in clinically

relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs

caffeine, debrisoquine, S-warfarin, and omeprazole.

In vitro

data show that tolterodine immediate release is a

competitive inhibitor of CYP2D6 at high concentrations (K

1.05 µM), while tolterodine immediate release as

well as the 5-HMT are devoid of any significant inhibitory potential regarding the other isoenzymes.

11

NONCLINICAL TOXICOLOGY

11.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with tolterodine were conducted in mice and rats. At the maximum tolerated dose in

mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), exposure margins were

approximately 6-9 times, 7 times, and 11 times the clinical exposure to the pharmacologically active

components of DETRUSITOL

SR (based on AUC of tolterodine and its 5-HMT metabolite). At these

exposure margins, no increase in tumors was found in either mice or rats.

No mutagenic or genotoxic effects of tolterodine were detected in a battery of

in

vitro

tests, including bacterial

mutation assays (Ames test) in 4 strains of

Salmonella typhimurium

and in 2 strains of

Escherichia coli,

a gene

mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes.

Tolterodine was also negative

in vivo

in the bone marrow micronucleus test in the mouse.

In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (about 9-12 times the

clinical exposure via AUC), neither effects on reproductive performance or fertility were seen. In male mice, a

dose of 30 mg/kg/day did not induce any adverse effects on fertility.

12

CLINICAL STUDIES

DETRUSITOL

SR Capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study.

DETRUSITOL

SR 4 mg was evaluated for the treatment of overactive bladder with symptoms of urge urinary

incontinence and frequency in a randomized, placebo-controlled, multicenter, double-blind, Phase 3, 12-week

study. A total of 507 patients received DETROL LA 4 mg once daily in the morning and 508 received placebo.

The majority of patients were Caucasian (95%) and female (81%), with a mean age of 61 years (range, 20 to 93

years). In the study, 642 patients (42%) were 65 to 93 years of age. The study included patients known to be

responsive to tolterodine immediate release and other anticholinergic medications, however, 47% of patients

never received prior pharmacotherapy for overactive bladder. At study entry, 97% of patients had at least 5 urge

incontinence episodes per week and 91% of patients had 8 or more micturitions per day.

The primary efficacy assessment was change in mean number of incontinence episodes per week at week 12

from baseline. Secondary efficacy measures included change in mean number of micturitions per day and mean

volume voided per micturition at week 12 from baseline.

2016-0018532, 2015-0013293

Patients treated with DETRUSITOL

SR experienced a statistically significant decrease in number of urinary

incontinence per week from baseline to last assessment (week 12) compared with placebo as well as a decrease

in the average daily urinary frequency and an increase in the average urine volume per void.

Mean change from baseline in weekly incontinence episodes, urinary frequency, and volume voided between

placebo and DETRUSITOL

SR are summarized in Table 4.

Table 4. 95% Confidence Intervals (CI) for the Difference between DETRUSITOL

SR (4 mg daily) and

Placebo for Mean Change at Week 12 from Baseline

*

DETRUSITOL

(n=507)

Placebo

(n=508)†

Treatment

Difference, vs.

Placebo

(95% Cl)

Number of incontinence episodes/

week

Mean Baseline

Mean Change from Baseline

22.1

–11.8 (SD 17.8)

23.3

–6.9 (SD 15.4)

-4.8‡

(–6.9, –2.8)

Number of micturitions/day

Mean Baseline

Mean Change from Baseline

10.9

–1.8 (SD 3.4)

11.3

–1.2 (SD 2.9)

-0.6‡

(–1.0, –0.2)

Volume voided per micturition

(mL)

Mean Baseline

Mean Change from Baseline

34 (SD 51)

14 (SD 41)

20‡

(14, 26)

SD = Standard Deviation.

Intent-to-treat analysis.

† 1 to 2 patients missing in placebo group for each efficacy parameter.

‡ The difference between DETRUSITOL

SR and placebo was statistically significant.

2016-0018532, 2015-0013293

13.

HOW SUPPLIED/STORAGE AND HANDLING

DETRUSITOL

SR Capsules are supplied as follows:

Carton with PVC-/PVDC/-Aluminum foil blisters containing 28 tablets.

DETRUSITOL

Capsules 2 mg are blue-green with symbol printed in white ink.

DETRUSITOL

Capsules 4 mg are blue with symbol printed in white ink.

