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Sandoz
1.3.1 spc-label-pl - common-spc - 2,226
(NL/H/0355/001-002-003/IB/029/G)
ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
1
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NAME OF THE MEDICINAL PRODUCT
Alprazolam Sandoz 0.25 mg tablets
Alprazolam Sandoz 0.5 mg tablets
Alprazolam Sandoz 1 mg tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 0.25 mg of Alprazolam.
Contains 97.32 mg lactose monohydrate.
One tablet contains 0.5 mg of Alprazolam.
Contains 97.00 mg lactose monohydrate.
One tablet contains 1 mg of Alprazolam.
Contains 96.53 mg lactose monohydrate.
For a the full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
Tablet.
Alprazolam Sandoz 0.25 mg tablets
White, oblong tablet with a score line and debossed "APZM 0.25".
Alprazolam Sandoz 0.5 mg tablets
Pink, oblong tablet with a score line and debossed "APZM 0.5"
Alprazolam Sandoz 1 mg tablets
Light blue, oblong tablet with a score line and debossed "APZM 1"
The tablets can be divided into equal halvesdoses.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
Symptomatic treatment of anxiety.
Only use Alprazolam if the disorder is severe or is causing invalidity, or if the patient is experiencing
inordinate suffering as a result of the disorder.
4.2
Posology and method of administration
Treatment The treatment period should be as short as possible. It is recommended that the patient be
reassessed at the endThe necessity of no longer than 4 weeks' treatment and the need for continued
treatment established, especially in casewith Alprazolam and the appropriate dosage should be
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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reassessed periodically for each patient is symptom free.. The overall durationtotal length of
treatment should not be more thanexceed 8-12 weeks, including a tapering off process.
In certain cases extension beyond the maximum treatment period may be necessary; if so, it should
not take place without re-evaluationthe period of the patient's status with special expertise. As with all
benzodiazepines, physicians should be aware that long-term use might lead to dependence in certain
patientsgradual dosage reduction. Prolonged treatment may be necessary in certain circumstances, but
this should not be done until the patient’s condition has been reassessed.
The The optimal dose of Alprazolam should be individually determined in accordance with the
severity of the symptoms and the patient’s response.
In most patients, the symptoms of anxiety can generally be effectively treated with a dose of between
0.5 mg per day and 3 mg per day, divided up into separately administered measures. Under no
circumstances should the maximum dose of 3 mg per day be exceeded. Patients who have never
previously taken psychotropic medications generally require lower doses than patients who have
either already been treated with tranquillisers, antidepressants or hypnotic drugs or those who are
chronic alcoholics. In order to avoid ataxia and over-sedation it is recommended that the lowest
effective dose be used.
Adults
Initial dosage *: 0.25 mg to 0.5 mg, three times a day
Dosage *: 0.5 mg to 3 mg per day in divided doses
The elderly, weakened patients, or patients with kidney or liver function disorders
Initial dosage *: 0.25 mg, twice or three times a day
Dosage *: 0.5 mg to 0.75 mg per day in divided doses: gradually increase the dose if necessary, and if
the disease permits.
* If side effects occur, the dose should be reduced.
Patients less than 18 years of age
Alprazolam should not be used in this specific patient group because safety and efficacy has not been
established.
Discontinuation of treatment
The dose should be gradually reduced. It is recommended that the daily dose of Alprazolam be
reduced at a rate not exceeding 0.5 mg per three days. In some patients, it may indeed be necessary to
reduce the dose even more gradually.
optimum dosage of Xanaxalprazolam should be based upon the severity of the symptoms and
individual patient response. The lowest dose which can control symptoms should be used. Dosage
should be reassessed at intervals of no more than 4 weeks. The usual dosage is stated below; in the
few patients who require higher doses, the dosage should be increased cautiously to avoid adverse
effects. When higher dosage is required, the evening dose should be increased before the daytime
doses. In general, patients who have not previously received psychotropic medications will require
lower doses than those so treated, or those with a history of chronic alcoholism.
Treatment should always be tapered off gradually. During discontinuation of alprazolam treatment,
the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the
daily dosage of alprazolam be decreased by no more than 0.5 mg every three days. Some patients
may require an even slower dosage reduction. (See section 4.4 Special warnings and precautions for
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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use)
There is a reduced clearance of the drug and, as with other benzodiazepines, an increased
sensitivity to the drug in elderly patients.
RMS-comments
Please delete : “.. as with other benzodiazepines….” as this not only holds for benzodiazepines but
also for several other CNS agents .
Anxiety: 250 micrograms (0.25 mg) to 500 micrograms (0.5 mg) three times daily increasing if
required to a total of 3 mg daily.
RMS-comments
Please delete the word “anxiety”. Mentioning anxiety suggested s that there are more indications, and
this is not the case.
Please maintain or justify its omission: “In most patients, the symptoms of anxiety can generally be
effectively treated with a dose of between 0.5 mg per day and 3 mg per day, divided up into separately
administered measures. Under no circumstances should the maximum dose of 3 mg per day be
exceeded.”
