Zopiclone Actavis

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Zopiclone 3.75 mg;  
Available from:
Teva Pharma (New Zealand) Limited
INN (International Name):
Zopiclone 3.75 mg
Dosage:
3.75 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Zopiclone 3.75 mg   Excipient: Calcium hydrogen phosphate dihydrate Colloidal silicon dioxide Hypromellose Indigo carmine aluminium lake Lactose monohydrate Macrogol 6000 Magnesium stearate Maize starch Povidone Purified talc Sodium starch glycolate Titanium dioxide
Prescription type:
Prescription
Manufactured by:
Centaur Pharmaceuticals Private Limited
Therapeutic indications:
Treatment of transient, short-term and chronic insomnia in adults including difficulties with falling asleep, nocturnal awakening and wakening.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/Al in outer cardboard carton - 28 tablets - 36 months from date of manufacture stored at or below 25°C protect from light - Blister pack, PVC/Al in outer cardboard carton - 30 tablets - 36 months from date of manufacture stored at or below 25°C protect from light - Bottle, plastic, white HDPE, with white screw cap and cap liner - 100 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, white HDPE, with white screw cap and cap liner - 500 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-9311
Authorization date:
2013-06-14

Read the complete document

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

Zopiclone Actavis

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 3.75 mg or 7.5 mg of zopiclone.

Excipient with known effect:

lactose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Zopiclone Actavis 3.75 mg tablets are blue coloured, round biconvex film coated tablets, plain on

both sides.

Zopiclone Actavis 7.5 mg tablets are white to off-white, oval shaped film coated tablets with

breakline on one side and plain on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of transient, short-term and chronic insomnia in adult’s including difficulties with falling

asleep, nocturnal awakening and wakening.

4.2

Dose and method of administration

Dose

Use the lowest effective dose. Zopiclone Actavis should be taken in a single intake and not be

readministered during the same night.

Adults

7.5 mg by oral administration shortly before retiring for a maximum of 2 to 4 weeks. This dose should

not be exceeded. Depending on clinical response, the dose may be lowered to 3.75 mg.

Treatment duration

Transient insomnia:

2 to 5 days.

Short term insomnia:

2 to 3 weeks.

Chronic insomnia:

long term treatment should be considered only after a consultation with a

specialist.

Zopiclone is not recommended for long term use (i.e. periods of more than 4 weeks). If physical

dependence is suspected treatment should be withdrawn gradually. (see section 4.4 Special warnings

and precautions for use).

Special populations

Elderly Patients

In the elderly and/or debilitated patient an initial dose of 3.75 mg is recommended. The dose may be

increased to a maximum of 7.5 mg if the starting dose does not offer adequate therapeutic effect, but

in clinical trials, 25% of elderly patients treated with zopiclone experienced CNS side-effects at the

higher dose. Zopiclone should be used with caution in these patients. (see section 4.4 Special

warnings and precautions for use).

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Hepatic Insufficiency

The recommended dose is 3.75 mg depending on acceptability and efficacy. Up to 7.5 mg may be

used with caution in appropriate cases.

In patients with severe hepatic insufficiency (serum albumin less than 30 g/l or presence of gross

oedema), treatment should be initiated on a dose of 3.75mg and if necessary, may be increased to

7.5mg.

Renal insufficiency

Although no accumulation of zopiclone or of its metabolites has been detected in cases of renal

insufficiency, it is recommended that patients with impaired renal function should start treatment with

3.75 mg.

Treatment should be as short as possible and should not exceed four weeks including the period of

tapering off. Extension beyond the maximum treatment period should not take place without re-

evaluation of the patient’s status. The product should be taken just before retiring for the night.

Respiratory Insufficiency

Caution should be exercised in treating patients with chronic respiratory insufficiency. Treatment

should be initiated on a dose of 3.75mg and if necessary, should be carried out at 7.5mg.

Paediatric Population

Zopiclone is contraindicated in children. Dosage has not been established.

Alternative Therapy

For long term treatment of insomnia, alternative non-pharmacological methods should be considered.

Effective practical management of insomnia must respond to the presenting characteristics of the

complaint. Giving accurate information is a form of treatment; there is benefit in discussing some

simple facts with the patient and relating them to the problem, thereby assisting the patient to place

the sleep problem in its context. Sleep hygiene such as reduction of caffeine intake, should be

exercised. Programmes designed to establish an optimal sleeping pattern for the patient may also be

useful as are relaxation techniques designed to assist the patient deal with tension and intrusive

thoughts in bed.

