XANAX X.R. 1 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
ALPRAZOLAM
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
N05BA12
Pharmaceutical form:
TABLETS SUSTAINED RELEASE
Composition:
ALPRAZOLAM 1 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
PFIZER ITALIA S.R.L, ITALY
Therapeutic group:
ALPRAZOLAM
Therapeutic area:
ALPRAZOLAM
Therapeutic indications:
For the treatment of anxiety and anxiety associated with depression. Treatment of panic disorder with or without phobic avoidance
Authorization number:
110 50 28805 21
Authorization date:
2013-04-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

27-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

28-03-2018

PAA099684

PAA099684

PATIENT PACKAGE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) – 1986

This medicine is dispensed with

a doctor’s prescription only

Xanax

TM

XR 0.5 mg

Xanax

TM

XR 1 mg

Xanax

TM

XR 2 mg

Sustained-release tablets

Alprazolam 0.5 mg, 1 mg, 2 mg

A list of inactive and allergenic ingredients in the

preparation can be found in section 6.

Read this leaflet carefully in its entirety before

using the medicine. This leaflet contains concise

information about the medicine. If you have further

questions, refer to the doctor or pharmacist.

This medicine has been prescribed for you. Do not

pass it on to others. It may harm them, even if it

seems to you that their medical condition is similar

to yours.

This medicine is not intended for children and

adolescents below the age of 18.

WHAT DO I HAVE TO KNOW ABOUT XANAX

TM

XR?

This medicine belongs to the benzodiazepine group,

which has special characteristics that require extra

caution when using it.

Taking this medicine with medicines from the

opioid family, alcohol, or other central nervous

system depressants (including drugs) may

cause a sense of severe drowsiness, difficulty

breathing (respiratory depression), coma and

death.

This medicine can make you feel sleepy or dizzy

and may slow your thinking and motor skills.

∙ Do not drive, do not operate dangerous machinery

or perform other dangerous activities until you

know how the medicine affects you.

∙ While taking the medicine, do not drink alcohol or

take other medicines that may make you sleepy

or dizzy, before first consulting with your doctor.

When taken with alcohol or other medicines that

cause sleepiness or dizziness, the medicine may

worsen these symptoms.

∙ Do not take more than prescribed for you.

∙ It is especially important to be under close medical

supervision when taking this medicine.

∙ Prolonged use with this medicine may reduce

the effects of the medicine. Such use can cause

a severe dependence effect, which will make it

difficult for the patient to discontinue taking the

medicine.

∙ Unsupervised discontinuation of treatment is

accompanied by withdrawal symptoms; for details,

see section 4 in this leaflet.

∙ Elderly patients are especially susceptible to

dosage-related effects when taking the medicine.

1. WHAT IS THE MEDICINE INTENDED FOR?

Xanax

XR is used to treat anxiety and anxiety

associated with depression and for the treatment of

panic disorder with or without phobic avoidance.

Therapeutic Group:

Benzodiazepines.

2. BEFORE USING THE MEDICINE



Do not use the medicine if:

x You are sensitive (allergic) to alprazolam, to

any of the additional ingredients contained in

the medicine or to other medicines from the

benzodiazepine group.

x You are taking medicines to treat fungal infections,

such as: ketoconazole and itraconazole.

Do not use the medicine without consulting the

doctor before commencing treatment:

∙ If you are elderly

∙ If you suffer from obesity

∙ If you have or have had in the past depression,

mood problems, suicidal thoughts or behavior

∙ If you have liver or kidney problems

∙ If you have lung disease or respiratory problems

Special warnings regarding use of the medicine

∙ Prolonged use may cause dependence

∙ Inform the doctor if you suffer or have suffered in

the past from addiction to alcohol, prescription

medicines or drugs.



If you are taking, or have recently taken, other

medicines, including non-prescription medicines

or nutritional supplements, tell the doctor or

pharmacist.

In particular, inform the doctor or pharmacist if you

are taking:

∙ Do not use together with medicines to treat fungal

infections: ketoconazole and itraconazole, see “Do

not use the medicine if” at the beginning of this

section.

∙ Opioids, since the combination with Xanax

TM

may increase the chance for respiratory depression,

see “What do I have to know about Xanax

TM

XR?”

at the beginning of this leaflet.

∙ Medicines to treat anxiety and depression

(nefazodone, fluvoxamine, fluoxetine, sertraline,

paroxetine).

∙ Cimetidine (for ulcer).

∙ Medicines to treat HIV infection such as ritonavir.

∙ Contraceptive pills.

∙ Medicines that affect the central nervous system

such as: antipsychotics, anticonvulsants, medicines

to treat allergy (antihistamines).

∙ Digoxin – a medicine for treating heart disease,

since in combination with Xanax

XR, the levels

of digoxin may rise.

∙ Imipramine and desipramine.

∙ Propoxyphene, a narcotic analgesic.

∙ Medicines to treat angina pectoris and blood

pressure (diltiazem, nicardipine and nifedipine).

∙ Isoniazid to treat tuberculosis.

∙ Macrolides

such

erythromycin

clarithromycin.

∙ Ergotamine, for preventing and treating headaches

caused by migraine.

∙ Cyclosporine.

∙ Amiodarone to treat rhythm disorders.

∙ Carbamazepine,

decrease

blood

concentration of the medicine.



Use of Xanax

TM

XR and food

The medicine can be taken with or without food.

Swallow the medicine with a little water.

Consumption of grapefruit juice during the course

of treatment may increase the blood concentration

of Xanax



Use of Xanax

TM

XR and alcohol consumption

Do not consume any alcohol during the course of

treatment with the medicine. Alcohol consumption

can increase your chances of having serious side

effects.



Pregnancy and breastfeeding

If you are pregnant or planning to become pregnant,

you must consult with the doctor, as this medicine

may harm the unborn baby.

If you are breastfeeding or planning to breastfeed,

consult with the doctor . The medicine passes into

the breast milk and may harm your baby. Do not use

the medicine if you are breastfeeding.



Driving and operating machinery

The medicine can cause you to be drowsy. Do not

drive or operate dangerous machinery until you know

how the medicine affects you.



Important information about some of the

ingredients in the medicine

The medicine contains lactose and may cause an

allergy in people who are sensitive to lactose.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are

uncertain.

The dosage and treatment regimen will be determined

by the doctor only.

Do not increase the dosage even if you think the

medicine “no longer works” without consulting the

doctor. Benzodiazepines, even when taken according

to the doctor’s instructions, can cause emotional

and/or physical dependence.

Do not stop taking the medicine suddenly or lower

the dosage without consulting with the doctor, since

withdrawal symptoms may occur.

Some of the patients may experience difficulty

stopping treatment with Xanax

XR because of severe

emotional and physical dependence. It is important

to consult with your doctor in order stop treatment

in a careful and safe manner. Proper cessation of

treatment will help lessen the possibility of withdrawal

reactions that can vary from mild reactions to severe

reactions such as an attack.

Do not exceed the recommended dosage!

Swallow the tablets whole. Do not crush/halve/chew,

since the tablets are sustained-release tablets and the

active ingredient has to be gradually released from

them over an extended period of time.

If you took 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.

If you forgot to take the medicine at the required time,

do not take a double dose. Take the next dose at the

regular time and consult the doctor.

Adhere to the treatment regimen recommended by

the doctor.

Do not take medicines in the dark! Check the label

and the dose each time you take medicine. Wear

glasses if you need them.

If you have further questions regarding use of the

medicine, consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Xanax

XR may cause

side effects in some users. Do not be alarmed by

the list of side effects. You may not suffer from any

of them.

∙ Please see “What do I have to know about

Xanax

TM

XR?” at the beginning of the leaflet.

Abuse and Dependence. Taking the medicine may

cause physical and psychological dependence.

Physical and psychological dependence is not the

same as addiction to the medicine.

Withdrawal symptoms. You may have withdrawal

symptoms if you stop taking the medicine suddenly.

Withdrawal symptoms can be serious and include

seizures. Moderate withdrawal symptoms include

decreased mood and trouble sleeping. Talk to your

doctor regarding gradual cessation of treatment in

order to avoid these symptoms.

Seizures. Cessation of the medicine can cause

seizures and seizures that do not stop (status

epilepticus).

Mania. The medicine can increase activity and

talking (mania and hypomania) in people who have

depression.

The most common side effects include:

Sedation, drowsiness, difficult or unclear ability to

talk, depression, coordination problems, memory

disorders and tiredness.

Common side effects (effects that occur in 1-10

in 100 users):

Palpitations, vertigo, blurred vision, diarrhea, vomiting,

digestion difficulties, abdominal pain, malaise,

weakness, chest pain, back pain, muscle cramps

and twitching, headache, dizziness, tremor, irritability,

insomnia, nervousness, derealization, increased

libido, restlessness, agitation, depersonalization

(feeling detached), nightmares, difficulty passing

urine, nasal congestion, hyperventilation, increased

sweating.

Uncommon side effects (effects that occur in 1-10

in 1,000 users):

Rapid heartbeat, tinnitus, ear pain, dilated pupils,

photophobia (intolerance to light), difficulty

swallowing, increased secretion of saliva, falls, high

fever, feeling thirsty, feeling hot and cold, edema,

feeling jittery, sluggishness, fatigue, feeling drunk,

chest tightness, sensation of increased energy, feeling

of relaxation, hangover, loss of control of legs, chills,

amnesia, clumsiness, syncope, hypotonia, seizures,

depressed level of consciousness, sleep apnea

syndrome, sleep talking, stupor, abnormal dreams,

apathy, euphoria, aggression and anger, slowness

of thought, excessive and irrational talk, mood

swings, difficulty speaking, hallucinations, homicidal

thoughts, mania, hypomania, uncontrolled impulses,

psychomotor retardation, suicidal thoughts, urinary

frequency, urinary incontinence, choking sensation,

nosebleed, runny nose, clammy skin, rash, urticaria,

hypotension.

Side effects of unknown frequency:

Increased liver enzymes, hepatitis, jaundice, liver

failure, Stevens-Johnson syndrome, angioedema,

peripheral edema, irregular menstrual period, high

prolactin level, gynecomastia (increased breast tissue

in men), galactorrhea (breast milk production not

connected to birth).

If one of the side effects worsens or if you suffer from

a side effect not mentioned in this leaflet, consult

with the doctor.

Side effects can be reported to the Ministry of Health

by clicking on the link “Report Side Effects of Drug

Treatment” found on the Ministry of Health homepage

(www.health.gov.il) that directs you to the online form

for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequ

ence.aspx?formType=AdversEffectMedic@moh.gov.

5. HOW TO STORE THE MEDICINE?

∙ Avoid poisoning! This medicine, and any other

medicine, should be kept in a safe place out of the

reach of children and/or infants in order to avoid

poisoning. Do not induce vomiting unless explicitly

instructed to do so by the doctor.

∙ Do not use the medicine after the expiry date (Exp.

date) that appears on the package. The expiry date

refers to the last day of that month.

∙ Store below 30°C.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine

also contains:

Lactose, Methylhydroxypropylcellulose, Colloidal

anhydrous silica, Magnesium stearate, FD&C blue

#2 (in 0.5 mg and 2 mg tablets).

Each tablet contains 221.7 mg lactose.

What the medicine looks like and the contents of

the package:

Each package contains 30 tablets.

Xanax

XR 0.5 mg: a round, convex, blue tablet with

”P&U 57” imprinted on one side.

Xanax

XR 1 mg: a round, convex, white tablet with

”P&U 59” imprinted on one side.

Xanax

XR 2 mg: a pentagonal, blue tablet with

”P&U 66” imprinted on one side.

License holder: Pfizer PFE Pharmaceuticals Israel

Ltd., 9 Shenkar St., Herzliya Pituach 46725.

Manufacturer:

Pfizer Italia S.r.l., Ascoli Piceno, Italy.

This leaflet was checked and approved by the Ministry

of Health in February 2017.