Geriatric patients or in the presence of debilitating disease:
250 micrograms (0.25 mg) two to three times daily to be gradually increased if needed and
tolerated.
Paediatric patients:
Safety and efficacy of alprazolam have not been established in children and adolescents below the
age of 18 years; therefore use of alprazolam is not recommended.
If side-effects occur, the dose should be lowered. It is advisable to review treatment regularly and to
discontinue use as soon as possible. Should longer term treatment be necessary, then intermittent
treatment may be considered to minimize the risk of dependence.
RMS-comments
Please consider another place in this section for the latter section, as it could be interpreted as
information only applicable for the paediatric patients.
4.3
Contraindications
Alprazolam is contraindicated in patients with a known hypersensitivityMyasthenia gravis.
Hypersensitivity to benzodiazepines, alprazolam Benzodiazepines or to any of the excipients listed in
section 6.1any component of the product's formulation.
Benzodiazepines are also contraindicated in patients with myasthenia gravis, severeexcipients of the
tablet.
Severe respiratory insufficiency, sleep.
Sleep apnoea syndrome, severe hepatic.
Severe liver insufficiency.
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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4.4 Special warnings and precautions for use
Tolerance
The hypnotic effect can diminish following repeated use over a period of several weeks.
Dependence
Caution is recommended when treating patients with impaired renal function or mild to moderate
hepatic insufficiency
In patients presenting with major depression or anxiety associated with depression, benzodiazepines
and benzodiazepine-like agents should not be used alone to treat depression as they may precipitate
or increase the risk of suicide. Therefore , alprazolam should be used with caution and the
prescription size should be limited in patients with signs and symptoms of a depressive disorder or
suicidal tendencies.
Safety and efficacy of alprazolam have not been established in children and adolescents below the
age of 18 years; therefore use of alprazolam is not recommended.
It is recommended that general principle of using the lowest effective dose to be followed in elderly
and /or debilitated patients to preclude development of ataxia or oversedation (See section 4.2
Posology and method of administration). A lower dose is also recommended for patients with
chronic respiratory insufficiency due to risk of respiratory depression.
Chronic use of Benzodiazepines should be used with extreme caution in patients with a history
of alcohol or drug abuse (See section 4.5 Interactions with other medicinal products and other
form of interactions).
can
RMS-comments
Please incorporate text omitted under posology in this section or justify the deletion of that text i.e.
“Patients who have never previously taken psychotropic medications generally require lower doses
than patients who have either already been treated with tranquillisers, antidepressants or hypnotic
drugs or those who are chronic alcoholics. In order to avoid ataxia and over-sedation it is
recommended that the lowest effective dose be used.”
Dependence
Use of benzodiazepines may lead to the development of physical and psychicmental dependence
upon these products.. The risk of dependence increases withis greater as the dose and durationlength
of treatment; it is also greater in patients with a history of alcohol and drug abuse.
Pharmacodependency may occur at therapeutic doses and/or in patients with no individualised risk
factor. increase. There is also an increased risk of pharmacodependencyin patients with the
combined use of several benzodiazepines regardless of the anxiolytic or hypnotic indication. Cases
ofa history of drug and alcohol abuse have also been reported.
Withdrawal symptoms: Once. If there is physical dependence has developed, abrupt termination,
the suspension of treatment will beis accompanied by withdrawal symptoms. These may consist
of headaches,headache and muscle pain, extremesevere anxiety, and tension, sleep disorders,
restlessness, confusion, and irritability and insomnia.. In severe cases the following symptoms
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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may occur: derealization, depersonalisation, derealisation, hyperacusis, numbnessloss of
sensation and tingling ofsensations in the extremitieslimbs, hypersensitivity to light, noisesound
and physical contacttouch, hallucinations orand epileptic seizures. (See section 4.2 Posology and
method of administration)
During discontinuation of alprazolam treatment, the dosage should be reduced slowly in keeping with
good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more
that 0.5 mg every threeWithdrawal symptoms can appear several days. Some patients may require
even slower dosage reduction after the end of treatment.
Rebound insomnia and anxiety: and tension
When treatment with Alprazolam is suspended, a transient syndrome wherebycan occur in which the
symptoms that led to treatment with a benzodiazepine recur in an enhanced form may occur on
withdrawal ofprompted treatment. It may with a Benzodiazepine (or Benzodiazepine-like substance)
in the first place recur with greater intensity than before. The syndrome can be accompanied by other
reactions including mood changes, anxiety or sleep disturbancesswings, insomnia and restlessness.
Since the risk of withdrawal phenomenasymptoms/rebound phenomenasymptoms is greater
afterfollowing rapid dose reduction or the abrupt discontinuationsuspension of treatment, it is
recommended that the dosagedose be decreasedreduced gradually by no more than 0.5 mg every three
days. Some patients may require an even slower dose reduction. (See section 4.2 Posology and
method of administration).(tapering off).