Method of administration

For oral use only.

4.3

Contraindications

Patients with known hypersensitivity to zopiclone or any of the excipients.

Prior or concomitant use of alcohol.

Myasthenia gravis.

Severe impairments of respiratory function.

Acute cerebrovascular accident.

Sleep apnoea syndrome.

Severe hepatic insufficiency.

Zopiclone is contraindicated in children.

4.4

Special warnings and precautions for use

Prolonged use of hypnotics is not recommended especially in the elderly.

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Dependence

Zopiclone should be prescribed for short periods only (2 to 4 weeks). Continuous long term use is not

recommended. Use of sedative-hypnotic agents like zopiclone may lead to the development of

physical and psychological dependence or abuse. It is therefore recommended that if physical

dependence is suspected the dose should be decreased gradually and the patient advised about such a

possibility (see section 4.8 Undesirable effects).

Risks of dependence or abuse increase with:

Dose and duration of treatment

History of alcohol and/or drug abuse

Use with alcohol or other psychotropics.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by

withdrawal symptoms (see section 4.8 Undesirable effects).

Rebound insomnia

A transient syndrome whereby the symptoms that led to treatment with sedative-hypnotic agents recur

in an enhanced form, may occur on withdrawal of hypnotic treatment. It may be accompanied by

other reactions including mood changes, anxiety and restlessness. Since the risk of such phenomena is

greater after abrupt discontinuation of zopiclone, especially in patients with physical dependence, it is

therefore recommended to decrease the dosage gradually and to advise the patient accordingly (see

section 4.8 Undesirable effects).

Amnesia

Anterograde amnesia may occur, specially when sleep is interrupted or when retiring to bed is delayed

after the intake of the tablet.

To reduce the possibility of anterograde amnesia, patients should ensure that: they take the tablet

strictly when retiring for the night they are able to have a full night sleep.

Other Psychiatric and Paradoxical Reactions

Other psychiatric and paradoxical reactions have been reported (see section 4.8 Undesirable effects)

like

restlessness,

agitation,

irritability,

aggression,

delusion,

anger,

nightmares,

hallucinations,

inappropriate behaviour and other adverse behavioural effects are known to occur when using

sedative/hypnotic agents like zopiclone. Should this occur, use of zopiclone should be discontinued.

These reactions are more likely to occur in the elderly.

Depression, Psychosis and Schizophrenia

As with other hypnotics, zopiclone does not constitute a treatment of depression and may even mask

its symptoms. Caution should be exercised if zopiclone is prescribed to depressed patients, including

those with latent depression, particularly when suicidal tendencies may be present and protective

measures may be required. Patients should be closely monitored for any signs or symptoms of

psychiatric disorders. Patients should be advised to go to the emergency department at their nearest

hospital if they notice they are becoming depressed, have suicidal thoughts or are experiencing a

change in their behaviour. Patients may wish to consider asking a family member or close friend to

help them stay alert to signs of depression or behavioural changes.

Somnambulism and Associated Behaviours

Sleep walking and other associated behaviours such as ‘sleep driving’, preparing and eating food, or

making phone calls, with amnesia for the event, have been reported in patients who have taken

zopiclone and were not fully awake. The use of alcohol and other CNS-depressants with zopiclone

appears to increase the risk of such behaviours, as does the use of zopiclone at doses exceeding the

maximum recommended dose. Discontinuation of zopiclone would be strongly considered for patients

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who report such behaviours (see section 4.5 Interactions with other medicines and other forms of

interaction, Alcohol and section 4.8 Undesirable effects).

Epilepsy

Patients with a history of seizures should not be abruptly withdrawn from any CNS depressant drug,

including zopiclone.

Severe Anaphylactic and Anaphylactoid Reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after

taking the first or subsequent doses of sedative-hypnotics, including zopiclone. Some patients have

had additional symptoms such as dyspnoea, throat closing, or nausea and vomiting that suggest

anaphylaxis.

Some

patients

have

required

medical

therapy

emergency

department.

angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients

who develop angioedema after treatment with zopiclone should not be rechallenged with the drug.

Hepatic Insufficiency

In patients with severe hepatic insufficiency (serum albumin less than 30 g/l or presence of gross

oedema), the elimination of zopiclone may be significantly reduced and hence, a reduced dosage is

recommended (see section 4.2 Dose and method of administration).

Renal Insufficiency

A reduced dosage is recommended (see section 4.2 Dose and method of administration). Zopiclone

is removed by dialysis.