Registration number of the medicine in the National

Drug Registry of the Ministry of Health:

Xanax

XR 0.5 mg: 110-49-28804

Xanax

XR 1 mg:

110-50-28805

Xanax

XR 2 mg:

110-51-28806

©¥£³¡´ ¶¡¬³¶¥°¨«§´²¨«¡¨®

u}|zq¡fªµ¶ l©¥´¥µ§¶m

žœ§œ›¯ ³¨´³©¤¯§­µ² ´©Ÿ¯ ³µŸ

žfªtry

XR



TM

­³œ¬­³

žfªu

XR



TM

­³œ¬­³

žfªv

XR



TM

­³œ¬­³

µ¡ª´¡´£µ¨¶¡¥¨¤

žfªvpžfªupžfªtry©œ¨¡¢œ´°¨œ

Alprazolam 0.5 mg, 1 mg, 2 mg

²³¯œ³¤´¦µœ¨¤¤«³§› ¨¤§¤­¯¤µ§œ¨¤³© ¢µ©¤´³

r °¡´¶µª¶µ¶©´¤¡°¡­Ÿ®«¡¨® ¶œ«¡¥®œ´³

µ §›´¥§´¤¨›rŸ¯ ³µŸ§­¤µ¤±©µ­ž¤©§¤¦©Ÿ¡ª §­

r¢² ³Ÿ§› ››¯ ³Ÿ§›Ÿ«¯pµ ¯¬ «

›¤Ÿr¨¤³¢›§Ÿµ ›³¤œ­µ§›r¥³ œ­Ÿ©´³« ¡Ÿ¯ ³µ

¤› ¯³Ÿ¨œ±©¤¦¥§Ÿ›³«¨› §¤¯›¨Ÿ§²¤¡Ÿ§Ÿ§ §­

r¥§´§Ÿ© ž

§¤§µ¢µ©¨¤³œµ©§ ¨¤ž§¤§µž­ ¤©Ÿ«¤› ¡Ÿ¯ ³µ

ƒ

XR



TM

­³œ¬­³¨®ž¡¬¶®Ÿ¨¥¨® ª

µ « ¦µŸ§´p¨¤«¤¯¡›¤ž ¡«œŸµ± œ²§µ¦¤¤´ ¡Ÿ¯ ³µ

rŸœ´ ©¤´œŸœ³µ ³¤Ÿ¡µ œ¤¤¢©Ÿµ ž¢ ¤©

p©¥Ÿ¥œ¡¥°¡œ ¶£°µªª¶¡°¡´¶©®¡¢ °¡´¶¶¨¥¤¬∙

¶§´®ª¶¡œ§Ÿª ¶¡´£œ¶¡°¡´¶¡œp¨¡ ¡§¨œ

¶µ¡£¶¨©¡´ž¨ ¨¡¨®l©¥ª­¨¨¡§m¶¥¢§´ª©¥²®

pl¥¶ª¥µ¬¥¡§¥Ÿm ª¥µ¬¥¥µ³p ³¡ª®¶¡¥¬¡¬µ¥

r¶¡¡ª¡¶ªŸ´¶

p´´£¡­ª¡œ¥¬¡¬µ¥µ¥ž´ ¨¦¨©¡´ž¨ ¨¡¨®¡¢ °¡´¶∙

¶¡¨¡§¥ ¶œ¡ ¥µ£ ²³¶œ¤œ ¨ ¨¡§¥¡

r¦¨µ¶¡¥´¡¤¡ª

µ ´­§ ›µ «¦ ¬©µ « ¦©§¤­¯Ÿ§ª¤›p Ÿ«§ª¤› ∙

Ÿ¯ ³µŸž±¤¦­žµ´ž­µ ³¢›µ «¦ ¬©µ ¤ §¤­¯

r¥¤§­Ÿ­¤¯´©

µ § §­Ÿµ ³¢›µ ¯ ³µµ¢²§ ›§ Ÿ ¦§›µ µ´§ª¤› ∙

Ÿ¯ ³µŸµ§¤£«ª©¡œµ³ ¢³¢¬ ›µ ¤« «´¤§¥§¨ ³§

Ÿ§¤£«œr¥§´›¯ ³Ÿ¨­Ÿ« ´›³§°­¤¤µ©Ÿµ›´¤«¯§

pµ³ ¢³¢¬ ›µ ¤« «´¤§µ ©³ Ÿµ ¯ ³µ ›§ Ÿ ¦§›¨­

r §›¨¤«¤©¬µ³¤©¢Ÿ§Ÿ§ §­Ÿ¯ ³µŸ

r¥³ œ­¨´³«´Ÿ©©³µ ¤µ¢²§ª¤› 

Ÿ¯ ³µµ§¤£«¨­ž ©±¤› ¯³œ²­©œŸœ³µ œ¤´¢´¤ 

r ¡

µ­¯´Ÿ´¥¦§¨ ³§§ §­ ¡Ÿ¯ ³µœ¥´ ©©´ ©¤´ 

Ÿ´²Ÿ­¯ µ§¨ ³§§ §­Ÿ¡¦´ ©¤´rµ¢¯µŸ¯ ³µŸ

µ›§ £¤§²¤¬¯Ÿ§Ÿ§ ¢Ÿ§­Ÿ´²¤Ÿœpµ §µ§´

rŸ¯ ³µŸ

µ ­¯ µœŸ §©§ ¯¤£Ÿ§´µ³² œ©¤µ§œŸ²¬¯Ÿ 

rŸ¡ª §­œx²³¯§Ÿ«¯›«›£ ³¤¯§pŸ§¤©

ª «¤©µ ¤ §µµ ­¯ µ§ž¢ ¤©œ¨¤´¤³¨¤´¤´²¨¤§¯ £© 

rŸ¯ ³µŸµ§¤£«ª©¡œ

ƒ °¡´¶ ¶Ÿ®¡¥ª ª¨

ru

Ÿ §©ŸŸž³¢œ Ÿž³¢œ§ ¯¤£§µ´©´©



¬²›«¬²

rµ­«©«Ÿ¤œ ¯›§§ ›¨­Ÿ²¤«›¯µ­³¯Ÿœ ª ›¦¤žœ

~¶¥¤¥¡°´¶ ²¡³

r¨¤«¤¯¡›¤ž ¡«œ

 °¡´¶µ¡ª¥µ¥¬°¨

rv

~©œ °¡´¶µª¶µ ¨«¥œ 

¨¤œ¤¦³©Ÿ©ž¢›§¦§p¨›§ ¡›³¯§›§l¤³§›m´¤³Ÿµ›

µ ³¢›µ ¯ ³µ§ ›Ÿ¯ ³µŸŸ§¤¦©³´›¨¤¯¬ «Ÿ

r¨¤«¤¯¡›¤ž ¡«œŸµ± œ²©

~ª ¦p¨¤¤µ¤¤³£¯¨¤© Ÿ¤¡œ§ ¯¤£§µ ¯ ³µ§£ «¥«Ÿ 

r§ ¡›« ²›³£¤› § ¡›« ² £²

¥¬°¨œ°¡´±®¡¡¥ ¨¥¨ª °¡´¶µª¶µ ¨«¥œ

~¨¡°¥¤ ¶¨£¶

´¤´²¥«Ÿ¨› 

³µ¤µ«©´Ÿ©§œ ¬¥«Ÿ¨› 

µ œ´¢©p¢ ³¤œ±©pª ›¦¤ž©³œ­œµ§œ¬ ›§œ ¬¥«Ÿ¨› 

µ¤«žœ ›µ Ÿ«µŸ ›

Ÿ¤§¦ ›žœ¦µ ¤­œ©§œ ¬¥«Ÿ¨› 

Ÿ©¤´«œµ ¤­œ ›Ÿ›¤³µ§¢©©§œ ¬¥«Ÿ¨› 

°¡´¶µ¡ª¥µ¨¶¡®ž¡¬ ¶¡Ÿ£¡¥ª¶¡´ ¢œ

µ §µ§¨ ³§§ §­¥´ ©©´ ©¤´ 

µ ³¦©µŸ©³œ­œµ§œ¬ ›§œ ¬¥«Ÿ¨››¯ ³§­¤ž Ÿ§´¤ ∙

r¨¤©¬ ›¨´³©µ ¯ ³µp§ Ÿ ¦§›§

¶¡°¡´¶p ¬¡´£œ¨¶£³¨©œ¡œp£³¡¨ ¶œ©œ 

´°­p ¬¡¢¶¥°­¡¶¡©µ´ªœ¨¨¶¡°¡´¶¨¨¡§¶¡´£œ

r£³¡´¨¡œœ°¡´¨¦§¨®

~¢² §Ÿµ›¨›¢² ³Ÿ ››¯ ³Ÿµ›­ž¤§´¤ž¢ ¤©œ

~¨¤¤µ¤¤³£¯¨¤© Ÿ¤¡§µ ¯ ³µ¨­ž¢¤´©µ´Ÿ§ª¤› ∙

Ÿ¯ ³µœ´©µ´Ÿ§ª¤›fŸ›³p§ ¡›« ²›³£¤› § ¡›« ² £²

rŸ¡²³¯µ§¤¢µœf¨›

³¤œŸ§§ §­



¬²›«¬²¨­œ §¤´Ÿª¦´p¨¤ž¤› ¤¯ › 

®ž¡¬¶®Ÿ¨¥¨® ªfŸ›³p¤µ©¤´«¤ ¦¤ž§¤ ¦¤¬Ÿµ›

rŸ¡ª §­µ§¤¢µœ

XR

TM

­³œ¬­³¨

pª¤©›¬² œ §¯pª ž ¡›¯«mª ›¦¤ž Ÿž³¢œ§ ¯¤£§µ ¯ ³µ 

rlª¤£¬² ³›¯pª¤§³£³¬pª¤£¬² › §¯

rl¬ ²§ ›§mª¤ž£©¤¬ 

r³¤œ« £¤³ª ¦

§´¨ Ÿ¤¡œ§ ¯¤£§µ ¯ ³µ 

rª ¤³Ÿµ­¤«©§µ § § 

~ª ¦µ¤¡¦³©Ÿ¨¤œ±­Ÿµ¦³­©§­µ ­¤¯´©Ÿµ ¯ ³µ 

µ ¯ ³µp¨¤¬ ¦³¯µ ž «µ ¯ ³µpŸ¡ ¦¤¬¯µ ž «µ ¯ ³µ

rl¨¤«¤©£¬¤Ÿq¤£«›mŸ¤³§›œ§ ¯¤£§

œ §¤´œ´ª ¤¦©pœ§µ §¢©œ§ ¯¤£§Ÿ¯ ³µqª¤¬² ¤ž 

rµ §­§Ÿ§ §­ª¤¬² ¤žŸµ©³



¬²›«¬²¨­

rª¤©›³¯¤¬ž ª¤©›³¯¤©¤› 

r¤£ ²³«œ›¦¥¦´©pª¯¤¬² ¯ ³¯ 

p¨¡›¤£§¤žm¨ž°¢§§ Ÿ¡¢µ² ­µœ§ ¯¤£§µ ¯ ³µ 

rlª¤¯¤ž¯¤« ª¤¯¤ž³²¤«

rµ¯¢´œ§ ¯¤£§ž¤¡›¤« ¡¤› 

rª¤±¤© ³µ¤³›§² ª¤±¤© ³µ¤³›ª ¦¨¤ž¤§ ³²© 

¨¤©³«Ÿ ´›³ ¤œ›¦œ § ¯¤£ Ÿ­¤«©§ pª¤©›£ ³› ∙

rŸ«³¤©©

rª¤³ ¯¬ §²¤± 

rœ±²µ ­³¯Ÿœ§ ¯¤£§ª ³›ž ¤©› 

r¨žœŸ¯ ³µŸ¡ ¦¤³µ›ž¤³ Ÿ§Ÿ§ §­pª¤¯¡›©›œ³›² 

«¡¢ª¡

XR



TM

­³œ¬­³µ¡ª¥µ 

µ›­ §œ§´¤r§¦ ›¤§œ ›¨­Ÿ¯ ³µŸµ›§ £¤§ªµ¤«

r¨¤©£­©¨­Ÿ¯ ³µŸ

µ›µ §­Ÿ§Ÿ§ §­§ ¯¤£Ÿ¥§Ÿ©œµ ¤§ ¦´›°¤©µ¦¤³±

r¨žœ



¬²›«¬²¡ ¦¤³

¨¡ ¡§¨œ¶§¥´²¡

XR



TM

­³œ¬­³µ¡ª¥µ 

µ¦¤³±rŸ¯ ³µœ§ ¯¤£Ÿ¥§Ÿ©œ§ Ÿ ¦§›§§¦¥ ³±§ª¤›

¤› §µ ­¯ µ§¥§´¨¤¤ ¦¤¬Ÿµ›³¤œŸ§Ÿ§ ¦¤§ Ÿ ¦§›

rµ ³ ©¢

 ³¬ ¡«¡¥´ 

ª ¤³Ÿµ««¦µ© ›ª ¤³Ÿœ¥«Ÿ¨››¯ ³œ°­ ¤Ÿ§¥¤¤§­

r³œ ­œ­ ¯§Ÿ§ §­Ÿ¯ ³µŸ ³¢›©

r²¤«Ÿ§µ««¦µ© ›Ÿ²¤«©¥«Ÿ¨››¯ ³œ°­ ¤Ÿ§¥¤¤§­

r¥§´² «¤µœ­ ¯§Ÿ§ §­ ¨›Ÿœ§¢§µ³œ ­Ÿ¯ ³µŸ

rŸ²¤«©¥«Ÿ¨›Ÿ¯ ³µœ´©µ´Ÿ§ª¤›

¶¡¬¡§ªµ¡ª¥µ¡ ž¥ ¬ 

§¤­¯Ÿ§ › Ÿ«§ª¤›p¤« «´¤µ ¤Ÿ§¥§¨ ³§Ÿ§ ¦¤Ÿ¯ ³µŸ

r¥¤§­Ÿ­¤¯´©Ÿ¯ ³µŸž±¤¦­žµ´ž­µ «¦ ¬©µ « ¦©

°¡´¶ ¨µ©¥¥§´ª ª³¨£¨®¡µ£®Ÿ¥ª 

¨¤´«›§±›Ÿ¤³§›§¨ ³§Ÿ§ §­ ¡ £²§Ÿ§¤¦©Ÿ¯ ³µŸ

r¡ £²§§¨¤´¤³Ÿ

ƒ °¡´¶µª¶µ¶Ÿ²¥§rw

¨­² žœ§¥¤§­r›¯ ³Ÿµ ›³ Ÿ¤¯§´©µ´Ÿ§´¤ž¤©µ

r¢ £œ¥«¤›¨›¢² ³Ÿ ››¯ ³Ÿ

ržœ§œ›¯ ³Ÿ¤ž¤§­ ­œ²¤§ ¯¤£Ÿª¯ › ª «¤©Ÿ

›§fŸ¯ ³µŸ´œ´ ¢Ÿµ›¨›¨ª «¤©Ÿµ›§¤žŸ§ª¤›

³´›¦¨p¨¤«¤¯¡›¤ž ¡«œr›¯ ³œ°­ ¤Ÿ§¤§œ©f³µ ¤µžœ ­

 ›s µ¤´³µ §µ³±¤¤§¨¤¤ ´­p›¯ ³Ÿµ ›³ Ÿ¤¯§¨¤§£ «

rµ¤¡¤¯

µ›ª¤£²Ÿ§ ›µ ¤© ›µ¯œŸ¯ ³µŸµ›§ £¤§²¤¬¯Ÿ§ª¤›

rŸ§¤©¤«¤©¬µ «¦µ¤ª¦´p›¯ ³œ°­ ¤Ÿ§¤§œ©ª «¤©Ÿ

¨­§ ¯¤£Ÿµ²¬¯Ÿœ¤´ ²µ ¢§¨¤§ §­¨¤§ ¢Ÿ©²§¢

œ ´¢rŸ³ ©¢µ¤¡¤¯ µ¤´³µ §µ§´œ



¬²›«¬²

ª¯ ›œ§ ¯¤£Ÿµ›²¤¬¯Ÿ§¤ž¦¥§´›¯ ³Ÿ¨­°­¤¤µµ´

µ ³´¯›Ÿµ›ª¤£²Ÿ§­¤¤¬µŸ« ¦«Ÿ²¬¯Ÿr¢ £œ ³¤Ÿ¡

µ œ µ§µ §²µ œ µª¤œ­ «§µ § ¦¤´Ÿ§¤©µ œ µ§´

r®²µŸª ¦µ ´²

e¶²¨ª¡ª  ¬ª ¨®´¡®¨«¥œ

sµ ±¢§s´ µ¦§³ ¬›rŸµ ©§´œŸ¤§œ£Ÿµ›­ §œ§´¤

ŸŸ´ ©³ ³¢´§µ ¤§œ£ª«¤Ÿµ ¤§œ£Ÿ´ª ¤¦©p¬ ­§§

¥³ ›§ ¤µ³žŸª¯ ›œª¦³ž³³¢µ´Ÿ§¥¤³±§¤­¯Ÿ³© ¢Ÿ

rœ³ª©¡

p °¡´¶ «ªŸ¨¥®¨¶¡®¤©œ¡œ´¶¥¶¬ª¶¨¤¬©œ

Ÿ¯ ³µŸµ¡¤³››œŸ ¨¤§ ¢µ¤œ§´ª ¤©³ž¢§ž¤©Ÿ«¯

r¥µ¤›

Ÿ«©§ £¤§ª¤›p´ ³žŸª©¡œ ¡Ÿ¯ ³µ§ £¤§µ¢¦´¨›

r›¯ ³œ°­ ¤Ÿ §¤³Ÿª©¡œŸ›œŸŸ«©Ÿµ›¢²rŸ§ ¯¦

r›¯ ³Ÿ¤ž¤§­°§© Ÿ´¤¯¦§ ¯¤£œž¤©µŸ§´¤

¨­¯§¦œŸ«©Ÿ µ¤ µŸ² žœe¥´ ¢œµ ¯ ³µ§ £¤§ª¤›

r¨Ÿ§² ²¡¥«Ÿ¨›¨¤¤¯²´©œ¦³ŸrŸ¯ ³µ§£ «¥«Ÿ´

°­ ¤ŸpŸ¯ ³µœ´ ©¤´§­ «œµ ¯¬ «µ §›´¥§´¤¨›

r¢² ³œ ››¯ ³œ

¥œ¡¡¨¶¡®°¡¶ 

rx

¨ ³§§ §­



¬²›«¬²œ´ ©¤´ŸpŸ¯ ³µ§¦œ ©¦

›³²©§§Ÿœ¤µ§›r¨¤´©µ´©Ÿ©²§¢œ¤› §µ ­¯ µ§

µ¢›®›©§ œ¬µ›§ ª¦µ¤p¤› §Ÿµ ­¯ µµ©¤´³

rªŸ©



XR



TM

­³œ¬­³¨®ž¡¬¶®Ÿ¨¥¨® ªfŸ›³›«›∙

rª §­Ÿµ§¤¢µœ

¨ ³§Ÿ§ ¦¤Ÿ¯ ³µŸµ§¤£«r¶¡¨¶¡ ®´¨µ¡ª¥µ ∙