Duration of treatment
The duration of treatment should be as short as possible (See sectionsee 4.2 ‘Posology and method of
administrationadministration’) depending on the indication, but in cases of anxiety and tension should
not exceed eight to twelve8-12 weeks, including the so called tapering off process. Extension beyond
these periods should not take place withoutperiod of gradual dosage reduction. Prolongation of the
duration of treatment is only possible after re-evaluation of the situationcondition of the patient.
It may be usefulimportant to inform the patient whenat the start of treatment is started that it the
course of treatment will be of limited duration and to explain preciselyclearly how the dosagedosages
will be progressively decreased. Moreover itgradually reduced.
It is important thatto prepare patients for the patient should be aware of the possibilityoccurrence of
rebound phenomena, thereby minimising anxiety oversymptoms in order to avoid as much as possible
unease about the occurrence of such symptoms should they occur while the medicinal product is being
discontinued. Thereduring the cessation of therapy. In the case of Benzodiazepines with a short halflife time, there are indications, that in the case of benzodiazepines with a short duration of action, that
withdrawal phenomenasymptoms can become manifestoccur within the dosagedose interval,
especially when the dosagea high dose is high. When benzodiazepinesinvolved. If Benzodiazepines
with a long duration of actionhalf-life times are being used, it is important to warn against
changingpoint out that it is prudent not to a benzodiazepineswitch to Benzodiazepines with a short
durationhalf-life times because of action, asthe withdrawal symptoms that may develop. occur.
Amnesia
As with other Benzodiazepines may induce, Alprazolam can cause anterograde amnesia. The
conditionThis usually occurs most often several hours after ingesting the product and therefore to
reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours.
(See sectionhas been taken (see also 4.8. ‘Undesirable Effects)effects’).
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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RMS-comments
Please deleted the amended text: “and therefore to reduce the risk patients should ensure that they
will be able to have uninterrupted sleep of 7-8 hours. (See section 4.8. Undesirable Effects).”
The suggestion that alprazolam is intended as hypnotic as well, should be avoided.
Psychiatric and paradoxical reactions
Reactions likeIf restlessness, agitation, irritability, aggressiveness, delusion, ragesfits of rage,
nightmares, aggravated insomnia, hallucinations, psychoses, inappropriate behaviour, oneiroid
delirium and other adverse behavioural effects are known to occur when using benzodiazepines.
Should thisdisorders occur, use of the medicinal productmedication should be discontinued. They are
terminated. Paradoxical reactions occur more likely to occuroften in children and the elderly.
patients.
Tolerance
Some lossSpecific patient groups
Alprazolam should not be used in patients less than 18 years of age because safety and efficacy to the
hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Episodes of hypomania and mania havehas not been reported in associationestablished.
The elderly should be treated preferably with the use of alprazolam ina lower than usual dose (see 4.2
'Posology and method of administration').
In patients with chronic respiratory insufficiency a lower dose should be used, given the possibility of
respiratory depression.
Benzodiazepines are not recommendedindicated for the treatment of patients with severe liver
disorders, since Benzodiazepines can promote the development of encephalopathy.
Benzodiazepines are not effective for the primary treatment of psychotic illnesspsychoses.
Patients with rareIn a few cases manic episodes were reported in patients with latent depression.
Benzodiazepines are not effective for the primary treatment of severe depression and should not be
used alone for the treatment of anxiety associated with severe depression, since suicide could occur in
such patients. When administering to severely depressed and suicidal patients it is necessary to take
suitable precautions and to prescribe appropriate amounts.
Due to possible anticholinergic side effects benzodiazepines should be used with great caution in
patients with acute narrow angle glaucoma or in those patients that may be predisposed.
Benzodiazepines should also be used with the greatest caution in patients with a history of alcohol and
drug abuse.
The tablets contain lactose. Therefore, patients with hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
RMS-comments
The omissions here of the warnings in the current SPC are not accepted as there is no justification
and the information is considered relevant for the prescriber. The following text is proposed:
Benzodiazepines are not recommended for the primary treatment of psychotic illness since
benzodiazepines are not effective for the primary treatment of psychoses.
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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Benzodiazepines are not effective for the primary treatment of severe depression and should not be
used alone for the treatment of anxiety associated with severe depression, since suicide could occur in
such patients. When administering to severely depressed and suicidal patients it is necessary to take
suitable precautions and to prescribe appropriate amounts.
In patients with chronic respiratory insufficiency a lower dose should be used, given the possibility of
respiratory depression.
Due to possible anticholinergic side effects benzodiazepines should be used with great caution in
patients with acute narrow angle glaucoma or in those patients that may be predisposed.
The tablets contain lactose. Therefore, patients with hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5
Interactions with other medicinal products and other forms of interaction
Benzodiazepines produce an additive effect when co-administeredCOMBINATIONS NOT
RECOMMENDED
Alcohol: combination with alcohol or other CNS depressants. Concomitant intake with potentates the
sedative effect of Alprazolam. This will affect patients’ ability to drive and use machines. Intake of
alcohol should be avoided during treatment with Alprazolam.