Respiratory Insufficiency

Caution should be exercised in treating patients with chronic respiratory insufficiency. A lower dose

is recommended for patients with chronic respiratory insufficiency due to the risk of respiratory

depression (see section 4.2 Dose and method of administration).

As hypnotics have the capacity to depress respiratory drive, precautions should be observed if

zopiclone is prescribed to patients with compromised respiratory function.

Hormonal Systems

Treatment of rats with zopiclone increases hepatic thyroid hormone metabolism of T4, resulting in

increases in TSH and T3 levels, and decreases in T4 levels. It is suggested that zopiclone not be

administered

individuals

with

impaired

thyroid

hormone

homeostatic

mechanisms

with

conditions linked to hormonal imbalances.

Abuse

Caution must be exercised in administering zopiclone to individuals known to be addiction prone or

those whose history suggests they may increase the dosage on their own initiative.

Elderly Patients

Such patients may be particularly susceptible to the sedative effects of zopiclone and associated

giddiness, ataxia and confusion, which may increase the possibility of a fall (see section 4.2 Dose and

method of administration).

Use in Children

The safe and effective dose of zopiclone in children and adolescents under 18 years of age has not

been established (see section 4.3 Contraindications).

4.5

Interaction with other medicines and other forms of interaction

Alcohol

Concomitant intake with alcohol is not recommended. The sedative effect of zopiclone may be

enhanced when the product is used in combination with alcohol.

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CNS Depressants

Additive CNS depressant effects should be expected if zopiclone is administered concomitantly with

other

medications

which

themselves

produce

depression,

example,

barbiturates,

benzodiazepines, alcohol, sedatives, tricyclic antidepressants and other antidepressants, non-selective

MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines,

narcotic analgesics, anaesthetics, neuroleptics, hypnotics, anxiolytics, antiepileptics (see section 4.4

Special warnings and precautions for use). In the case of narcotic analgesics, enhancement of

euphoria may also occur leading to an increase in psychic dependence.

Other

Erythromycin has been reported to increase significantly zopiclone concentrations at 0.5 and 1 hour

after ingestion of zopiclone. The total AUC of zopiclone increased by 80% in 10 healthy volunteers.

Accelerated absorption of zopiclone in the presence of erythromycin may lead to faster hypnotic

effects.

Plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors such as

erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir.

Plasma levels of zopiclone may be decreased when co-administered with CYP3A4 inducers, such as

rifampicin, carbamazepine, phenobarbital, phenytoin, and St. John’s wort.

4.6

Fertility, pregnancy and lactation

Use in pregnancy (Category C)

Insufficient data are available on zopiclone to assess its safety during human pregnancy and lactation,

therefore the use of zopiclone during pregnancy is not recommended. Studies in animals have not

shown evidence of an increased occurrence of foetal damage. However, zopiclone has been shown to

cross the placenta, and increase postnatal mortality in rats given 10 mg/kg/d and above. Although the

significance of this for humans is not known, it is likely that zopiclone may be harmful to the neonate.

Treatment should be as short as possible and should not exceed four weeks including the period of

tapering off. Moreover, infants born to mothers who took sedative/hypnotics agents chronically

during the latter stages of pregnancy may have developed physical dependence and may be at some

risk for developing withdrawal symptoms in the postnatal period.

If zopiclone is prescribed to a woman of childbearing potential, she should be warned to contact her

physician regarding discontinuation of the product if she intends to become or suspects that she is

pregnant.

Moreover, if zopiclone is used during the last three months of pregnancy or during labour, due to the

pharmacological action of the product, effects on the neonate, such as hypothermia, hypertonia and

respiratory depression can be expected.

Lactation

Zopiclone and/or its metabolites are excreted in breast milk so therefore use in nursing mothers is not

recommended.

Fertility

Zopiclone has been shown to severely reduce fertility in male rats treated with 50 mg/kg/day or

greater. The significance of this finding for humans is not known.

4.7

Effects on ability to drive and use machines

Because of its pharmacological properties, zopiclone may adversely affect the ability to drive or to

use machines. The risk is increased by concomitant intake of alcohol (see section 4.4 Special

warnings and precautions for use).

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As with all patients taking CNS depressant medications, patients receiving zopiclone should be

warned not to operate dangerous machinery or motor vehicles until it is known that they do not

become drowsy after zopiclone therapy. Abilities may be impaired on the day following use. It has

been reported that the risk that zopiclone adversely affects driving ability is increased by concomitant

intake of alcohol. Therefore, driving is not recommended after the concomitant intake of zopiclone

and alcohol.

