MYCOBUTIN

Israel - English - Ministry of Health

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Active ingredient:
RIFABUTIN
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
J04AB04
Pharmaceutical form:
CAPSULES
Composition:
RIFABUTIN 150 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
PFIZER ITALIA S.R.L, ITALY
Therapeutic group:
RIFABUTIN
Therapeutic area:
RIFABUTIN
Therapeutic indications:
For the treatment of chronic tuberculosis where there is evidence of acid fast bacteria resistant to rifampicin or to two other alternative drugs. For the treatment of infections caused by MAC or other atypical mycobacteria where there is evidence of resistant bacteria as above. For the treatment of infections caused by MAC or other atypical mycobacteria in AIDS patients in all cases not subject to the above restrictions. For prevention of MAC infections in AIDS patients whose CD4 counts lower or eqval to 200/mm3
Authorization number:
068 76 28228 00
Authorization date:
2016-07-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

14-03-2017

Mycobutin , Israel 28 February 2017

Page 1 of 9

PfLEET No: 2014-0006377

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Mycobutin.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 150.0 mg of rifabutin.

For the full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Hard capsule

Opaque, red-brown, Size N°. 0 hard gelatin capsules.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Mycobutin is indicated for:

the treatment of chronic tuberculosis where there is evidence of acid fast bacteria resistant to

rifampicin or to two other alternative drugs.

the treatment of infections caused by MAC or other atypical mycobacteria where there is

evidence of resistant bacteria as above.

treatment of infections caused by MAC or other atypical mycobacteria in AIDS patients in all

cases not subject to the above restrictions.

prevention of MAC infections in AIDS patients whose CD4

counts lower or eqval to

200/mm

4.2.

Posology and method of administration

Mycobutin is generally administered as a single, daily, oral dose at any time independently of

meals.

Adults

Mycobutin as a single agent:

prophylaxis of MAC infection in immunodepressed patients: 300 mg (2 capsules).

Mycobutin in combination regimens:

Non-tuberculous mycobacterial disease: 450-600 mg (3 to 4 capsules) for up to 6

months after negative cultures are obtained.

MAC treatment: when Mycobutin is given in association with clarithromycin, the

dosage of Mycobutin should be reduced to 300 mg after the first month of treatment (see

Mycobutin , Israel 28 February 2017

Page 2 of 9

PfLEET No: 2014-0006377

Section 4.4, Special Warnings and Special Precautions For Use, and Section 4.5, Interactions

with Other Medications & Other Forms of Interactions)

Pulmonary tuberculosis: 150 mg daily (1 capsule), for 6-9 months, or for at least 6

months after negative cultures are obtained. This dosage should be increased to 300-450

mg/day in patients previously treated with antituberculous drugs.

In accordance with the commonly accepted criteria for the treatment of mycobacterial

infections, Mycobutin should always be given in combination with other anti-mycobacterial

drugs not belonging to the family of rifamycins.

Paediatric population

There are inadequate data to support the use of Mycobutin in children at the present time.

Elderly

No specific recommendations for dosage alterations in the elderly are suggested.

4.3.

Contraindications

Hypersensitivity or history of hypersensitivity to the active substance, other rifamycins (e.g.

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

Due to insufficient clinical experience in pregnant and breast-feeding women and in children,

Mycobutin should not be used in these patients.

4.4.

Special warnings and precautions for use

Before starting Mycobutin prophylaxis, patients should be assessed to ensure that they do not

have active disease caused by pulmonary tuberculosis or other mycobacteria.

Prophylaxis against MAC infection may need to be continued throughout the patient's lifetime.

Mycobutin may impart a red-orange colour to the urine and possibly to skin and body

secretions. Contact lenses, especially soft, may be permanently stained.

Mild hepatic impairment does not require a dose modification. Mycobutin should be used with

caution in cases of severe liver insufficiency. Mild to moderate renal impairment does not

require any dosage adjustment.

Severe renal impairment (creatinine clearance below 30 ml/min) requires a dosage reduction of

50%.

It is recommended that white blood cell and platelet counts and liver enzymes be monitored

periodically during treatment.

When Mycobutin is used concomitantly with clarithromycin for MAC treatment, a decreased

dose of Mycobutin is recommended due to the increase in plasma concentrations of Mycobutin

(See Section 4.2 Posology & Method of Administration, and Section 4.5 Interactions with other

Medications & Other Forms of Interactions).