Anti-mycotics: In view of pharmacokinetic interactions (cytochrome P-450, mechanism described
under ‘CAREFUL USE’) concurrent use of Ketoconazole, Itraconazole and other anti-fungal agents
of the azole type (cytochrome P-450 3A4 inhibitors) is not recommended. Alprazolam should be used
with caution when combined with CNS depressants.
Special care should be made with drugs depressing respiratory function such as opioids
(analgesics, antitussives, substitutive treatments), notably in the elderly people.
Enhancement
TO BE CONSIDERED
Psychotropic pharmaceuticals: Increased depression of the activity of the central depressive effect
may occur in cases of concomitant use with antipsychoticsnervous system can occur when using the
tablets concurrently with psychotropic pharmaceuticals, such as anti-psychotics (neuroleptics),
hypnotics, anxiolytics/sedatives, some antidepressant agentsantidepressants, narcotic analgesics, antiepileptic drugs, anaesthetics and sedativesedating antihistamines. InHowever, when taking the case of
tablets in combination with narcotic analgesics enhancement, potentiation of the euphoria may
alsocan occur leadingwhich may lead to an increase inincreased psychic dependence.
Nefazodone, Fluvoxamine and Cimetidine: In view of pharmacokinetic interactions (cytochrome P 450, mechanism described under ‘CAREFUL USE’) caution is required when using these agents
(cytochrome P-450 3A4 inhibitors) and Alprazolam concurrently and a possible reduction of the
Alprazolam dose should be considered.
CAREFUL USE
Since Alprazolam is metabolised by certain liver enzymes (especially cytochrome P-450 3A4), its
effect is enhanced by pharmaceuticals that inhibit these enzymes. Alprazolam should therefore be
used with caution in patients taking these medicines. Particularly, appropriate caution should be
exercised in the case of concurrent use with HIV protease inhibitors, Fluoxetine,
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ALPRAZOLAM 250 MCG, 500 MCG, 1 MG, TABLET
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Dextropropoxyphene, oral contraceptives, Sertralin, Diltiazem or macrolide antibiotics, such as
Erythromycin and Troleandomycin (cytochrome P-450 3A4 inhibitors).
Digoxin: Increase of Digoxin plasma levels has been reported with concomitant use of 1 mg
Alprazolam daily, particularly in the elderly. Therefore, patients receiving Alprazolam and Digoxin
concurrently should be closely monitored for signs and symptoms of Digoxin toxicity.
Carbamazepine and St John’s wort: In view of pharmacokinetic interactions a reduced effect of
Alprazolam might occur in patients taking Carbamazepine or St John’s wort (cytochrome P -450 3A4
inducer). The plasma Alprazolam concentrations in the elimination phase are dependent on certain
hepatic enzymes (in particular cytochrome P-450 3A4) for the metabolism and are reduced by
pharmaceuticals that induce these enzymes. When St. John’s wort therapy is suddenly stopped,
overdose symptoms of alprazolam may occur.
Muscle relaxants: one should be prepared for an increase of the muscle relaxing effect when
Alprazolam is used during therapy with a muscle relaxant, especially during the beginning of
treatment with Alprazolam.
Imipramine and desipramine: it has been reported that concurrent administration of Alprazolam (at
doses of up to 4 mg/day) with Imipramine and Desipramine caused the steady state plasma levels of
these substances to increase by 31% and 20% respectively. It is not yet known whether these changes
are of clinical significance.
Warfarin: it could not be determined whether there was any effect on prothrombin times and Warfarin
plasma levels.
No interaction was found with propranolol and disulfiram. Substances, which may induce CYP3A4
(e.g. rifampicin, phenytoin), can reduce the effect of Alprazolam.
PregnancyPharmacokinetic interactions can occur when alprazolam is administered along with drugs
that interfere with its metabolism.
CYP3A Inhibitors
Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) 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 metabolised 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:
4.6
and lactation
The possibility of harmful effects cannot be evaluated since insufficient data is available concerning
the use of Benzodiazepines during human pregnancy. Observations of human subjects indicate that
this substance can put pregnancies at risk (the foetus and the birth). Accordingly, use during
pregnancy is only permissible if there is a critical indication. Physicians prescribing Alprazolam to
women of reproductive age should caution their patients to consult them about possible
discontinuation of treatment if they believe themselves to be pregnant or if they are planning to
become pregnant.
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Based on its pharmacological action, this substance can be expected to have an effect (hypothermia,
hypotonia and moderate respiratory depression) on the new-born child. Accordingly, its use during
birth is only permissible if there is a critical indication.
In addition, the children of mothers who used Benzodiazepines regularly at the end of their pregnancy
may display withdrawal symptoms during the postnatal period.
Alprazolam passes into breast milk. Accordingly, women are advised not to breastfeed while they are
using Alprazolam.