The risk of psychomotor impairment, including impaired driving ability, is increased if:

zopiclone is taken within 12 hours of performing activities that require mental alertness;

a higher dose than recommended is taken; or

zopiclone is co-administered with other CNS depressants, alcohol, or with other drugs that

increase the blood levels of zopiclone.

Patients should be cautioned against engaging in hazardous occupations requiring complete mental

alertness or motor coordination such as operating machinery or driving a motor vehicle following

administration of zopiclone and in particular during the 12 hours following that administration.

4.8

Undesirable effects

The side-effects most commonly seen in clinical trials is taste alteration (bitter taste).

More Common Reactions

Gastrointestinal:

bitter taste, dry mouth

Nervous System:

drowsiness, headaches, fatigue

Less Common Reactions

Gastrointestinal

: heartburn, constipation, diarrhoea, nausea, coated tongue, bad breath, anorexia or

increased appetite, vomiting, epigastric pains, dyspepsia.

Cardiovascular:

palpitations in elderly patients.

Reproductive:

impotence, ejaculation failure, libido disorder.

Nervous system:

agitation, anxiety, loss of memory including retrograde amnesia, anterograde

amnesia, confusion, dizziness, weakness, somnolence, asthenia, feeling of drunkenness, euphoria,

depression,

co-ordination

abnormality,

hypotonia,

speech

disorder,

hallucinations

(auditory

visual),

behavioural

disorders,

aggression,

tremor,

rebound

insomnia,

muscle

pain,

nightmares,

irritability, abnormal and/or inappropriate behaviour possibly associated with amnesia, sleep walking

(see

section

Special

warnings

precautions

Somnambulism

Associated

Behaviours), restlessness, delusion, anger, dependence, ataxia, paresthesia, cognitive disorders such as

memory impairment, disturbance in attention, speech disorder.

Withdrawal syndrome has been reported upon discontinuation (see section 4.4 Special warnings and

precautions for use). Withdrawal symptoms vary and may include rebound insomnia, anxiety, tremor,

sweating,

agitation,

confusion,

headache,

palpitations,

tachycardia,

delirium,

nightmares,

hallucinations, and irritability. In severe cases the following symptoms may occur: derealisation,

depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light,

noise and physical contact, hallucinations. In very rare cases, seizures may occur.

Respiratory, Thoracic and Mediastinal Disorders:

dyspnoea and respiratory depression have been

reported.

Allergic or cutaneous

: pruritus, rash, urticaria and tingling have been rarely reported. Angioedema

and/or anaphylactic reactions have been reported very rarely.

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Miscellaneous:

blurred vision, micturition, mild to moderate increases in serum transaminases and/or

alkaline phosphatase have been reported very rarely. Falls, predominantly in elderly patients, diplopia

and muscular weakness have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked

to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

Overdose of zopiclone can be manifested by varying degrees of CNS depression ranging from

drowsiness to coma according to the quantity ingested. In mild cases, symptoms include drowsiness,

confusion, and lethargy. In more severe cases, symptoms may include ataxia, hypotonia, hypotension,

methaemoglobinaemia, respiratory depression and coma. Overdosage could be life-threatening when

combined with other CNS depressants, including alcohol. Other risk factors, such as the presence of

concomitant illness and the debilitated state of the patient, may contribute to the severity of symptoms

and very rarely can result in fatal outcome.

Treatment

Symptomatic and supportive treatment in adequate clinical environment is recommended, attention

should be paid to respiratory and cardiovascular functions. Activated charcoal is only useful when

performed soon after ingestion. Haemodialysis is of no value due to the large volume of distribution

of zopiclone. Flumazenil may be useful as an antidote. As in the management of overdosage with any

medication, it should be borne in mind that multiple agents may have been taken.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and sedatives, ATC code: N05CF01

chemical

name

Zopiclone

6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]

pyrazin-5-yl 4-methylpiperazine-1-carboxylate

Molecular Formula

Molecular Weight

388.8

CAS Number

43200-80-2

Zopiclone is a fine white or slightly cream crystalline powder with a melting point of 176-178

C. It is

practically insoluble in acetone, soluble in dimethyl formamide and 0.1N hydrochloric acid and freely

soluble in chloroform and dichloromethane.

Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent. Zopiclone belongs to a novel

chemical class which is structurally unrelated to existing hypnotics. The pharmacological profile of

zopiclone is similar to that of the benzodiazepines.