Because of the possibility of occurrence of uveitis, patients should be carefully monitored when

rifabutin is given in combination with clarithromycin (or other macrolides) and/or fluconazole

(and related compounds). If such an event occurs, the patient should be referred to an

ophthalmologist and, if considered necessary, Mycobutin treatment should be suspended.

Uveitis associated with Mycobutin must be distinguished from other ocular complications of

HIV.

Mycobutin , Israel 28 February 2017

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PfLEET No: 2014-0006377

Protease inhibitors act as substrates or inhibitors of CYP450 IIIA4 mediated metabolism.

Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin,

their concomitant use should be based on the overall assessment of the patient and patient

specific drug profile (see Section 4.5, Interactions with other Medications & Other Forms of

Interactions).

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all

antibacterial agents, including rifabutin, and may range in severity from mild diarrhoea to

fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to

overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these

infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must

be considered in all patients who present with diarrhoea following antibiotic use. Careful

medical history is necessary since CDAD has been reported to occur over two months after

the administration of antibacterial agents.

4.5.

Interaction with other medicinal products and other forms of interaction

Rifabutin has been shown to induce the enzymes of the cytochrome P450 3A subfamily and

therefore may affect the pharmacokinetic behaviour of drugs metabolised by the enzymes

belonging to this subfamily. Upward adjustment of the dosage of such drugs may be required

when administered with Mycobutin.

Similarly, Mycobutin might reduce the activity of analgesics, anticoagulants, corticosteroids,

cyclosporin, digitalis (although not digoxin), oral hypoglycaemics, narcotics, phenytoin and

quinidine.

Clinical studies have shown that Mycobutin does not affect the pharmacokinetics of didanosine

(DDI), and isoniazid (however, for the latter refer also to undesirable effects). On the basis of

the above metabolic considerations no significant interaction may be expected with ethambutol,

theophylline, sulphonamides, pyrazinamide and zalcitabine (DDC).

As p-aminosalicylic acid has been shown to impede GI absorption of rifamycins it is

recommended that when it and Mycobutin are both to be administered they be given with an

interval of 8 - 12 hours.

The following table provides details of the possible effects of co-administration, on rifabutin

and the co-administered drug, and risk-benefit statement.

Coadministered drugs

Effect on

rifabutin

Effect on co-administered

drug

Comments

ANTIVIRALS

Amprenavir

2.9-fold ↑ AUC,

2.2-fold ↑ Cmax

No significant change in

kinetics.

A 50% reduction in the rifabutin dose

is recommended when combined with

amprenavir. Increased monitoring for

adverse reactions is warranted.

Fosamprenavir/ritonavir

64% ↑ AUC **

35% ↑ AUC and 36% ↑

Cmax, no effect Ctrough

(amprenavir)

Dosage reduction of rifabutin by at

least 75% (to 150 mg every other day

or three times per week) is

recommended when combined with

fosamprenavir

Indinavir

173%

AUC, 134% ↑

in AUC, 25%

Cmax

Dose reduction of rifabutin to half the

standard dose and increase of

Mycobutin , Israel 28 February 2017

Page 4 of 9

PfLEET No: 2014-0006377

Cmax

indinavir to 1000 mg every 8 hours are

recommended when rifabutin and

indinavir are coadministered.

Lopinavir/ritonavir

5.7-fold ↑ AUC,

3.4 fold ↑

Cmax**

No significant change in

lopinavir kinetics

Dosage reduction of rifabutin by at

least 75% of the usual dose of 300

mg/day is recommended (i.e., a

maximum dose of 150 mg every other

day or three times per week).

Increased monitoring for adverse

reactions is warranted. Further dosage

reduction of rifabutin may be

necessary.

Saquinavir

No data.

40% decrease in AUC.

Ritonavir

4-fold increase

in AUC, 2.5-fold

increase in Cmax

No data

Due to this multifold increase in

rifabutin concentrations and the

subsequent risk of side effects, patients

requiring both rifabutin and a protease

inhibitor, other protease inhibitors

should be considered.