Store below 25

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

14. MANUFACTURER:

Pfizer Italia S.R.L, Ascoli Piceno, Italy.

15

. LICENSE MARKETING HOLDER

Pfizer PFE Pharmaceuticals Israel Ltd. 9 Shenkar St., Herzliya Pituach, 46725 Israel

16.LICENSE NUMBER

Detrusitol

SR 2mg:

125-56-30466

Detrusitol

SR 4mg:

125-55-30467

Revised in May 2020

מ"עב לארשי הקיטבצמרפ יא ףא יפ רזייפ

רקנש 'חר

.ד.ת ,

12133

לארשי ,חותיפ הילצרה

46725

:לט

972-9-9700500

:סקפ

972-9-9700501

יאמ

2020

,ה/דבכנ ת/חקור ,ה/אפור

אפורל ןולעב ןוכדע לע ךעידוהל וננוצרב

ןכרצל ןולעו

לש

רישכתה םי

אבה

םי

etrusitol SR 2 mg

D

Detrusitol SR 4 mg

:ליעפה ביכרמה

Tolterodine L- Tratrate

:היוותה

For the treatment of patients with an overactive bladder with symptoms of urinary frequency,

urgency or urge incontinence.

ןולעב םיירקיעה םינוכדעה ןלהל

ל

אפור

:

4.3

CONTRAINDICATIONS

……..

DETRUSITOL ® SR is contraindicated in patients with urinary retention, gastric

retention, or

uncontrolled narrow-angle glaucoma. DETRUSITOL®

also

contraindicated in patients with known hypersensitivity to the active substance or to

any of the excipients listed in section 9, or to fesoterodine fumarate extended-release

tablets

which, like

DETRUSITOL®

metabolized to

5-hydroxymethyl

tolterodine [see

WARNINGS AND PRECAUTIONS

(4.2) (4.3) (4.4)].

……

4

WARNINGS AND PRECAUTIONS

4.1

Angioedema

Anaphylaxis and angioedema requiring hospitalization and emergency medical

treatment have occurred with the first or subsequent doses of DETRUSITOL

SR. In

the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure,

DETRUSITOL

SR should be discontinued and appropriate therapy promptly

provided.

……

4.3 Gastrointestinal Disorders

……

DETRUSITOL

SR, like other antimuscarinic drugs, may decrease gastrointestinal

motility and should be used with caution in patients with conditions associated with

decreased gastrointestinal motility (e.g., intestinal atony)

[see

CONTRAINDICATIONS (3)]

……..

4.5

Central Nervous System Effects

DETRUSITOL

SR is associated with anticholinergic central nervous system (CNS)

effects [see Adverse Reactions (5

.

2)] including dizziness and somnolence [see

Adverse Reactions (5.1)]. Patients should be monitored for signs of anticholinergic

CNS effects, particularly after beginning treatment or increasing the dose. Advise

patients not to drive or operate heavy machinery until the drug’s effects have been

determined. If a patient experiences anticholinergic CNS effects, dose reduction or

drug discontinuation

4.6

Hepatic Impairment

…..

DETRUSITOL

SR is not recommended for use in patients with severe hepatic

impairment (Child-Pugh Class C)

[see DOSAGE AND ADMINISTRATION (2.2)

and USE IN SPECIFIC POPULATIONS (7.6)].

4.7

Renal Impairment

……

Patients with CCr<10 mL/min have not been studied and use of DETRUSITOL

in this population is not recommended

[see DOSAGE AND ADMINISTRATION (2)

and USE IN SPECIFIC POPULATIONS (7.5)]

……..

4.10 Important information regarding some of the ingredients of the medicine

galactose

rare hereditary problems of fructose intolerance, glucose

Patients with

isomaltase insufficiency should not take this medicine.

malabsorption or sucrase

……..

5 ADVERSE REACTIONS

.......

5.2

Post-marketing Experience

......

peripheral edema;

Gastrointestinal:

diarrhea

;

Central/Peripheral Nervous:

confusion,

disorientation, memory impairment, hallucinations.

……

6

DRUG INTERACTIONS

…..

6.6

Other Anticholinergics

The concomitant use DETRUSITOL

SR with other anticholinergic (antimuscarinic)

agents may increase the frequency and/or severity of dry mouth, constipation, blurred

vision, somnolence, and other anticholinergic pharmacological effects.