In sleep laboratory studies of 1 to 21 day duration in man, zopiclone reduced sleep latency, increased

the duration of sleep and decreased the number of nocturnal awakenings. Zopiclone delayed the onset

of REM sleep but did not reduce consistently the total duration of REM periods. The duration of stage

1 sleep was shortened, and the time spent in stage 2 sleep increased. In most studies, stage 3 and 4

sleep tended to be increased, but no change and actual decreases have also been observed. The effect

of zopiclone on stage 3 and 4 sleep differs from that of the benzodiazepines which suppress slow

wave sleep. The clinical significance of this finding is not known.

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5.2

Pharmacokinetic properties

Absorption

Zopiclone is rapidly absorbed and distributed after oral administration, the time of maximum

observed plasma concentration being about 1.75 hours.

Distribution & Metabolism

A study of 16 healthy volunteers receiving a single dose of 7.5 mg of zopiclone intravenously

demonstrated the apparent volume of distribution of zopiclone to be 104 ± 15.5L. Autoradiographic

studies in the rat showed rapid distribution into the blood and peak tissue levels at 0.5 hours in the

liver, small intestines, stomach, kidneys and the adrenals. After twenty four hours the total residual

radioactivity in the body of the rat was 8%.

The bioavailability of the 7.5 mg tablets in man is 76.3 ± 9.6%, a hepatic first pass effect has been

demonstrated. In fresh human plasma, zopiclone is approximately 45% protein bound in the 25-100

ng/mL concentration range.

Zopiclone is extensively and rapidly metabolised by the liver. A large number of metabolites have

been isolated and characterised, with the two major ones being the N-oxide, produced by oxidation of

the piperazine nitrogen and the N-desmethyl produced by oxidative demethylation of the N-methyl

piperazine. Only the N-oxide analogue has weak pharmacological activity.

Elimination & Excretion

Zopiclone is rapidly eliminated, mainly by means of hepatic metabolism. The elimination half-life

after a single oral dose is 5.26 ± 0.76 hours. The elimination half-life for the N-oxide metabolite is

4.44 ± 0.66 hours and that for the N-desmethyl metabolite is 7.28 ± 0.49 hours.

Renal clearance is 13.9 ± 7.0 mL/min which further shows that the major elimination pathway is by

hepatic metabolism.

The amount of renal excretion is also low; unchanged zopiclone 3.6%, the N-oxide metabolites 11.4%

and the N-desmethyl metabolite 13.4%.

Elderly

In elderly patients, the absolute bioavailability is increased (94% vs 77% in young subjects), and the

elimination half-life prolonged (approximately 7 hours).

Renal Insufficiency

In patients with mild to moderate renal insufficiency, the pharmacokinetics of zopiclone are not

altered. Haemodialysis does not appear to increase the plasma clearance of the drug.

Hepatic Insufficiency

In patients with hepatic insufficiency, elimination half-life is prolonged (11.9) and time to peak

plasma levels delayed (3.5 hours).

5.3

Preclinical safety data

Carcinogenicity

Treatment with zopiclone by dietary administration for 2 years increased the incidence of thyroid

carcinomas in male rats dosed with 100 mg/kg/day, and increased the incidence of mammary

carcinoma in female rats dosed with 100 mg/kg/day, probably due to interference with thyroid

hormone and 17-estradiol metabolism. Studies with mice treated with zopiclone at dietary doses up to

100 mg/kg/day showed no evidence of drug-related carcinogenicity.

Genotoxicity

Genotoxicity studies, using a standard battery of tests, showed no evidence of gene mutations or

chromosomal damage.

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6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Dibasic

calcium

phosphate,

lactose

monohydrate,

sodium

starch

glycolate

Type-A

(Primogel),

povidone K 30, maize starch, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium

dioxide, purified talc, macrogol 6000, indigo carmine lake (3.75 mg).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

36 months

6.4

Special precautions for storage

Blister pack: Store below 25°C. Protect from light.

Bottle: Store below 25°C.

6.5

Nature and contents of container

PVC/Aluminium foil blister strips. Pack sizes of 28 and 30 tablets.

HDPE bottle with PP screw cap. Pack sizes of 100 and 500 tablets (dispensing pack only).

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

7.

MEDICINE SCHEDULE

Prescription Medicine

8.

SPONSOR

Teva Pharma (New Zealand) Limited

PO Box 128 244

Remuera

Auckland 1541

Telephone: 0800 800 097

9.

DATE OF FIRST APPROVAL

22 May 2014

10.

DATE OF REVISION OF THE TEXT

11 September 2017

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