Tipranavir/ritonavir

2.9-fold ↑ AUC,

1.7-fold ↑ Cmax

No significant change in

tipranavir kinetics

Therapeutic drug monitoring of

rifabutin is recommended.

Coadministration of tipranavir with

rifabutin may increase concentrations

of rifabutin and its metabolite. Reduce

rifabutin dose 75% (e.g., 150 mg

every other day) and increase

monitoring

Zidovudine

No significant

change in

kinetics

Approx. 32% decrease in

Cmax and AUC.

A large clinical study has shown that

these changes are of no clinical

relevance.

Delavirdine

No data.

Oral clearance

5-fold

resulting in significantly

lower mean trough plasma

concentrations (18

15 to

Study conducted in HIV-1 infected

patients Rifabutin is not

recommended for patients dosed with

delavirdine mesylate 400 mg q8h.

Didanosine

No significant

change in

kinetics.

No significant change in

kinetics at steady state.

ANTIFUNGALS

Fluconazole

82% increase in AUC.

No significant change in

steady-state plasma

concentrations

Itraconazole

No data.

70-75% decrease in Cmax

and AUC.

A case report indicates an increase in

rifabutin serum levels in the presence of

itraconazole.

Posaconazole

31%↑ Cmax, 72%↑

43%↓ Cmax, 49%↓ AUC

Co-administration of posaconazole

with rifabutin increases rifabutin

plasma concentrations and decreases

posaconazole plasma concentrations.

Concomitant use of rifabutin and

posaconazole should be avoided unless

Mycobutin , Israel 28 February 2017

Page 5 of 9

PfLEET No: 2014-0006377

the benefit to the patient outweighs the

risk. However, if concomitant

administration is required, close

monitoring of breakthrough fungal

infections as well as frequent

monitoring for adverse reactions due to

increased rifabutin plasma

concentrations (e.g., uveitis,

leukopenia) are recommended.

Voriconazole

195%↑ Cmax,

331%↑ AUC ***

Rifabutin (300 mg once

daily) decreased the Cmax

and AUC of voriconazole at

200 mg twice daily by 69%

and 78%, respectively.

During co-administration

with rifabutin, the Cmax and

AUC of voriconazole at 350

mg twice daily were 96%

and 68% of the levels when

administered alone at 200

mg twice daily. At a

voriconazole dose

of 400 mg twice daily Cmax

and AUC were 104% and

87% higher, respectively,

compared with voriconazole

alone at 200 mg twice daily.

If the benefit outweighs the risk,

rifabutin may be coadministered with

voriconazole if the maintenance dose

of voriconazole is increased to 5 mg/kg

intravenously every 12 hours or from

200 mg to 350 mg orally, every 12

hours (100 mg to 200 mg orally, every

12 hours in patients less than 40 kg).

Careful monitoring of full blood counts

and adverse events to rifabutin (e.g.

uveitis) is recommended when

rifabutin is coadministered with

voriconazole

Ketoconazole/

miconazole

No data.

No data.

Co-administered medications, such as

ketoconazole, that competitively inhibit

the Cyt P450IIIA activity may increase

circulating drug levels of rifabutin.

Coadministered drugs

Effect on

rifabutin

Effect on co-administered

drug

Comments

ANTI-PCP (Pneumocystis carinii pneumonia)

Dapsone

No data.

Approximately 27%-40%

decrease in AUC.

Study conducted in HIV infected

patients (rapid and slow acetylators)

Sulfamethoxazole-

Trimethoprim

No significant change

in Cmax and AUC.

Approx. 15-20% decrease in

AUC.

In another study, only trimethoprim (not

sulfamethoxazole) had 14% decrease in

AUC and 6% in Cmax but were not

considered clinically significant.

ANTI-TB (Tuberculosis)

Ethambutol

No data.

No significant change in

AUC or Cmax

Isoniazid

No data.

Pharmacokinetics not

affected

Mycobutin , Israel 28 February 2017

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PfLEET No: 2014-0006377

Pyrazinamide

No data.

No data.

Study data being evaluated.

ANTI-MAC (Mycobacterium avium intracellulare complex)

Azithromycin

No PK

interaction

No PK interaction

Clarithromycin

Approx. 77%

increase in

AUC.

Approx. 50% decrease in

AUC.