The co-administration of alprazolam with ketoconazole, itraconazole, or other azole- type
antifungals is not recommended.

The co-administration of nefazodone or fluvoxamine increases the AUC of alprazolam by
approximately 2-fold. Caution and consideration of dose reduction is recommended when
alprazolam is co-administered with nefazodone, fluvoxamine and cimetidine.

Caution is recommended when alprazolam is co-administered with fluoxetine, propoxyphene, oral
contraceptives, sertraline, diltiazem, or macrolide antibiotics such as erythromycin, clarithromycin
and troleandomycin.
RMS comment:
Please include the following in line with the CSP established following procedure FR/H/PSUR/0036:
“Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that
inhibit the hepatic enzyme CYP3A4) by increasing the plasma levels of alprazolam.”
“The co-administration of alprazolam with strong CYP3A4 inhibitors like azole antifungals
(ketoconazole, itraconazole, posaconazole, voriconazole), protease inhibitors or some macrolides
(erythromycin, clarithromycin, telithromycin) should be made with caution and a substancial dose
reduction considered.”
CYP3A4 Inducers
Since alprazolam is metabolized by CYP3A4, inducers of this enzyme may enhance the metabolism
of alprazolam. Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are
complex and time dependent. Short term, 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.
RMS-comments
Several interactions mention in the original text have been deleted. These should be reintroduced
again unless further justified i.e.:
“Digoxin: Increase of Digoxin plasma levels has been reported with concomitant use of 1 mg
Alprazolam daily, particularly in the elderly. Therefore, patients receiving Alprazolam and Digoxin
concurrently should be closely monitored for signs and symptoms of Digoxin toxicity.
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Carbamazepine and St John’s wort: In view of pharmacokinetic interactions a reduced effect of
Alprazolam might occur in patients taking Carbamazepine or St John’s wort (cytochrome P-450 3A4
inducer). The plasma Alprazolam concentrations in the elimination phase are dependent on certain
hepatic enzymes (in particular cytochrome P-450 3A4) for the metabolism and are reduced by
pharmaceuticals that induce these enzymes. When St. John’s wort therapy is suddenly stopped,
overdose symptoms of alprazolam may occur.
Muscle relaxants: one should be prepared for an increase of the muscle relaxing effect when
Alprazolam is used during therapy with a muscle relaxant, especially during the beginning of
treatment with Alprazolam.
Imipramine and desipramine: it has been reported that concurrent administration of Alprazolam (at
doses of up to 4 mg/day) with Imipramine and Desipramine caused the steady state plasma levels of
these substances to increase by 31% and 20% respectively. It is not yet known whether these changes
are of clinical significance.
Warfarin: it could not be determined whether there was any effect on prothrombin times and Warfarin
plasma levels.
No interaction was found with propranolol and disulfiram. Substances, which may induce CYP3A4
(e.g. rifampicin, phenytoin), can reduce the effect of Alprazolam”
4.6
Fertility, pregnancy and lactation
Pregnancy
The data concerning teratogenicity and effects on postnatal development and behavior following
benzodiazepine treatment are inconsistent. A large amount of data based on cohort studies indicate
that first trimester exposure to benzodiazepine is not associated with an increase in the risk of major
malformation. However, some early case-control epidemiological studies have found a twofold
increased risk of oral clefts.
Benzodiazepine treatment at high dose, during the second and/or the third trimester of pregnancy,
has revealed a decrease of foetal active movements and a variability of foetal cardiac rhythm.
When treatment has to be administered for medical reasons during the last part of pregnancy, even at
low doses, floppy infant syndrome such as axial hypotonia, sucking troubles leading to a poor weight
gain may be observed. These signs are reversible but they may last from 1 up to 3 weeks, according
to the half life of the product. At high doses, respiratory depression or apnoea and hypothermia in
newborn may appear. Moreover, neonatal withdrawal symptoms with hyperexcitability, agitation and
tremor may be observed a few days after birth, even if no floppy infant syndrome is observed. The
apparition of withdrawal symptoms after birth depends on the half life of the substance.
Alprazolam should not be used during pregnancy unless the clinical condition of the woman requires
treatment with alprazolam. If alprazolam is used during pregnancy, or of the patient becomes pregnant
while taking alprazolam, the patient should be apprised of the potential hazard to the foetus.
If alprazolam treatment is necessary during last part of pregnancy, high doses should be avoided
and withdrawal symptoms and/or floppy infant syndrome should be monitored in newborn.
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RMS comment:
The text was largely rewritten corresponding to the UK innovator text. However, the CSP as
established following procedure FR/H/PSUR/0036/001 reflects other wording with regards to this
section. The applicant is requested to follow the CSP text unless otherwise justified.
In accordance with the Guideline on risk assessment of medicinal products on human reproduction
and lactation: from data to labelling (EMEA/CHMP/203927/2005), a text should be added regarding
fertility. In section 5.3, the applicant proposes to add that treatment of male rats at high doses prior to
mating resulted in a decrease in the percentage of dams conceiving. This information could however
not be verified in the literature. We therefore propose to add that no data are available regarding
effects of alprazolam on fertility.