›¤Ÿµ¤ § ¦¤¬¯ µ¤¡¤¯µ §µrµ¤ § ¦¤¬¯ µ¤¡¤¯µ §µ§

rŸ¯ ³µ§µ ³¦©µŸ ©¦›§

²¤¬¯µ¨›Ÿ§¤©¤«¤©¬µ©§ œ¬µ ª¦µ¤r ¨¥ªž¥¬¥ª­¶ ∙

¨¤§ ¦¤Ÿ§¤©¤«¤©¬µrµ ¤© ›µ¯œŸ¯ ³µŸµ›µ¢²§

¨¤« µ©Ÿ§¤©¤«¤©¬µr¨¤¬ ¦³¯§ §¦§ ¨¤³ ©¢µ ¤Ÿ§

¥§´›¯ ³Ÿ¨­³œžrŸ«¤´¤¤´² ž ³¤¢ ³œ±©¨¤§§ ¦

­«©¤Ÿ§µ«©§­Ÿ¯ ³µŸ§´µ¤µ³žŸŸ²¬¯Ÿ§­ «œ

r §›¨¤«¤©¬µ©

¨¤¬ ¦³¯§¨ ³§Ÿ§ ¦¤Ÿ¯ ³µŸµ²¬¯Ÿr©¥­¡§´° ∙

rl¬ ²¤£¯§¤¯›¬ ££¬m¨¤²¤¬¯©¨«¤›´¨¤¬ ¦³¯§

Ÿ¤«›©m³ œ¤ž µ §¤­¯³¤œŸ§Ÿ§ ¦¤Ÿ¯ ³µŸr ¥¬œª ∙

rª ›¦¤ž¨¤ ¢´¨¤´«›œlŸ¤«›© ¯¤Ÿ

~¶¡¨¨¡§´¶¡¥¶¡£¥§µ ¥œ¡¡¨¶¡®°¡¶

pª ›¦¤žp³ œ¤žœ¤´ ² ›³ ³œ›§³ œ¤žpµ ¤« «´¤p´ £´£

rµ ¯¤¤­ ª ³¦¤¡œµ ­³¯ŸpŸ¤±«¤ž³ › ²µ ¤­œ

uqutq¶¡®¥°¡ªµ¶¡®°¡¶m¶¡£¥§µ¥œ¡¡¨¶¡®°¡¶

~lutt¦¡¶ª©¥µª¶µª

¤¤´²pŸ›²Ÿp§ ´§´pŸ¤¤›³œ´ £´£p ¤£³ pœ§µ ²¤¯ž

pŸ¡¢œœ›¦pŸ´§ ¢pµ¤§§¦¤§ ¢µ´ ¢µpª£œœ›¦p§ ¦¤­

pµ³ ¢³¢¬p´›³œ›¦p¨¤³¤³´µ¤ ­ µ ¤ ± ¦µŸpœœ›¦

µ¤µ ›¤±©›§Ÿ´ ¢µpµ «œ±­pŸ«¤´¤ž ž«p¤ ³¤pž­³

p£²´¤›pŸ¢ «©³¬ ¢p¤«¤©Ÿ®¢žœŸ¤§­plŸ¤±¡¤§›³žm

pªµ´ªµ©œ¤´ ²p¨¤£ ¤¬pl² µ¤«µ´ ¢µmŸ¤±¡¤§« ¬³¯ž

rµ³œ ©Ÿ­¡Ÿpµ±› ©Ÿ©¤´«p®›œ´ž 

¶¡®¥°¡ªµ¶¡®°¡¶m¶¡£¥§µ«¬¥œµ¥œ¡¡¨¶¡®°¡¶

~lupttt¦¡¶ª©¥µª¶µªuqutq

¨¤« ´¤›p¨¤¤«¡ ›¤œ›¦p¨¤¤«¡ ›œ¨¤¯ ±¯±p³¤Ÿ©œ§œ±²

pŸ­¤§œœ¤´ ²pl³ ›§µ §¤œ¬¤›mŸ¤œ ¯ £ ¯p¨¤œ¢³ ©

p›©±µ´ ¢µpŸ œ¨ ¢pµ §¤¯«pµ³œ ©² ³µ´³¯Ÿ

pµ ´¤´µpµ ¤£¤›pµ «œ±­µ´ ¢µpµ²±œp³ ² ¨ ¢µ´ ¢µ

pŸ­¤³µ´ ¢µp°³©µ´ ¢µpŸ¡¢œ°¢§pµ ³¦¤´µ´ ¢µ

pŸ¢¦´pµ³ ©³©±p¨¤¤§³œŸ£¤§´³¬ ¢pµ³ ©³©¢

p¨¤¬ ¦³¯p¨¤³¤³´Ÿ¢µ©œŸž¤³¤pµ ¯§­µŸpµ ¤« §©

ª©¡œ³ œ¤žpŸ«¤´œŸ©¤´«¨ žµ« ©¬µpŸž ³¤Ÿ³¦Ÿµ©³

µ´ ¢µpµ ´¤ž›p¨¤« ´©µ © §¢p¨¤´ ¢§ ¯³­pŸ«¤´

¡³¯ ©³ œ¤žpµ¤µœ´¢©µ ¤£¤›p¬­¦ µ «¯² µpŸ¤³ ¯ ›

µ œ´¢©pµ ¤¡Ÿp³ œ¤žœ¤´ ²p¢ ³Ÿœ±©œ¤ «¤´p¤« ¤Ÿ›§

Ÿ£›Ÿp¨¤¯¢žœŸ£¤§´¤›pŸ¤«›© ¯¤ŸpŸ¤«›©pµ ¤«¢±³

pªµ´ªµ©œµ ¯¤¦µpµ ¤«žœ ›µ œ´¢©pµ¤³ £ ©q ¦¤¬¯

p²¤œž³ ­pµ§¡«p®›Ÿ©¨ ©¤žp²«¢µ´ ¢µpªµ´µ¯¤§ž

r¨žŸ°¢§œŸž¤³¤pµ§³¢pŸ¢¤³¯p³¤³² ¢§

~ ®¡Ÿ¥ ¬¥œ«¶¡£¥§µµ¥œ¡¡¨¶¡®°¡¶

p¤žœ¦§´¦pµœŸ±pµ¤¯¤«žœ¦µ²§žpžœ¦¤©¤¡«›œŸ¤§­

µ¬ pµ¤¯²¤Ÿµ²±œpŸ©ž› ¤«›pª ¬« kq¬«œ¤£¬µ« ©¬µ

µ§žŸmŸ¤£¬© ²«¤pŸŸ œª¤£²§ ³¯µ©³pŸ³¤ž¬›§

›§§ž´œœ§¢µ³¤±¤mŸ›³ £²§pl¨¤³œœž´Ÿµ©²³

rlŸž¤§§³´²

§œ ¬Ÿµ›³´›¦ ›pŸ³¤©¢©¤› §Ÿµ ­¯ µ©µ¢›¨›

r›¯ ³Ÿ¨­°­¤¤µŸ§¥¤§­pª §­œŸ³¦¡ Ÿ›§´¤› §µ­¯ µ©

µ ­±©›œµ ›¤³œŸž³´©§¤› §µ ­¯ µ§­¢ ž§ªµ¤«

§ ¯¤£œ²­¤› §µ ­¯ µ§­¢ ¤žf³ ´¤²Ÿ§­Ÿ±¤¢§

µ ›¤³œŸž³´©³µ›§´µ¤œŸ®žœ›±©«´f¤µ¯ ³µ

§­¢ ¤ž§ª ²©Ÿ¬¯ £§Ÿ«¯©Ÿl

www.health.gov.il

~³ ´¤²§Ÿ¬¤«¦¤f­ ›p¤› §µ ­¯ µ

https://forms.gov.il/globaldata/getsequence/getseque

nce.aspx?formType=AdversEffectMedic@moh.gov.il

ƒ °¡´¶ ¶œ«­£œ¨¦¥œ

ry

³ ©´§´¤µ³¢›Ÿ¯ ³µ§¦  ¡Ÿ¯ ³µeŸ§­³Ÿ­«© ∙

µ ² «¤µ ›s ¨¤ž§¤§´¨ž¤´¤Ÿ§° ¢©³ ¬¨ ²©œ

Ÿ›³ Ÿ›§§Ÿ›²Ÿ§¨ ³µ§›rŸ§­³Ÿ­«©µ¥¦¤ž¤§­

r›¯ ³Ÿ©µ´³ ¯©

Exp. Date

Ÿ ¯µŸ¥¤³›µ¤³¢›Ÿ¯ ³µœ´©µ´Ÿ§ª¤›

∙

¨ ¤§¬¢¤¤µ©Ÿ ¯µŸ¥¤³›µrŸ¡¤³›Ÿ¤œ§­­¤¯ ©Ÿ

r´ž ¢ µ ›§´ª ³¢›Ÿ

.30°C

q§µ¢µ©ª¬¢›§´¤ 

¯­¡¬®Ÿ¥ª rz

~©ž ¨¥§ª °¡´¶ ¨¥®° ´ª¡£ ¨®¯­¡¬

Lactose, Methylhydroxypropylcellulose, Colloidal

anhydrous silica, Magnesium stearate, FD&C blue # 2

(in 0.5 mg and 2 mg tablets)

r¡ £²§f©vvur{Ÿ§¤¦©Ÿ¤§œ£§¦

~ ¢¥´œ «§¡¶ ª¡ °¡´¶ ¶¥œ´¬Ÿ²¥§

rµ ¤§œ£wtŸ§¤¦©Ÿ¬¯ ²§¦

§ ¢¦­œ±œŸ³ ©²Ÿ§ ­Ÿ¤§œ£~f©try



¬²›«¬²

rž¢›ž±œ­œ£ ©f

P&U 57

fª©¤¬Ÿ¨­

¨­ªœ§­œ±œŸ³ ©²Ÿ§ ­Ÿ¤§œ£~f©u



¬²›«¬²

rž¢›ž±œ­œ£ ©f

P&U 59

fª©¤¬Ÿ

¨­§ ¢¦­œ±œµ´© ¢©Ÿ¤§œ£~f©v



¬²›«¬²

rž¢›ž±œ­œ£ ©f

P&U 66

fª©¤¬Ÿ

p©f­œ§›³´¤Ÿ²¤£œ±©³¯¤›r®›r¤¯³¡¤¤¯~©¡µ¥´ ¨®

rxz{vy¢ µ¤¯Ÿ¤§±³Ÿp}³²«´

~«´²¥ ©µ

rŸ¤§£¤›p «k±¤¯¤§ ²¬›p

S.r.l

rŸ¤§£¤›³¡¤¤¯

³› ³œ¯~¥¤³›µœµ ›¤³œŸž³´©¤f­³´ › ²žœ«Ÿ¡ª §­

vtu{

ž³´©œ¤µ¦§©©Ÿµ ¯ ³µŸ¬²«¯œŸ¯ ³µŸ¨ ´¤³³¯¬©

~µ ›¤³œŸ

uutqx}qv||tx

~f©try



¬²›«¬²

uutqytqv||ty

~f©u



¬²›«¬²

uutqyuqv||tz

~f©v



¬²›«¬²

r³¦¡ª ´§œ¢¬ «Ÿ¡ª §­pŸ›¤³²Ÿµ§²Ÿ§ µ £´¯Ÿ¨´§

¨¤«¤©Ÿ¤«´¤«œ§µž­ ¤©Ÿ¯ ³µŸpµ›¡®›§­

XANA TAB PL SH 150218

PGM ASCOLI PICENO PLANT

PAA099684/Ph06

COPYRIGHT / PROPRIETA’

DO NOT TAMPER - RETURN AFTER PRINTING / VIETATA LA MANOMISSIONE - RENDERE DOPO LA STAMPA

Pfi zer Italia S.r.l.

MAPS Description:

Ascoli Code:

Artwork Date:

Material type:

Country - Language:

Character type:

Min. Size:

Particular indications:

IS XANAX XR CPR IL

ISTRUZIONE

Lay-out:

ISTR0022

Aggiornamenti Documento/

Document Updatings

Color 1:

NERO

Color 2:

Color 3:

Color 4:

Color 5:

Color 6:

Color 7:

Color 8:

Color 9:

N.of

colors:

1

STIST0209 (148,00 x 700,00) - Prepiegata stesa 148,00 x 233,00 - N. lembi piega 3 - DATA MATRIX

Israele

---

-

PAA099684

16.02.2018

D01

1

2

3

4

5

Date/Date:

Date/Date:

Date/Date:

Date/Date:

Date/Date:

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

FULL PRESCRIBING INFORMATION

NAME OF THE MEDICINAL PRODUCT

XANAX

XR 0.5 mg

XANAX

XR 1 mg

XANAX

XR 2 mg

QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is Alprazolam.

For the full list of excipients, see section "DESCRIPTION" below.

PHARMACEUTICAL FORM

Sustained-release tablets

DESCRIPTION

XANAX XR Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine

class of central nervous system-active compounds.

The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4]

benzodiazepine. The molecular formula is C

which corresponds to a molecular

weight of 308.76.

The structural formula is represented below:

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation,

respiratory depression, coma, and death [see Warnings, Drug Interactions].

Reserve concomitant prescribing of these drugs for use in patients for whom

alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which

has no appreciable solubility in water at physiological pH.

Each XANAX XR sustained -release tablet, for oral administration, contains 0.5 mg, 1 mg or

2 mg of alprazolam. The inactive ingredients are: lactose, magnesium stearate, colloidal

anhydrous silica, and methylhydroxypropylcellulose. In addition, the 0.5 mg and 2 mg