7

USE IN SPECIFIC POPULATIONS

…..

7.5

Renal Impairment

……

Patients with CCr<10 mL/min have not been studied and use of DETRUSITOL

in this population is not recommended

[see DOSAGE AND ADMINISTRATION (2)

WARNINGS AND PRECAUTIONS (4.7)].

DETRUSITOL

SR has not been

studied in patients with mild to moderate renal impairment [CCr 30-80 mL/min].

7.6

Hepatic Impairment

…..

DETRUSITOL

SR is not recommended for use in patients with severe hepatic

impairment (Child-Pugh Class C)

[see DOSAGE AND ADMINISTRATION (2)

WARNINGS AND PRECAUTIONS (4.6)].

ןולעב םיירקיעה םינוכדעה ןלהל ןכרצל

:

2

.

הפורתב שומישה ינפל

הפורתב שמתשהל ןיא

: םא

......

פורתל שיגר ךנה תו

ליכמ רשא

תו .ןידורטוספ רמוחה תא

תורהזא

הפורתב שומישל תועגונה תודחוימ

.......

עטקמ תכראה" תארקנה בלב הרידנ היעב החפשמה ינבמ והשימל וא ךל שי

תנומסת) "

(ךראומ

.......

ןיב תובוגת

-

תויתפורת

תא םא

ה

לע ירפס ,הנוזת יפסותו ימשרמ אלל תופורת ללוכ תורחא תופורת ,הנורחאל תחקל םא וא ,חקול

.חקורל וא אפורל ךכ

......

תופורת

םוהיזב לופיטל תומיוסמ

.ריבאנאזאטא ,ריבאניווקאס ,ריבאנוטיר ןוגכ

.......

תונוכמב שומישו הגיהנ

גוהנל ןיא

תונוכמ ליעפהל תונכוסמ

תורחא תונכוסמ תויוליעפ עצבל וא

לוטיסורטד ךיא עדת רשא דע

לוטיסורטד ןוגכ תוינירקסומ יטנא תופורתל .ךילע העיפשמ

היאר : ןוגכ יאוול תועפות תויהל תולולע

.םונמנ וא תרוחרחס ,תשטשוטמ

4

.

יאוול תועפות

......

ל ךילע לוטיסורטדב שומישה תא קיספה

SR

ידימ ןפואב תיאופר הרזע תלבקל תונפלו

הווח התא םא

תא םיאבה םינימסתה

:

לוטיסורטד

תיגרלא הבוגתל םינימסתה . תורומח תויהל תולולע רשא תויגרלא תובוגתל םורגל יושע

,םינפה תוחפנתה לולכל םילוכי הרומח

,םייתפש

ןורג

וא ןושלה

תכרעמ לש המיסח ,המישנ יישק ,

וא המישנה

.םדה ץחלב הליפנ

.....

: תופסונ יאוול תועפות

לוכיע ישק ,תרוחרחס ,תופייע ,

,היאר שוטשט ,ןיעב שבוי

,הדרח ,תוינונשי

תותגה לש תקלד

באכ ,(סיטיסוניס) .ןתש ןתמב

תיגרלא הבוגת השק

סיסקליפנא)

תקצבו (

תת

הידרקיכט) תוריהמ בל תוקיפד , תירוע

תוקזח בל תוקיפד

(תויצטיפלפ)

,לובלב ,לושלש ,( םייפגב תקצב) תירפירפ תקצב ,

בחרמב תואצמתה רסוח

,ןורכיזב שוביש ,

תויזה

......

.הרמחה םיווהמ בוהצ עקרב םישגדומה םייונישה

םיפסונ םייוניש ועצוב ,ןכ ומכ

ןכרצלו אפורל ןולעב

םיללוכה

עדימ תטמשה ,עדימ תפסות .הרמחה םיווהמ םניאש חסונ ינוכדעו

העדוהב

וז

םיניוצמ

קר

םינוכדעה

םיירקיעה

םימייק

םינוכדע

םיפסונ

םינולעה םינכדועמה

:תואירבה דרשמ רתאבש תופורתה רגאמב םמוסרפ ךרוצל תואירבה דרשמל וחלשנ

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=h

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רקנש

.ד.ת ,

12133

,חותיפ הילצרה

46725

,הכרבב

תירשוא תשע

הנוממ תחקור

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