Breastfeeding
Alprazolam is excreted in breast milk at low level. However, alprazolam is not recommended during
breastfeeding.
4.7
Effects on ability to drive and use machines
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the
ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired
alertness may be increased (See section 4.5 Interactions with other Medical Products and other forms
of Interaction).
Persons whose functioning involves the ability to carry out keen and continuous observations,
alertness so as to make the right decisions and full control over the use of limbs, should be warned
that their abilities to are affected by sedation, amnesia, reduced concentration and muscular weakness.
If a patient does not get enough sleep the risk of reduced alertness increases.
Patients should be warned of this hazard and advised not to drive or operate machinery during
treatment. These effects are potentiated by alcohol (See section 4.5 Interactions with other Medical
Products and other forms of Interaction).see section 4.5)
Patients should be cautioned about operating motor vehicles or engaging in other dangerous activities
while taking Xanaxalprazolam.
4.8
Undesirable effects
Adverse events, if theySymptoms marked by an asterisk (*) occur, are generally observed particularly
at the beginningstart of therapytreatment or higher doses and usually disappear upon continued
medication or decreased dosage.
RMS-comments
Please delete ..”if they occur” …
The following undesirable effects have been observed and reported during treatment with alprazolam
with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be
estimated from the available data).continued use.
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MedDRA System Organ Class Frequency
Undesirable Effects
Endocrine disorders
Uncommon
Hyperprolactinaemia
Metabolism and nutrition
disorders
Common
Decreased appetite
Psychiatric disorders
Common
Confusional state, depression, disorientation,
libido decreased
Uncommon
Anxiety, insomnia, nervousness, hypomania,
mania (see section 4.4 Special warnings and
precautions for use ), hallucination, anger,
aggression, hostility, agitation, libido disorder,
thinking abnormal, psychomotor hyperactivity
Very common
Sedation, somnolence
Common
Ataxia, balance disorder, coordination
abnormal, memory impairment, dysarthria,
disturbance in attention, hypersomnia, lethargy,
dizziness, headache
Uncommon
Amnesia, tremor, dystonia
Not Known
Autonomic nervous system imbalance
Eye disorders
Common
Vision blurred
Gastrointestinal disorders
Common
Constipation, dry mouth, nausea
Uncommon
Gastrointestinal disorder
Hepatobiliary disorders
Uncommon
Hepatitis, hepatic function abnormal, jaundice
Skin and subcutaneous tissue
disorders
Uncommon
Dermatitis
Not Known
Angioedema
Musculoskeletal and
connective tissue disorders
Uncommon
Muscular weakness
Renal and urinary disorders
Uncommon
Incontinence, urinary retention
Reproductive system and
breast disorders
Uncommon
Sexual dysfunction, menstruation irregular
General disorders and
administration site conditions
Common
Fatigue, irritability
Not Known
Peripheral oedema
Uncommon
Change in weight, intraocular pressure
increased
Nervous system disorders
Investigations
Withdrawal symptoms have occurred following rapid decrease or abrupt discontinuance of
benzodiazepines including alprazolam. These can range from mild dysphoria and insomnia to a major
syndrome, which may include abdominal and muscle cramps, vomiting, sweating, tremor and
convulsions. In addition, withdrawal seizures have occurred upon rapid decrease or abrupt
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discontinuation of therapy with alprazolam.
Endocrine disorders
Hyperprolactinaemia
Metabolism and nutrition disorders
Anorexia, stimulation of appetite
Psychiatric disorders
Concentration disturbances, confusion*. depression, psychiatric and paradoxical disorders and
dependence (see paragraphs below)
Nervous system disorders
Numbness of feeling*, reduced alertness*, drowsiness*, headache*, dizziness*, dystonia, speech
disturbances. Amnesia (see paragraphs below at the end of this section).
Eye disorders
Visual disturbances* (such as double or blurred vision), increase in intra-ocular pressure
Cardiac disorders
Tachycardia
Vascular disorders
Hypotension
Respiratory, thoracic and mediastinal disorders
Nasal congestion
Gastrointestinal disorders
Constipation, diarrhoea, nausea, vomiting, dry mouth, increased salivation, dysphagia
Hepatobiliary disorders
Hepatic function disorders, jaundice
Skin and subcutaneous tissue disorders
Skin reactions
Musculoskeletal and connective tissue disorders
Muscular weakness*, ataxia*
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Renal and urinary disorders
Incontinence, urinary retention
Reproductive system and breast disorders
Menstrual disturbances, reduced libido
General disorders and administration site conditions
Fatigue*, increase in weight
..
RMS-comments
Not all of the adverse events mentioned in the above strike through text are mentioned in the adverse
events table above. These should be incorporates unless a sufficient justification can be given that
these are no longer relevant. The adverse events concern among others “anorexia, stimulation of
appetite, concentration disturbances, dependence numbness of feeling, tachycardia, hypotension,
nasal congestion, diarrhoea, vomiting, increased salivation, dysphagia”.