tablets contain FD&C blue No. 2 Aluminum lake.

CLINICAL PHARMACOLOGY

Pharmacodynamics

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at

stereospecific receptors at several sites within the central nervous system. Their exact

mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central

nervous system depressant activity varying from mild impairment of task performance to

hypnosis.

Pharmacokinetics

Absorption

Following oral administration of XANAX (immediate-release) Tablets, alprazolam is readily

absorbed. Peak concentrations in the plasma occur in one to two hours following

administration. Plasma levels are proportional to the dose given; over the dose range of 0.5

to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay

methodology, the mean plasma elimination half-life of alprazolam has been found to be about

11.2 hours (range: 6.3–26.9 hours) in healthy adults.

The mean absolute bioavailability of alprazolam from XANAX XR Tablets is approximately

90%, and the relative bioavailability compared to XANAX Tablets is 100%. The

bioavailability and pharmacokinetics of alprazolam following administration of XANAX XR

Tablets are similar to that for XANAX Tablets, with the exception of a slower rate of

absorption. The slower absorption rate results in a relatively constant concentration that is

maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam

and two of its major active metabolites (4-hydroxyalprazolam and

-hydroxyalprazolam) are

linear, and concentrations are proportional up to the recommended maximum daily dose of

10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination

of alprazolam are similar for the immediate-release and the sustained-release products.

Food has a significant influence on the bioavailability of XANAX XR Tablets. A high-fat

meal given up to 2 hours before dosing with XANAX XR Tablets increased the mean C

about 25%. The effect of this meal on T

depended on the timing of the meal, with a

reduction in T

by about 1/3 for subjects eating immediately before dosing and an increase

in T

by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure

(AUC) and elimination half-life (t

) were not affected by eating.

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

There were significant differences in absorption rate for the XANAX XR Tablet, depending

on the time of day administered, with the C

increased by 30% and the T

decreased by

an hour following dosing at night, compared to morning dosing.

Distribution

The apparent volume of distribution of alprazolam is similar for XANAX XR and XANAX

Tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin

accounts for the majority of the binding.

Metabolism

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4

(CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and

hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their

half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at

steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and

hydroxyalprazolam) were similar for XANAX and XANAX XR Tablets, indicating that the

metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-

hydroxyalprazolam and

-hydroxyalprazolam relative to unchanged alprazolam

concentration after both XANAX XR and XANAX Tablets were always less than 10% and

4%, respectively. The reported relative potencies in benzodiazepine receptor binding

experiments and in animal models of induced seizure inhibition are 0.20 and 0.66,

respectively, for 4-hydroxyalprazolam and

-hydroxyalprazolam. Such low concentrations

and the lesser potencies of 4-hydroxyalprazolam and

-hydroxyalprazolam suggest that they

are unlikely to contribute much to the pharmacological effects of alprazolam. The

benzophenone metabolite is essentially inactive.

Elimination

Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma

elimination half-life of alprazolam following administration of XANAX XR Tablet ranges

from 10.7–15.8 hours in healthy adults.

Special Populations

While pharmacokinetic studies have not been performed in special populations with XANAX

XR Tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect

the pharmacokinetics of alprazolam after the administration of XANAX Tablets would not be

expected to be different with the administration of XANAX XR Tablets.

Changes in the absorption, distribution, metabolism, and excretion of benzodiazepines have

been reported in a variety of disease states including alcoholism, impaired hepatic function,

and impaired renal function. Changes have also been demonstrated in geriatric patients. A

mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects

(range: 9.0–26.9 hours, n=16) compared to 11.0 hours (range: 6.3–15.8 hours, n=16) in

healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam

ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and

26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as

compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes

transplacental passage and that it is excreted in human milk.

Race — Maximal concentrations and half-life of alprazolam are approximately 15% and 25%

higher in Asians compared to Caucasians.

Pediatrics — The pharmacokinetics of alprazolam after administration of the XANAX XR

Tablet in pediatric patients have not been studied.