Study conducted in HIV infected

patients

Dose of rifabutin should be

adjusted in the presence of

clarithromycin.(See Section 4.2,

Posology and Method of Administration

and also, Section 4.4, Special Warnings

& Special Precautions for Use)

OTHER

Methadone

No data.

No significant effect.

No apparent effect of rifabutin on either

peak levels of methadone or systemic

exposure based upon AUC. Rifabutin

kinetics not evaluated.

Oral contraceptives

No data.

No data.

Contraceptive cover may not be

adequate during concomitant therapy

with rifabutin, therefore, patients should

be advised to use other methods of

contraception.

Tacrolimus

No data.

No data.

Rifabutin decreases tacrolimus trough

blood levels.

Theophylline

No data.

No significant change in

AUC or Cmax compared

with baseline.

** - Drug plus active metabolite

*** - voriconazole dosed at 400 mg twice daily

4.6.

Fertility, pregnancy and lactation

Due to lack of data in pregnant women, as a precautionary measure, Mycobutin should not be

administered to pregnant women or those breast-feeding children even though in experimental

animal studies the drug was not teratogenic.

Mycobutin may interact with oral contraceptives (see Section 4.5).

4.7.

Effects on ability to drive and use machines

There have been no reports of adverse effects on ability to drive and use machines.

4.8.

Undesirable effects

The tolerability of Mycobutin in multiple drug regimens, was assessed in both

immunocompetent and immunocompromised patients, suffering from tuberculosis and non-

tuberculous mycobacteriosis in long term studies with daily dosages up to 600 mg.

Bearing in mind that Mycobutin was often given in these studies as part of a multidrug

regimen it is not always possible to define with certainty a drug-event relationship. Treatment

discontinuation was necessary only in a very few cases. Adverse reactions identified through

clinical trials or post-marketing surveillance by system organ class (SOC) are listed below in

the following frequencies,

Mycobutin , Israel 28 February 2017

Page 7 of 9

PfLEET No: 2014-0006377

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 and ‘not known’.

MedDRA

System Organ Class

Frequency

Undesirable Effects

Blood and lymphatic

system disorders

Very

common

Leukopenia

Common

Anaemia

Uncommon

Pancytopenia

Agranulocytosis

Lymphopenia

Granulocytopenia

Neutropenia

White blood cell count decreased

Neutrophil count decreased

Thrombocytopenia

Platelet count decreased

Immune system

disorders

Common

Rash

Uncommon

Hypersensitivity

Bronchospasm

Eosinophilia

Eye disorders

Uncommon

Uveitis

Corneal deposits

Gastrointestinal

disorders

Common

Nausea

Uncommon

Vomiting

Hepatobiliary

disorders

Uncommon

Jaundice

Hepatic enzyme increased

Skin and

subcutaneous tissue

disorders

Uncommon

Skin discolouration

Musculoskeletal and

connective tissue

disorders

Common

Myalgia

Uncommon

Arthralgia

General disorders and

administration site

conditions

Common

Pyrexia

Clostridium difficile colitis is a mandated adverse reaction for the pharmacological class; this

event was neither observed in the clinical trials nor in the spontaneous reporting for rifabutin.

Anaphylactic shock has occurred with other antibiotics of the same class

Mild to severe, reversible uveitis has been reported less frequently when Mycobutin is

used at 300 mg as monotherapy in MAC prophylaxis, versus Mycobutin in combination with

clarithromycin (or other macrolides) for MAC treatment (see Section 4.4).

Flu-like syndrome, chest pressure or pain with dyspnoea and rarely hepatitis and haemolysis has

been reported.

Mycobutin , Israel 28 February 2017

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PfLEET No: 2014-0006377

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions 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.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

4.9.

Overdose

Gastric lavage and diuretic treatment should be carried out. Supportive care and symptomatic

treatment should be administered.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic Properties

Pharmacotherapeutic group: Antibiotics, ATC code: J04AB04

In vitro activity of rifabutin against laboratory strains and clinical isolates of M. tuberculosis has

been shown to be very high. In vitro studies carried out so far have shown that from one-third to

half of M.tuberculosis strains resistant to rifampicin are susceptible to rifabutin, indicating that

cross-resistance between the two antibiotics is incomplete.

The in vivo activity of rifabutin on experimental infections caused by M. tuberculosis was about

10 times greater than that of rifampicin in agreement with the in vitro findings.