Furthermore, some adverse events have been included in the adverse events table above, that have not
been mentioned in above strike through text nor have been stated in the CSP established following
procedure FR/H/PSUR/0036/001. The applicant is requested to justify the addition of these adverse
events. Also the frequency of some adverse events is not in line with the established CSP. As no
frequencies were stated in the strike through text above, the applicant is requested to justify these
frequencies as well.
Amnesia
Anterograde amnesia maycan occur even at therapeutic dosages,doses and the risk increasingincreases
at higher dosages. Amnesic effectsdoses. Amnesia may be associated withaccompanied by
inappropriate behaviour. (See (see also section 4.4 Special'Special warnings and precautions for
useuse').
Depression
Pre-existing depressionPreviously unnoticed depressions may be unmaskedbecome apparent, in
susceptible individuals, during benzodiazepineBenzodiazepine use.
Psychiatric and “paradoxical” reactions
Reactions likesuch as restlessness, agitation, irritability, aggressiveness, delusion,
ragesaggression, delusions, fits of rage, nightmares, hallucinations, psychoses, inappropriate
behaviour and other adverse behavioural effects are known to occur when using benzodiazepines
or benzodiazepine-like agents. They may be quite severe with this product. Theydisorders. Such
paradoxical reactions are more likely to occur in children and the elderly.
RMS-comments
Please delete: “They may be quite severe with this product.”´ This holds for all AEs.
patients. In many of the spontaneous case reports of adverse behavioural effects, patients were
receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric
conditions. Patients who have borderline personality disorder, a prior history of violent or aggressive
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behaviour, or alcohol or substance abuse may be at risk of such events. Instances of irritability,
hostility and intrusive thoughts have been reported during discontinuance of alprazolam in patients
with post-traumatic stress disorderparadoxical reactions treatment should be stopped.
RMS-comments
Please delete the paragraph starting with “In many ……. and ending with post traumatic stress
disorder” Paradoxal reaction may occur in any patient. Focussing on risk factors (which sensitivity is
moderate) would introduce a wrong perception of safe use in this respect in subjects who do not have
these risk factors.
Please reintroduce that in case of paradoxal reactions treatment should be stopped unless a sufficient
justification is given that this no longer applies.
Dependence
Use of this substance (even at therapeutic doses) may lead to can result in the development of physical
dependence: discontinuation of the therapy may result in . Suspension of treatment can therefore lead
to withdrawal orsymptoms and rebound phenomena (Seesymptoms (see also section 4.4
Special'Special warnings and precautions for use). Psychicuse'). Cases of psychic dependence maycan
also occur. AbuseInstances of benzodiazepines hasabuse have been reported.
4.9
Overdose
General information about toxicity
As with other benzodiazepinesBenzodiazepines, overdose should not present a threat to life unless
combined with other CNS depressants (including alcohol). In the management of overdose with any
medicinal product, it should be borneborn in mind that multiple agents may have been taken.
Treatment should be adjusted accordingly.
FollowingSymptoms
An overdose with oral benzodiazepines, vomiting should be induced (within one hour) if the
patient is conscious or gastric lavage undertaken with the airway protected if the patient is
unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given
to reduce absorption.
Special attention should be paid to respiratory and cardiovascular functions in intensive care.
Overdose of benzodiazepines is usually manifested by degrees takes the form of a depression of
central nervous system depression rangingactivity, varying from drowsiness to coma. In mild cases,
of overdosing the symptoms includeconsist of drowsiness, mental confusion and lethargy, in. In more
serioussevere cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression,
rarelyin rare cases coma and in very rarelyrare cases death.
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Therapy
Soon after ingestion it is advisable to stimulate vomiting if the patient is conscious, or, alternatively, if
the patient is subconscious, to perform gastric lavage while protecting the airway by intubation. If
emptying of the stomach does not result in an improvement of the patient's condition, activated
charcoal should be administered and, if necessary, be left behind in the stomach in combination with a
laxative. When the amount taken is known to be large, this still may be effective after a long time
forced diuresis or haemodialysis is of no value.
Flumazenil maycan be useful as an antidote.
RMS comment:
Changes were mainly textual. The text is agreed.
5 PHARMACOLOGICAL PROPERTIES
For individuals in coma, treatment is largely symptomatic. Measures should be taken to avoid
possible complications such as asphyxia due to patients swallowing their tongue or aspiration of the
stomach contents. The intravenous administration of liquids can be useful in preventing dehydration.
Especially when combined with other sedatives, supporting the vital functions, in particular
respiration, is important.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Alprazolam, like other benzodiazepines, has a high affinity for the benzodiazepine binding site in
the brain. It facilitates the inhibitory neurotransmitter action of gamma-aminobutyric acid, which
mediates both pre- and post synaptic inhibition in the central nervous system (CNS).