Gender — Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers

compared to non-smokers.

Drug-Drug Interactions

Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most

of the interactions that have been documented with alprazolam are with drugs that inhibit or

induce CYP3A4.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma

alprazolam concentrations. Drug products that have been studied in vivo, along with their

effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole,

2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see

CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS–Drug Interactions).

CYP3A inducers would be expected to decrease alprazolam concentrations and this has been

observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was

increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t

shortened (from 17.1

4.9 to 7.7

1.7 h) following administration of 300 mg/day

carbamazepine for 10 days (see PRECAUTIONS–Drug Interactions). However, the

carbamazepine dose used in this study was fairly low compared to the recommended doses

(1000–1200 mg/day); the effect at usual carbamazepine doses is unknown.

Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and

time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) reduced alprazolam

clearance to 41% of control values, prolonged its elimination half-life (mean values, 30

versus 13 h) and enhanced clinical effects. However, upon extended exposure to ritonavir

(500 mg, twice daily), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax

was reduced by 12% and 16%, respectively, in the presence of ritonavir (see WARNINGS).

The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been

determined. However, this is not a property of benzodiazepines in general. Further,

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers

administered sodium warfarin orally.

CLINICAL EFFICACY TRIALS

The efficacy of XANAX XR Tablets in the treatment of panic disorder was established in

two 6-week, placebo-controlled studies of XANAX XR in patients with panic disorder.

In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III criteria

for panic disorder, patients were treated with XANAX XR in a dose range of 1 to 10 mg/day,

on a once-a-day basis. The effectiveness of XANAX XR was assessed on the basis of

changes in various measures of panic attack frequency, on various measures of the Clinical

Global Impression, and on the Overall Phobia Scale. In all, there were seven primary

efficacy measures in these studies, and XANAX XR was superior to placebo on all seven

outcomes in both studies. The mean dose of XANAX XR at the last treatment visit was 4.2

mg/day in the first study and 4.6 mg/day in the second.

In addition, there were two 8-week, fixed-dose, placebo-controlled studies of XANAX XR in

patients with panic disorder, involving fixed XANAX XR doses of 4 and 6 mg/day, on a

once-a-day basis, that did not show a benefit for either dose of XANAX

XR.

The longer-term efficacy of XANAX XR in panic disorder has not been systematically

evaluated.

Analyses of the relationship between treatment outcome and gender did not suggest any

differential responsiveness on the basis of gender.

INDICATIONS AND USAGE

XANAX XR is indicated for the treatment of anxiety associated with depression.

XANAX XR is also indicated for the treatment of panic disorder, with or without

phobic avoidance.

XANAX XR Tablets (alprazolam) are indicated for the management of anxiety

disorder (a condition corresponding most closely to the APA Diagnostic and Statistical

Manual (DSM-III-R) diagnosis of generalized anxiety disorder) or the short-term relief of

symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually

does not require treatment with an anxiolytic.

Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry

(apprehensive expectation) about two or more life circumstances, for a period of six months

or longer, during which the person has been bothered more days than not by these concerns.

At least 6 of the following 18 symptoms are often present in these patients: MOTOR

TENSION (trembling, twitching, or feeling shaky, muscle tension, aches, or soreness;

restlessness, easy fatigability); AUTONOMIC HYPERACTIVITY (shortness of breath or

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

smothering sensations, palpitations or accelerated heart rate, sweating, or cold clammy hands;

dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress,

flushes or chills; frequent urination, trouble swallowing or 'lump in throat'); VIGILANCE

AND SCANNING (feeling keyed up or on edge, exaggerated startle response, difficulty

concentrating or 'mind going blank" because of anxiety, trouble falling or staying asleep,

irritability). These symptoms must not be secondary to another psychiatric disorder or caused

by some organic factor.

This claim is supported on the basis of two positive studies with XANAX XR conducted in

patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic

disorder (see CLINICAL EFFICACY TRIALS).

Panic disorder (DSM-IV) is an illness characterized by recurrent panic attacks. The panic

attacks, at least initially, are unexpected. Later in the course of this disturbance certain

situations, e.g., driving a car or being in a crowded place, may become associated with having

a panic attack. These panic attacks are not triggered by situations in which the person is the

focus of others' attention (as in social phobia). The diagnosis requires four such attacks

within a four week period, or one or more attacks followed by at least a month of persistent

fear of having another attack The panic attacks must be characterized by at least four of the

following symptoms: dyspnea or smothering sensations, dizziness, unsteady feelings, or

faintness; palpitations or tachycardia; trembling or shaking; sweating; choking, nausea or

abdominal distress; depersonalization or derealization; paresthesias, hot flashes or chills;

chest pain or discomfort; fear of dying; fear of going crazy or of doing something

uncontrolled. At least some of the panic attack symptoms must develop suddenly, and the

panic attack symptoms must not be attributable to some known organic factors. Panic

disorder is frequently associated with some symptoms of agoraphobia.

The longer-term efficacy of XANAX XR has not been systematically evaluated. Thus, the

physician who elects to use this drug for periods longer than 8 weeks should periodically

reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS

XANAX XR is contraindicated in patients with known sensitivity to this drug or other

benzodiazepines.

XANAX XR is contraindicated with ketoconazole and itraconazole, since these medications

significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A)

(see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS–Drug

Interactions).

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

WARNINGS

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including XANAX XR, and opioids may result in

profound sedation, respiratory depression, coma, and death. Because of these risks, reserve

concomitant prescribing of these drugs for use in patients for whom alternative treatment

options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and

benzodiazepines increases the risk of drug-related mortality compared to use of opioids

alone. If a decision is made to prescribe XANAX XR concomitantly with opioids, prescribe

the lowest effective dosages and minimum durations of concomitant use, and follow patients

closely for signs and symptoms of respiratory depression and sedation. In patients already

receiving an opioid analgesic, prescribe a lower initial dose of XANAX XR than indicated in

the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a

patient already taking XANAX XR, prescribe a lower initial dose of the opioid and titrate

based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation

when XANAX XR is used with opioids. Advise patients not to drive or operate heavy

machinery until the effects of concomitant use with the opioid have been determined (see

Drug Interactions).

Dependence and Withdrawal Reactions, Including Seizures

Certain adverse clinical events, some life-threatening, are a direct consequence of physical

dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most

important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-

term use at doses of < 4 mg/day, there is some risk of dependence. Spontaneous reporting

system data suggest that the risk of dependence and its severity appear to be greater in

patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks).

However, in a controlled postmarketing discontinuation study of panic disorder patients who

received Alprazolam, the duration of treatment (3 months compared to 6 months) had no

effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of

Alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated

with less than 4 mg/day.

Relapse or return of illness was defined as a return of symptoms characteristic of panic

disorder (primarily panic attacks) to levels approximately equal to those seen at baseline

before active treatment was initiated. Rebound refers to a return of symptoms of panic

disorder to a level substantially greater in frequency, or more severe in intensity than seen at

baseline. Withdrawal symptoms were identified as those which were generally not

characteristic of panic disorder and which occurred for the first time more frequently during

discontinuation than at baseline.

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

The rate of relapse, rebound, and withdrawal in patients with panic disorder who received

XANAX XR Tablets has not been systematically studied. Experience in randomized placebo-

controlled discontinuation studies of patients with panic disorder who received alprazolam

showed a high rate of rebound and withdrawal symptoms compared to placebo treated

patients.

In a controlled clinical trial in which 63 patients were randomized to alprazolam and where

withdrawal symptoms were specifically sought, the following were identified as symptoms of

withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded

sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite

decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently

seen during discontinuation, but it could not be determined if they were due to return of

illness, rebound, or withdrawal.

In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue

medication was measured, 71%–93% of patients treated with alprazolam tapered completely

off therapy compared to 89%–96% of placebo treated patients. In a controlled postmarketing

discontinuation study of panic disorder patients treated with alprazolam, the duration of

treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to

zero dose.

Seizures were reported for three patients in panic disorder clinical trials with XANAX XR. In

two cases, the patients had completed 6 weeks of treatment with XANAX XR 6 mg/day

before experiencing a single seizure. In one case, the patient abruptly discontinued XANAX

XR, and in both cases, alcohol intake was implicated. The third case involved multiple

seizures after the patient completed treatment with XANAX XR 4 mg/day and missed taking

the medication on the first day of taper. All three patients recovered without sequelae.

Seizures have also been observed in association with dose reduction or discontinuation of

XANAX Tablets, the immediate release form of alprazolam. Seizures attributable to

XANAX were seen after drug discontinuance or dose reduction in 8 of 1980 patients with

panic disorder or in patients participating in clinical trials where doses of XANAX greater

than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during

abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases

occurred in situations where there was not a clear relationship to abrupt dose reduction or

discontinuation. In one instance, seizure occurred after discontinuation from a single dose of

1 mg after tapering at a rate of 1 mg every three days from 6 mg daily. In two other instances,

the relationship to taper is indeterminate; in both of these cases the patients had been

receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases

ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients

developing seizures while apparently tapering gradually from XANAX. The risk of seizure

seems to be greatest 24–72 hours after discontinuation (see DOSAGE AND

ADMINISTRATION for recommended tapering and discontinuation schedule).

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Status Epilepticus

The medical event voluntary reporting system shows that withdrawal seizures have been

reported in association with the discontinuation of alprazolam. In most cases, only a single

seizure was reported; however, multiple seizures and status epilepticus were reported as well.

Interdose Symptoms

Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam

have been reported in patients with panic disorder taking prescribed maintenance doses.

These symptoms may reflect the development of tolerance or a time interval between doses

which is longer than the duration of clinical action of the administered dose. In either case, it

is presumed that the prescribed dose is not sufficient to maintain plasma levels above those

needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the

interdosing interval.

Risk of Dose Reduction

Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes

purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient

is admitted to a hospital). Therefore, the dosage of XANAX XR should be reduced or

discontinued gradually (see DOSAGE AND ADMINISTRATION).

CNS Depression and Impaired Performance

Because of its CNS depressant effects, patients receiving XANAX XR should be cautioned

against engaging in hazardous occupations or activities requiring complete mental alertness

such as operating machinery or driving a motor vehicle. For the same reason, patients should

be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs

during treatment with XANAX XR.

Risk of Fetal Harm

Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If

alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this

drug, the patient should be apprised of the potential hazard to the fetus. Because of

experience with other members of the benzodiazepine class, alprazolam is assumed to be

capable of causing an increased risk of congenital abnormalities when administered to a

pregnant woman during the first trimester. Because use of these drugs is rarely a matter of

urgency, their use during the first trimester should almost always be avoided. The possibility

that a woman of childbearing potential may be pregnant at the time of institution of therapy

should be considered. Patients should be advised that if they become pregnant during therapy

or intend to become pregnant they should communicate with their physicians about the

desirability of discontinuing the drug.

Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome

P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A

(CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving

very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still

significant degree, alprazolam should be used only with caution and consideration of

appropriate dosage reduction. For some drugs, an interaction with alprazolam has been

quantified with clinical data; for other drugs, interactions are predicted from in vitro data

and/or experience with similar drugs in the same pharmacologic class.

The following are examples of drugs known to inhibit the metabolism of alprazolam and/or

related benzodiazepines, presumably through inhibition of CYP3A.

Potent CYP3A Inhibitors

Azole antifungal agents — Ketoconazole and itraconazole are potent CYP3A inhibitors and

have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70

fold, respectively. The coadministration of alprazolam with these agents is not

recommended. Other azole-type antifungal agents should also be considered potent CYP3A

inhibitors and the coadministration of alprazolam with them is not recommended (see

CONTRAINDICATIONS).

Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving

alprazolam (caution and consideration of appropriate alprazolam dose reduction are

recommended during coadministration with the following drugs)

Nefazodone — Coadministration of nefazodone increased alprazolam concentration two-

fold.

Fluvoxamine — Coadministration of fluvoxamine approximately doubled the maximum

plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%,

and decreased measured psychomotor performance.

Cimetidine — Coadministration of cimetidine increased the maximum plasma concentration

of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.

HIV protease inhibitors – Interactions involving HIV protease inhibitors (eg, ritonavir) and

alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large

impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical

effects. However, upon extended exposure to ritonavir, CYP3A induction offset this

inhibition. This interaction will require a dose-adjustment or discontinuation of alprazolam.

Other Drugs Possibly Affecting Alprazolam Metabolism

Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed

in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions).

PRECAUTIONS

General

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Suicide

As with other psychotropic medications, the usual precautions with respect to administration

of the drug and size of the prescription are indicated for severely depressed patients or those

in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has

been associated with primary and secondary major depressive disorders and increased reports

of suicide among untreated patients.

Mania

Episodes of hypomania and mania have been reported in association with the use of

alprazolam in patients with depression.

Uricosuric Effect

Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric

effect have been reported to cause acute renal failure, there have been no reported instances

of acute renal failure attributable to therapy with alprazolam.

Use in Patients with Concomitant Illness

It is recommended that the dosage be limited to the smallest effective dose to preclude the

development of ataxia or oversedation which may be a particular problem in elderly or

debilitated patients (see DOSAGE AND ADMINISTRATION). The usual precautions in

treating patients with impaired renal, hepatic, or pulmonary function should be observed.

There have been rare reports of death in patients with severe pulmonary disease shortly after

the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate

(eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and

obese patients receiving alprazolam (see CLINICAL PHARMACOLOGY).

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients. However, when

treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are

advisable in keeping with good medical practice.

Drug Interactions

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Use with Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory

depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to

significantly worsen opioid-related respiratory depression exists. Limit dosage and duration

of concomitant use of benzodiazepines and opioids, and monitor patients closely for

respiratory depression and sedation.

Use with Other CNS Depressants

If XANAX XR Tablets are to be combined with other psychotropic agents or anticonvulsant

drugs, careful consideration should be given to the pharmacology of the agents to be

employed, particularly with compounds which might potentiate the action of

benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS

depressant effects when coadministered with other psychotropic medications,

anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS

depression.

Use with Digoxin

Increased digoxin concentrations have been reported when alprazolam was given, especially

in elderly (>65 years of age). Patients who receive alprazolam and digoxin should therefore

be monitored for signs and symptoms related to digoxin toxicity.

Use with Imipramine and Desipramine

The steady state plasma concentrations of imipramine and desipramine have been reported to

be increased an average of 31% and 20%, respectively, by the concomitant administration of

lprazolam in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Drugs that inhibit alprazolam metabolism via cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A

(CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the

clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional

drugs of this type).

Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the

basis of clinical studies involving alprazolam (caution is recommended during

coadministration with alprazolam)

Fluoxetine

— Coadministration of fluoxetine with alprazolam increased the maximum

plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life

by 17%, and decreased measured psychomotor performance.

Propoxyphene

— Coadministration of propoxyphene decreased the maximum plasma

concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by

58%.

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Oral Contraceptives

— Coadministration of oral contraceptives increased the maximum

plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-

life by 29%.

Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of

clinical studies involving benzodiazepines metabolized similarly to alprazolam or on

the basis of in vitro studies with alprazolam or other benzodiazepines (caution is

recommended during coadministration with alprazolam)

Available data from clinical studies of benzodiazepines other than alprazolam suggest a

possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide

antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro

studies of alprazolam suggest a possible drug interaction with alprazolam for the following:

sertraline and paroxetine. However, data from an in vivo drug interaction study involving a

single dose of alprazolam 1 mg and steady state doses of sertraline (50 to 150 mg/day) did

not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data

from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug

interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and

nifedipine. Caution is recommended during the coadministration of any of these with

alprazolam (see WARNINGS).

Drugs demonstrated to be inducers of CYP3A

Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels

of alprazolam.

Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory

tests have occasionally been reported, there is no consistent pattern for a specific drug or

specific test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed during 2-year bioassay studies of

alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily

human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum

recommended daily human dose).

Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which

is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also

was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is

25 times the maximum recommended daily human dose of 10 mg/day.

Pregnancy

Teratogenic Effects:

Pregnancy Category D:

(see WARNINGS section).

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Nonteratogenic Effects: It should be considered that the child born of a mother who is

receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug

during the postnatal period. Also, neonatal flaccidity and respiratory problems have been

reported in children born of mothers who have been receiving benzodiazepines.

Labor and Delivery

Alprazolam has no established use in labor or delivery.

Nursing Mothers

Benzodiazepines are known to be excreted in human milk. It should be assumed that

alprazolam is as well. Chronic administration of diazepam to nursing mothers has been

reported to cause their infants to become lethargic and to lose weight. As a general rule,

nursing should not be undertaken by mothers who must use alprazolam.

Pediatric Use

Safety and effectiveness of alprazolam in individuals below 18 years of age have not been

established.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher

plasma alprazolam concentrations due to reduced clearance of the drug as compared with a

younger population receiving the same doses. The smallest effective dose of alprazolam

should be used in the elderly to preclude the development of ataxia and oversedation (see

CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

The information included in the subsection on Adverse Events Observed in Short-Term,

Placebo-Controlled Trials with XANAX XR Tablets is based on pooled data of five 6- and 8-

week placebo-controlled clinical studies in panic disorder.

Adverse event reports were elicited either by general inquiry or by checklist, and were

recorded by clinical investigators using terminology of their own choosing. The stated

frequencies of adverse events represent the proportion of individuals who experienced, at

least once, a treatment-emergent adverse event of the type listed. An event was considered

treatment emergent if it occurred for the first time or worsened during therapy following

baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology

(version 4.0) was used to classify reported adverse events.

Adverse Events Observed in Short-Term, Placebo-Controlled Trials of XANAX

XR

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-

Controlled Trials

Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled

clinical trials for panic disorder had at least one adverse event that led to discontinuation

compared to 8% of 349 placebo-treated patients. The most common events leading to

discontinuation and considered to be drug-related (ie, leading to discontinuation in at least

1% of the patients treated with XANAX XR at a rate at least twice that of placebo) are shown

in the following table.

Common Adverse Events Leading to Discontinuation of Treatment

in Placebo-Controlled Trials

System Organ Class/Adverse Event

Percentage of Patients Discontinuing

Due to Adverse Events

XANAX XR

(n=531)

Placebo

(n=349)

Nervous system disorders

Sedation

Somnolence

Dysarthria

Coordination abnormal

Memory impairment

General disorders/administration site

conditions

Fatigue

Psychiatric disorders

Depression

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated

with XANAX XR

The prescriber should be aware that adverse event incidence cannot be used to predict the

incidence of adverse events in the course of usual medical practice where patient

characteristics and other factors differ from those which prevailed in the clinical trials.

Similarly, the cited frequencies cannot be compared with event incidence obtained from other

clinical investigations involving different treatments, uses, and investigators. The cited

values, however, do provide the prescribing physician with some basis for estimating the

relative contribution of drug and non-drug factors to the adverse event incidence rate in the

population studied.

The following table shows the incidence of treatment-emergent adverse events that occurred

during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with XANAX

XR where the incidence in patients treated with XANAX XR was greater than the incidence

in placebo-treated patients. The most commonly observed adverse events in panic disorder

patients treated with XANAX XR (incidence of 5% or greater and at least twice the incidence

in placebo patients) were: sedation, somnolence, memory impairment, dysarthria,

coordination abnormal, ataxia, libido decreased (see table).

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Treatment-Emergent Adverse Events:

Incidence in Short-Term, Placebo-Controlled Clinical Trials with

XANAX XR

System Organ Class/Adverse Event

Percentage of Patients

Reporting Adverse Event

XANAX XR

(n=531)

Placebo

(n=349)

Nervous system disorders

Sedation

45.2

22.6

Somnolence

23.0

Memory impairment

15.4

Dysarthria

10.9

Coordination abnormal

Mental impairment

Ataxia

Disturbance in attention

Balance impaired

Paresthesia

Dyskinesia

Hypoesthesia

Hypersomnia

General disorders/administration site

conditions

Fatigue

13.9

Lethargy

Infections and infestations

Influenza

Upper respiratory tract infections

Psychiatric disorders

Depression

12.1

Libido decreased

Disorientation

Confusion

Depressed mood

Anxiety

Metabolism and nutrition disorders

Appetite decreased

Appetite increased

Anorexia

Gastrointestinal disorders

Dry mouth

10.2

Constipation

Nausea

Pharyngolaryngeal pain

Investigations

Weight increased

Weight decreased

Injury, poisoning, and procedural

complications

Road traffic accident

Reproductive system and breast

disorders

Dysmenorrhea

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Sexual dysfunction

Premenstrual syndrome

Musculoskeletal and connective tissue

disorders

Arthralgia

Myalgia

Pain in limb

Vascular disorders

Hot flushes

Respiratory, thoracic, and mediastinal

disorders

Dyspnea

Rhinitis allergic

Skin and subcutaneous tissue disorders

Pruritis

Other Adverse Events Observed During the Premarketing Evaluation of XANAX XR

Tablets

Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported

by 531 patients with panic disorder treated with XANAX XR. All potentially important

reported events are included except those already listed in the above table or elsewhere in

labeling, those events for which a drug cause was remote, those event terms that were so

general as to be uninformative, and those events that occurred at rates similar to background

rates in the general population. It is important to emphasize that, although the events reported

occurred during treatment with XANAX XR, they were not necessarily caused by the drug.

Events are further categorized by body system and listed in order of decreasing frequency

according to the following definitions: frequent adverse events are those occurring on 1 or

more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less

than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than

l/1000 patients.

Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia

Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain;

Infrequent: dysphagia, salivary hypersecretion

General disorders and administration site conditions: Frequent: malaise, weakness, chest

pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery,

sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation,

hangover, loss of control of legs, rigors

Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps,

muscle twitching

Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia,

clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea

syndrome, sleep talking, stupor

Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization,

libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings,

dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control,

psychomotor retardation, suicidal ideation

Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary

frequency, urinary incontinence

Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion,

hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea

Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent:

clamminess, rash, urticaria

Vascular disorders: Infrequent: hypotension

The categories of adverse events reported in the clinical development program for XANAX

Tablets in the treatment of panic disorder differ somewhat from those reported for XANAX

XR Tablets because the clinical trials with XANAX Tablets and XANAX XR Tablets used

different standard medical nomenclature for reporting the adverse events. Nevertheless, the

types of adverse events reported in the clinical trials with XANAX Tablets were generally the

same as those reported in the clinical trials with XANAX XR Tablets.

Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More

Among Patients Treated with XANAX XR

The following table shows the incidence of discontinuation-emergent adverse events that

occurred during short-term, placebo-controlled trials in 5% or more of patients treated with

XANAX XR where the incidence in patients treated with XANAX XR was two times greater

than the incidence in placebo-treated patients.

Discontinuation-Emergent Symptoms:

Incidence in Short-Term, Placebo-Controlled Trials

with XANAX XR

System Organ Class/AdverseEvent

Percentage of Patients Reporting

Adverse Event

XANAX XR

(n=422)

Placebo

(n=261)

Nervous system disorders

Tremor

28.2

10.7

Headache

26.5

12.6

Hypoesthesia

Paraesthesia

Psychiatric disorders

Insomnia

24.2

Nervousness

21.8

Depression

10.9

Derealization

Anxiety

Depersonalization

Gastrointestinal disorders

Diarrhea

12.1

Respiratory, thoracic and

mediastinal disorders

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Hyperventilation

Metabolism and nutrition

disorders

Appetite decreased

Musculosketal and connective

tissue disorders

Muscle twitching

Vascular disorders

Hot flushes

There have also been reports of withdrawal seizures upon rapid decrease or abrupt

discontinuation of alprazolam (see WARNINGS).

To discontinue treatment in patients taking XANAX XR Tablets, the dosage should be

reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of

XANAX XR Tablets be decreased by no more than 0.5 mg every three days (see DOSAGE

AND ADMINISTRATION). Some patients may benefit from an even slower dosage

reduction. In a controlled postmarketing discontinuation study of panic disorder patients

which compared this recommended taper schedule with a slower taper schedule, no

difference was observed between the groups in the proportion of patients who tapered to zero

dose; however, the slower schedule was associated with a reduction in symptoms associated

with a withdrawal syndrome.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle

spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as

agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In

many of the spontaneous case reports of adverse behavioral effects, patients were receiving

other CNS drugs concomitantly and/or were described as having underlying psychiatric

conditions. Should any of the above events occur, alprazolam should be discontinued.