ATC code: NO5B A12
Alprazolam is an effective anxiolytic medication. Like other Benzodiazepines, in addition to its
anxiolytic properties, Alprazolam has sedative, hypnotic, muscle-weakening and anticonvulsive
properties.
RMS comment:
It is not clear why the ATC code was removed. Also it is not clear why the statement regarding the
anxiolytic and other properties of benzodiazepines was removed. We propose to leave it in, as it gives
relevant information regarding the activity of alprazolam.
5.2
Pharmacokinetic properties
RMS-comments
Current proposed text omits relevant information, which is included in the original text.
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Absorption
Alprazolam is readilyrapidly absorbed. Following following oral administration peak concentration in
. After oral administration, bioavailability is 80% or more. Maximum plasma levels are reached one to
two hours after oral administration.
Distribution
Following a single administration, the plasma occurs after 1 -2 hourslevels are directly proportional to
the administered dose. The maximum plasma levels observed following a dose of 0.5 mg to 3 mg are
8 to 37 ng/ml. Following several administrations of 1.5 mg to 10 mg/day, the average steady-state
level was 18.3 to 100 ng/ml.
The meanIn vitro, 70% of Alprazolam is bound to serum proteins.
Biotransformation
The most important metabolites of Alprazolam present in urine are alpha-hydroxy-Alprazolam and a
benzophenone derivative. The major metabolites in plasma are alpha-hydroxy-Alprazolam and 4hydroxy-Alprazolam.
The benzophenone derivative is virtually inactive. The biological activity of alpha-hydroxyAlprazolam is comparable with that of Alprazolam, while 4-hydroxy-Alprazolam is about 10 x less
active. The plasma levels of these metabolites are low. Their half-lives appear to be of the same order
of magnitude as that of Alprazolam. The metabolites therefore make only a limited contribution to the
biological activity of Alprazolam.
Elimination
The average half-life of Alprazolam is between 12 -and 15 hours. Repeated dosage may lead to
accumulation and this should be borne in mind in elderly patients and those with impaired renal or
hepatic function. Alprazolam and its metabolites are mainly excreted primarily invia the urine.
In vitro alprazolam is bound (80%) to human serum protein.
5.3
Preclinical safety data
Non-clinical data reveal no special hazardIn rats administered Alprazolam for humans based on
conventional studies of genotoxicity and carcinogenic potential.
When rats were treated orally with alprazolam for 2 years, 24 months a tendency for a dose -related
increase in the number of cataracts (females) and in corneal vascularization (males)vascularisation
was observed. These lesions did not appear until after 11 months of treatmentevident in females and
males, respectively.
In reproductive toxicity studies administration of alprazolam in rats and rabbits is associated at very
high doses with developmental delay and an increased incidence of fetal death and skeletal
malformations. In fertility studies, treatment of male rats at high doses prior to mating resulted in a
decrease in the percentage of dams conceiving.
In a repeated dose toxicity study (12 months) with high dosages p.o. convulsions were observed in
dogs, some of which were lethal. Relevance for men is not clear.
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There was no evidence of carcinogenic potential as revealed by carcinogenicity studies conducted in
rats and mice.
RMS comment:
Statements regarding reproductive toxicity were added and a statement regarding the observation of
convulsions in dogs was deleted.
It is not clear why the statement regarding convulsions in dogs was deleted. We propose to leave this
statement in the text. This observation is also mentioned in section 5.3 of other European established
texts such as for Alprazolam Mylan (DK/H/0109/001) or Alprazolam PCH (NL/H/0203/001).
The text mentions that reduced male fertility was found at high dose in a rat fertility study. This
information could however not be verified in the literature. The applicant should provide the reference
behind this finding or delete the statement.
6
PHARMACEUTICAL PARTICULARS
6.1 List of excipient(s)
Docusate sodium
Sodium benzoate
Pregelatinised starch (potato starch)
Microcrystalline cellulose
Lactose monohydrate
Magnesium stearate
Silica, colloidal anhydrous
Erythrosine (E 127) (only for 0. 5 mg)
Indigotine (E 132) (only for 1 mg).
6.2 Incompatibilities
Not applicable.
6.3 Shelf-life
3 years.
6.4 Special precautions for storage
Do not store above 25 °C.
Keep container in the outer carton
6.5 Nature and contents of container
20 tablets in blister pack (PVC/Aluminium).
30 tablets in blister pack (PVC/Aluminium).
40 tablets in blister pack (PVC/Aluminium).
50 tablets in blister pack (PVC/Aluminium).
60 tablets in blister pack (PVC/Aluminium).
6.5 Special precautions for disposal and or handling
No special requirements.
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7
MARKETING AUTHORIZATION HOLDER
[To be completed nationally]
8
MARKETING AUTHORIZATION NUMBER
[To be completed nationally]
9 DATE OF FIRST AUTHORIZATION / RENEWAL OF AUTHORIZATION
[To be completed nationally]/30 October 2007
10 DATE OF REVISION OF THE TEXT
[To be completed nationally]
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