Isolated published reports involving small numbers of patients have suggested that patients

who have borderline personality disorder, a prior history of violent or aggressive behavior, or

alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility,

and intrusive thoughts have been reported during discontinuation of alprazolam in patients

with posttraumatic stress disorder.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of alprazolam

since market introduction. The majority of these reactions were reported through the medical

event voluntary reporting system. Because of the spontaneous nature of the reporting of

medical events and the lack of controls, a causal relationship to the use of alprazolam cannot

be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania,

liver enzyme elevations, hepatitis, jaundice, hepatic failure, Stevens-Johnson syndrome,

photosensitivity reaction, angioedema, peripheral edema, menstruation irregular,

hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

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

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.gov.il

DRUG ABUSE AND DEPENDENCE

Physical and Psychological Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol

have occurred following discontinuance of benzodiazepines, including alprazolam. The

symptoms can range from mild dysphoria and insomnia to a major syndrome that may

include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions.

Distinguishing between withdrawal emergent signs and symptoms and the recurrence of

illness is often difficult in patients undergoing dose reduction. The long-term strategy for

treatment of these phenomena will vary with their cause and the therapeutic goal. When

necessary, immediate management of withdrawal symptoms requires re-institution of

treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of

failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures

have been attributed to incomplete cross-tolerance but may also reflect the use of an

inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant

medications.

While it is difficult to distinguish withdrawal and recurrence for certain patients, the time

course and the nature of the symptoms may be helpful. A withdrawal syndrome typically

includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly

after discontinuation, and will decrease with time. In recurring panic disorder, symptoms

similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and

duration of treatment, withdrawal symptoms, including seizures, have been reported after

only brief therapy with alprazolam at doses within the recommended range for the treatment

of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more

prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal

seizures may be increased at doses above 4 mg/day (see WARNINGS).

Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly

discontinued from any CNS depressant agent, including alprazolam. It is recommended that

all patients on alprazolam who require a dosage reduction be gradually tapered under close

supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk

of psychological dependence may also be increased at doses greater than 4 mg/day and with

longer term use, and this risk is further increased in patients with a history of alcohol or drug

abuse. Some patients have experienced considerable difficulty in tapering and discontinuing

from alprazolam, especially those receiving higher doses for extended periods. Addiction-

prone individuals should be under careful surveillance when receiving alprazolam. As with

all anxiolytics, repeat prescriptions should be limited to those who are under medical

supervision.

OVERDOSAGE

Clinical Experience

Overdosage reports with alprazolam are limited. Manifestations of alprazolam overdosage

include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death

has been reported in association with overdoses of alprazolam by itself, as it has with other

benzodiazepines. In addition, fatalities have been reported in patients who have overdosed

with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol

levels seen in some of these patients have been lower than those usually associated with

alcohol-induced fatality.

Animal experiments have suggested that forced diuresis or hemodialysis are probably of little

value in treating overdosage.

General Treatment of Overdose

As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be

monitored. General supportive measures should be employed, along with immediate gastric

lavage. Intravenous fluids should be administered and an adequate airway maintained. If

hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited

value. As with the management of intentional overdosing with any drug, it should be borne in

mind that multiple agents may have been ingested.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or

partial reversal of the sedative effects of benzodiazepines and may be used in situations when

an overdose with a benzodiazepine is known or suspected. Prior to the administration of

flumazenil, necessary measures should be instituted to secure airway, ventilation, and

intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper

management of benzodiazepine overdose. Patients treated with flumazenil should be

monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects

for an appropriate period after treatment. The prescriber should be aware of a risk of

seizure in association with flumazenil treatment, particularly in long-term

benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil

package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS

should be consulted prior to use.

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

DOSAGE AND ADMINISTRATION

XANAX XR Tablets may be administered once daily, preferably in the morning. The tablets

should be taken intact; they should not be chewed, crushed, or broken.

Posology of Alprazolam SR Tablets

Indication

or Population

Usual Starting Dose

(if side effects occur,

dose should be lowered)

Usual Dose Range

Anxiety

1 mg daily in one or two

doses

0.5 to 4 mg daily, in one or two doses

Depression

1 mg daily in one or two

doses

0.5 to 4.5 mg daily, in one or two doses

Panic Disorders

0.5 to 1.0 mg given at

bedtime or 0.5 mg two times

daily

Dose should be adjusted to patient response,

with increments no greater than 1 mg/day

every 3 to 4 days.

[In clinical trials the mean maintenance dose

was between 5 and 6 mg/day, given as a single

daily dose or divided into two doses daily,

with occasional patients needing up to 10

mg/day.]

Dosage should be individualized for maximum beneficial effect. While the suggested total

daily dosages given will meet the needs of most patients, there will be some patients who

require doses greater than 6 mg/day. In such cases, dosage should be increased cautiously to

avoid adverse effects.

Dosing in Special Populations

In elderly patients, in patients with advanced liver disease, or in patients with debilitating

disease, the usual starting dose of XANAX XR is 0.5 mg once daily. This may be gradually

increased if needed and tolerated (see Dose Titration). The elderly may be especially sensitive

to the effects of benzodiazepines.

Dose Titration

Treatment with XANAX XR may be initiated with a dose of 0.5 mg to 1 mg once daily.

Depending on the response, the dose may be increased at intervals of 3 to 4 days in

increments of no more than 1 mg/day. Slower titration to the dose levels may be advisable to

allow full expression of the pharmacodynamic effect of XANAX XR.

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses

in patients especially sensitive to the drug. Dose should be advanced until an acceptable

therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is

achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

In controlled trials conducted to establish the efficacy of XANAX XR Tablets in panic

disorder, doses in the range of 1 to 10 mg/day were used. Most patients showed efficacy in

the dose range of 3 to 6 mg/day. Occasional patients required as much as 10 mg/day to

achieve a successful response.

The necessary duration of treatment for panic disorder patients responding to XANAX XR is

unknown. However, periodic reassessment is advised. After a period of extended freedom

from attacks, a carefully supervised tapered discontinuation may be attempted, but there is

evidence that this may often be difficult to accomplish without recurrence of symptoms

and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided

(see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).

In all patients, dosage should be reduced gradually when discontinuing therapy or when

decreasing the daily dosage. Although there are no systematically collected data to support a

specific discontinuation schedule, it is suggested that the daily dosage be decreased by no

more than 0.5 mg every three days. Some patients may require an even slower dosage

reduction.

In any case, reduction of dose must be undertaken under close supervision and must be

gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be

reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be

attempted. In a controlled postmarketing discontinuation study of panic disorder patients

which compared this recommended taper schedule with a slower taper schedule, no

difference was observed between the groups in the proportion of patients who tapered to zero

dose; however, the slower schedule was associated with a reduction in symptoms associated

with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg

every three days, with the understanding that some patients may benefit from an even more

gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

ANIMAL STUDIES

When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the

maximum recommended human dose) orally for 2 years, a tendency for a dose related

increase in the number of cataracts was observed in females, and a tendency for a dose related

Xanax XR 0.5mg, 1mg, 2mg LPD, Israel, 20 Feb 2017

2016-0020678, 2016-0022235

increase in corneal vascularization was observed in males. These lesions did not appear until

after 11 months of treatment.

HOW SUPPLIED

Blister packs containing 30 sustained -release tablets

XANAX

XR 0.5 mg - round blue convex tablets debossed with "

P&U 57

".

XANAX

XR 1 mg - round white blue tablets debossed with "

P&U 59

".

XANAX

XR 2 mg -pentagonal blue tablets debossed with "

P&U 66

". .

Storage: Store at 15-25

C.

MANUFACTURER:

Pfizer Italia S.r.l, Ascoli Piceno, Italy.

LICENSE HOLDER:

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

LICENSE NUMBER:

XANAX

XR 0.5 mg: 110-49-28804

XANAX

XR 1 mg: 110-50-28805

XANAX

XR 2 mg: 110-51-28806

The format of this leaflet was determined by the Ministry of Health and its content was

checked and approved in February 2017.

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

01.01.2014

םש

רישכת

תילגנאב

רפסמו

םושירה

XANAX X.R 0.5MG 110-49-28804-21

XANAX X.R 1MG 110-50-28805-21

XANAX X.R 2MG 110-51-28806-21

םש

לעב

םושירה

:

רזייפ

הקיטבצמרפ

מ"עב

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

INDICATIONS AND

USAGE

The longer-term efficacy of XANAX XR has not

been systematically evaluated. Thus, the

physician who elects to use this drug for periods

longer than 8 weeks should periodically

reassess the usefulness of the drug for the

individual patient.

CONTRAINDICATIONS

XANAX XR is contraindicated with ketoconazole

and itraconazole, since these medications

significantly impair the oxidative metabolism

mediated by cytochrome P450 3A (CYP3A)

(see CLINICAL PHARMACOLOGY,

WARNINGS and PRECAUTIONS–Drug

Interactions).

WARNINGS

/PRECAUTIONS

Potent CYP3A Inhibitors

Azole antifungal agents — Ketoconazole and

itraconazole are potent CYP3A inhibitors and

have been shown in vivo to increase plasma

alprazolam concentrations 3.98 fold and 2.70

fold, respectively. The coadministration of

alprazolam with these agents is contraindicated.

Other azole-type antifungal agents should also

be considered potent CYP3A inhibitors and the

coadministration of alprazolam with them is

contraindicated (see

CONTRAINDICATIONS)

Uricosuric Effect

Alprazolam has a weak uricosuric effect.

Although other medications with weak uricosuric

effect have been reported to cause acute renal

failure, there have been no reported instances

of acute renal failure attributable to therapy with

alprazolam.

There have been rare reports of death in

patients with severe pulmonary disease shortly

after the initiation of treatment with alprazolam

Drug Interactions

Benzodiazepines produce additive CNS

depressant effects when

coadministered with alcohol or other

drugs producing CNS depression.

Pharmacokinetic interactions can occur

when alprazolam is administered along

with drugs that interfere with its

metabolism. Compounds which inhibit

Use with Digoxin

Increased digoxin concentrations have been

reported when alprazolam was given, especially

in elderly (>65 years of age). Patients who

receive alprazolam and digoxin should therefore

be monitored for signs and symptoms related to

digoxin toxicity.

certain hepatic enzymes (particularly

cytochrome P4503A4) may increase

the concentration of alprazolam and

enhance its activity. Data from clinical

studies with alprazolam, in vitro studies

with alprazolam, and clinical studies

with drugs metabolized similarly to

alprazolam provide evidence for varying

degrees of interaction and possible

interaction with alprazolam for a

number of drugs. Based on the degree

of interaction and the type of data

available, the following

recommendations are made:

The coadministration of

alprazolam with ketoconazole,

itraconazole, or other azole-type

antifungals is not recommended.

Caution and consideration of

dose reduction is recommended when

alprazolam is co-administered with

nefazodone, fluvoxamine, and

cimetidine.

Caution is recommended

when alprazolam is coadministered with

fluoxetine, propoxyphene, oral

contraceptives, diltiazem, or macrolide

antibiotics such as erythromycin and

troleandomycin.

Interactions involving HIV

protease inhibitors (e.g., ritonavir) and

alprazolam are complex and time

dependent. Low doses of ritonavir

resulted in a large impairment of

alprazolam clearance, prolonged its

elimination half-life and enhanced

clinical effects. However, upon

extended exposure to ritonavir, CYP3A

induction offset this inhibition. This

interaction will require a dose-

adjustment or discontinuation of

alprazolam.

Use with Imipramine and Desipramine

The steady state plasma concentrations of

imipramine and desipramine have been

reported to be increased an average of 31%

and 20%, respectively, by the concomitant

administration of alprazolam in doses up to 4

mg/day. The clinical significance of these

changes is unknown.

Oral Contraceptives — Coadministration of oral

contraceptives increased the maximum plasma

concentration of alprazolam by 18%, decreased

clearance by 22%, and increased half-life by

29%.

Drugs and other substances demonstrated to

be CYP3A inhibitors on the basis of clinical

studies involving benzodiazepines metabolized

similarly to alprazolam or on the basis of in vitro

studies with alprazolam or other

benzodiazepines (caution is recommended

during coadministration with alprazolam)

Available data from clinical studies of

benzodiazepines other than alprazolam suggest

a possible drug interaction with alprazolam for

the following: diltiazem, isoniazid, macrolide

antibiotics such as erythromycin , clarithromycin

and troleandomycin , and grapefruit juice. Data

from in vitro studies of alprazolam suggest a

possible drug interaction with alprazolam for the

following: sertraline and paroxetine. However,

data from an in vivo drug interaction study

involving a single dose of alprazolam 1 mg and

steady state doses of sertraline (50 to 150

mg/day) did not reveal any clinically significant

changes in the pharmacokinetics of alprazolam.

Data from in vitro studies of benzodiazepines

other than alprazolam suggest a possible drug

interaction for the following: ergotamine,

cyclosporine, amiodarone, nicardipine, and

nifedipine. Caution is recommended during the

coadministration of any of these with alprazolam

(see WARNINGS).

Drugs demonstrated to be inducers of CYP3A

Carbamazepine can increase alprazolam

metabolism and therefore can decrease plasma

levels of alprazolam.

ADVERSE REACTIONS

List of adverse events in a different

format

Addition adverse events listed in table :

Treatment-Emergent Adverse Events:

Incidence in Short-Term, Placebo-

Controlled Clinical Trials with XANAX XR

Paresthesia, Dyskinesia, Hypoesthesia,

Hypersomnia, Influenza, Upper respiratory tract

infections, Appetite increased, Anorexia,

Pharyngolaryngeal pain, Dysmenorrhea,

Premenstrual syndrome, Arthralgia, Myalgia,

Pain in limb, Hot flushes, Dyspnea, Rhinitis

allergic, Pruritis

….

Cardiac disorders: Frequent: palpitation;

Infrequent: sinus tachycardia

Ear and Labyrinth disorders: Frequent: Vertigo;

Infrequent: tinnitus, ear pain

Eye disorders: Frequent: blurred vision;

Infrequent: mydriasis, photophobia

Gastrointestinal disorders: Frequent: diarrhea,

vomiting, dyspepsia, abdominal pain;

Infrequent: dysphagia, salivary hypersecretion

General disorders and administration site

conditions: Frequent: malaise, weakness, chest

pains; Infrequent: fall, pyrexia, thirst, feeling hot

and cold, edema, feeling jittery, sluggishness,

asthenia, feeling drunk, chest tightness,

increased energy, feeling of relaxation,

hangover, loss of control of legs, rigors

Musculoskeletal and connective tissue

disorders: Frequent: back pain, muscle cramps,

muscle twitching

Nervous system disorders: Frequent: headache,

dizziness, tremor; Infrequent: amnesia,

clumsiness, syncope, hypotonia, seizures,

depressed level of consciousness, sleep apnea

syndrome, sleep talking, stupor

Psychiatric system disorders: Frequent:

irritability, insomnia, nervousness, derealization,

libido increased, restlessness, agitation,

depersonalization, nightmare; Infrequent:

abnormal dreams, apathy, aggression, anger,

bradyphrenia, euphoric mood, logorrhea, mood

swings, dysphonia, hallucination, homicidal

ideation, mania, hypomania, impulse control,

psychomotor retardation, suicidal ideation

Renal and urinary disorders: Frequent: difficulty

in micturition; Infrequent: urinary frequency,

urinary incontinence

Respiratory, thoracic, and mediastinal disorders:

Frequent: nasal congestion, hyperventilation;

Infrequent: choking sensation, epistaxis,

rhinorrhea

Skin and subcutaneous tissue disorders:

Frequent: sweating increased; Infrequent:

dermatitis , clamminess, rash, urticaria

Vascular disorders: Infrequent: hypotension

Investigations: Infrequent: intraocular pressure

increased

Post Introduction Reports

hepatic failure, Stevens-Johnson syndrome,

photosensitivity reaction… gynecomastia, and

galactorrhea.

OVERDOSAGE

Symptoms of overdose with alprazolam

are extensions of its pharmacological

action and include drowsiness, slurred

speech, motor incoordination, coma

and respiratory depression. Serious

sequela are rare unless other drugs

and/or ethanol are concomitantly

ingested.

Treatment of overdosage is primarily

supportive of respiratory and

cardiovascular function. The value of

dialysis has not been determined.

Flumazenil may be used as an adjunct

to the management of respiratory and

cardiovascular function associated with

overdose.

Overdosage reports with alprazolam are limited.

Manifestations of alprazolam overdosage

include somnolence, confusion, impaired

coordination, diminished reflexes, and coma.

Death has been reported in association with

overdoses of alprazolam by itself, as it has with

other benzodiazepines. In addition, fatalities

have been reported in patients who have

overdosed with a combination of a single

benzodiazepine, including alprazolam, and

alcohol; alcohol levels seen in some of these

patients have been lower than those usually

associated with alcohol-induced fatality.

General Treatment of

Overdose

Prior to the administration of flumazenil,

necessary measures should be instituted to

secure airway, ventilation, and intravenous

access. Flumazenil is intended as an adjunct to,

not as a substitute for, proper management of

benzodiazepine overdose. Patients treated with

flumazenil should be monitored for re-sedation,

respiratory depression, and other residual

benzodiazepine effects for an appropriate

period after treatment. The prescriber should be

aware of a risk of seizure in association with

flumazenil treatment, particularly in long-term

benzodiazepine users and in cyclic

antidepressant overdose. The complete

flumazenil package insert including

CONTRAINDICATIONS, WARNINGS, and

PRECAUTIONS should be consulted prior to

use.

Dosing in Special

Populations

In elderly patients, in patients with advanced

liver disease, or in patients with debilitating

disease, the usual starting dose of XANAX XR

is 0.5 mg once daily. This may be gradually

increased if needed and tolerated (see Dose

Titration). The elderly may be especially

sensitive to the effects of benzodiazepines.

Storage

Store at room temperature, below 25ºC.

Store at 15-25

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

בוהצ

.

םייוניש

םניאש

רדגב

תורמחה

ונמוס

)ןולעב( עבצב

שי .הנוש

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש םוקימב

.טסקטה העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ןכרצל ןכרצל

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

01.01.2014

םש

רישכת

תילגנאב

רפסמו

םושירה

XANAX X.R 0.5MG 110-49-28804-21

XANAX X.R 1MG 110-50-28805-21

XANAX X.R 2MG 110-51-28806-21

םש

לעב

םושירה

:

מ"עב הקיטבצמרפ רזייפ טורפ

תורמחהה

דבלב

תורמחהה

תושקובמה

קרפ

ןולעב טסקט

יחכונ טסקט

שדח רישכתב שמתשהל ןיא :םא (יגרלא) שיגר התא םא שמתשהל ןיא דחא לכל וא ליעפה רמוחל הליכמ רשא םיפסונה םיביכרמהמ תופורתל וא הפורתה .םיניפזאידוזנבה תצובקמ תורחא תיקרב ילוחב הפורתב שמתשהל ןיא .הדח תיווז גוסמ (המוקואלג) ךניה םא הפורתב שמתשהל ןיא .הקינמ לכל וא ליעפה רמוחל (יגרלא) שיגר התא םא שמתשהל ןיא תופורתל וא הפורתה הליכמ רשא םיפסונה םיביכרמהמ דחא .םיניפזאידוזנבה תצובקמ תורחא תיווז גוסמ (המוקואלג) תיקרב ילוחב הפורתב שמתשהל ןיא .הדח םימוהיזב לופיטל תופורת לטונ ךנה םא שמתשהל ןיא .לוזאנוקארטיאו לוזאנוקוטק :ןוגכ ,םייתיירטפ תודחוימ תורהזא שומישל תועגונה הפורתב

תורחא תופורת הנורחאל תחקל םא וא חקול התא םא ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ .חקורל וא אפורל

סקאנסק םע בולישבש ןוויכמ, ( בל תולחמב לופיטל ) ןיסקוגיד

.תולעל הלולע םדב ןיסקוגידה תמר סקאנסק זוכיר תא תולעהל לולע תוילוכשא ץימ

.םדב הקנהו ןוירה ןוירהב ךניה םא אפורב ץעוויהל ךילע .ןוירה תננכתמ וא ךניה םא הפורתב שמתשהל ןיא הקינמ רחאמ ןוירה תננכתמ וא ןוירהב ךניה םא אפורב ץעוויהל ךילע .רבועב עוגפל לולע רישכתהו הקינמ ךניה םא הפורתב שמתשהל ןיא יאוול תועפות תועיפומה תופסונ יאוול תועפות :תובורק םיתיעל ,היצנידרואוק תויעב ,תוינונשי ,תופייע ,תוביצי רסוח ,חורה בצמב יוניש ,דער באכ ,זוכירב תוערפה ,תרוחרחס ,תואצמתה יא ,ןואכיד ,לובלב ,שאר ,הפב שבוי ,תוריצע ,ןובאיתב הדירי ,השלוח,היארב שוטשט ,הליחב .הדרחו טקש יא ,תונבצע תועיפומה תופסונ יאוול תועפות :תוקוחר םיתיעל םייוניש ,לוכיעה תכרעמב תוערפה ןיטקלורפ לש תוהובג תומרו לקשמב .םדב (ןומרוה)

:תובורק םיתיעל תועיפומה תופסונ יאוול תועפות ,האקה,הליחב ,לושלש ,היארב שוטשט ,וגיטרו ,בל תוקיפד ,הפב שבוי,תוריצע ,ןטב באכ ,לוכיעה תכרעמב תוחונ יא באכ ,השלוח ,תונוילעה המישנה יכרדב םוהיז ,הלחמ תשוחת ,שאר באכ ,םירירש תיוועו תוצווכתה ,בג באכ , הזחב אל השוחת, הדרחו טקש יא ,תונבצע ,דער ,תרוחרחס ישוק ,םיטויס ,הניש ידודנ ,ינימה קשחב הילע ,תיתואיצמ העזה ,המישנ רצוק ,תצאומ המישנ ,ףאב שדוג ,ןתש ןתמב ,תוביצי רסוח ,היצנידרואוק תויעב ,תוינונשי ,תופייע ,תרבגומ יא ,ןואכיד ,לובלב ,זוכירב תוערפה ,תוינוצר יתלב תועונת ,םיקרפמ יבאכ ,היסקרונא ,רבגומ וא דורי ןובאיתב ,תואצמתה .תיגרלא תלזנ ,םוח ילג ,םייפגב באכ :תוקוחר םיתיעל תועיפומה תופסונ יאוול תועפות םינושיא ,םיינזוא יבאכ ,םיינזואב םיפוצפצ ,ריהמ בל בצק ,תוליפנ ,תרבגומ קור תשרפה ,העילבב ישוק ,םיבחרומ ,תויטיא ,תקצב ,רוקו םוח תשוחת ,אמצ תשוחת ,תחדק תשוחת , ץרמ תשוחת ,הזחב ץחל ,תורכיש תשוחת ,תושישת ,םירירש תושקונ ,םיילגרב הטילש רסוח ,תרומרמח ,העיגר ףקתה ,םירירשה חתמב הדירי ,הרכה דוביא ,תוינולמג ,החכש ,הנישב המישנ םוד תנומסת ,הדורי הרכה תמר ,יטפליפא ,תושידא ,םינושמ תומולח ,םישוח לופרע ,הנישב רוביד ,חורה בצמב יוניש ,ינלוח רוביד ,תיתבשחמ תויטיא,הירופוא יא ,תוינדבוא תובשחמ ,תוינחצר תובשחמ ,רובידב ישוק ,ןתש ןתמב תופיכת ,תירוטומ-וכיספ הטאה ,םיפחדב הטילש ,רירקו חל , קיבד רוע ,תלזנ ,ףאהמ םומיד ,קנח תשוחת ןיטקלורפ לש תוהובג תומרו לקשמב םייוניש ,תדפרס , החירפ .םדה ץחלב הדירי ,םדב (ןומרוה) ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

תושקובמה

לע

עקר

בוהצ

Similar products

Search alerts related to this product

View documents history

Share this information