Rifabutin was seen to be active against non-tuberculous (atypical) mycobacteria including M.

avium-intracellulare (MAC), in vitro as well as in experimental infections caused by these

pathogens in mice with induced immuno-deficiency.

5.2.

Pharmacokinetic Properties

Absorption

In man, rifabutin is rapidly absorbed and maximum plasma concentrations are reached around

2-4 hours after oral administration. The pharmacokinetics of rifabutin is linear after single

administration of 300, 450, and 600 mg to healthy volunteers. With these doses, C max is in the

range of 0.4-0.7 µg/ml. Plasma concentrations are maintained above the MIC values for M.

tuberculosis up to about 30 hours from administration.

Distribution

Rifabutin is widely distributed in various animal organs with the exception of the brain. In

particular, in human lung tissue the concentrations measured up to 24 hours after dosing were

about 5-10 times higher than the plasma levels.

The intracellular penetration of rifabutin is very high as demonstrated by

intracellular/extracellular concentration ratios which ranged from 9 in neutrophils to 15 in

monocytes, both obtained from human sources.

The high intracellular concentration is likely to play a crucial role in sustaining the efficacy of

rifabutin against intracellular pathogens such as mycobacteria.

Elimination

Rifabutin and its metabolites are eliminated mainly by the urinary route. The t

of rifabutin in

man is approximately 35-40 hours.

Mycobutin , Israel 28 February 2017

Page 9 of 9

PfLEET No: 2014-0006377

5.3.

Preclinical safety data

Preclinical safety studies of rifabutin indicate a good safety margin in rodents and in monkeys.

In repeated dose studies, target organs were identified at doses producing blood levels higher

than those achieved with recommended doses for human therapy. The main target organs are

liver and, to a lesser degree, erythrocytes.

Rifabutin did not show any teratogenic, mutagenic or carcinogenic potential.

Pharmaceutical Particulars

6.1.

List of excipients

Microcrystalline cellulose

Sodium lauryl sulphate

Magnesium stearate

Silica gel

Red iron Oxide

Titanium dioxide

Gelatin Ph.Eur.

6.2.

Incompatibilities

Not applicable.

6.3.

Shelf Life

2 years.

6.4.

Special precautions for storage

Store below 25°C

6.5.

Nature and contents of container

Transparent PVC/Al blisters in cardboard cartons containing 30 capsules.

6.6.

Special precautions for disposal and other handling

No special requirements.

Manufacturer: Pfizer Italia S.R.L, Italy.

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

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

February 2017

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Undesirable

effects

Shock and Clostridium difficile colitis

are mandated adverse reactions for the

pharmacological class; both events were

neither observed in the clinical trials nor

in the

spontaneous reporting for

rifabutin.

Clostridium difficile colitis is a mandated

adverse reaction for the pharmacological

class; this event was neither observed in the

clinical trials nor in the spontaneous

reporting for rifabutin.

Anaphylactic shock has occurred with other

antibiotics of the same class

…..

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קט יחכונ טס

שדח טסקט

יאוול תועפות

ןיטובוקימב שומישה ,הפורת לכב ומכ קלחב יאוול תועפותל םורגל לולע ארקמל להבית לא .םישמתשמהמ

לולע ןיטובוקימב שומישה ,הפורת לכב ומכ לא .םישמתשמהמ קלחב יאוול תועפותל םורגל ןכתי ,יאוולה תועפות תמישר ארקמל להבית לובסת אלו ןכתי ,יאוולה תועפות תמישר .ןהמ תחא ףאמ

:לש הרקמב אפורל דימ תונפל שי

םיפוצפצב תאטבתמה רתי תושיגר אכ ,המישנ יישק ,םיימואתפ ,הזחב םיב וא םייתפשב תוחיפנ ,םייפעפעה תוחיפנ דחוימב(רועב דרגו החירפ ,םינפב .)ףוגה לכ לע בחרנ הזשכ

וא/ו האוצב םד ,ןטב יבאכ ,לושלש עיפוהל םילולע וליא םינימסת .םוח לופיט םויס רחאל וא ךלהמב עובנל םילולע םהו הקיטויביטנאב .יעמב הרומח תקלדמ

,חלו רק רוע ,תוינונשי ,לובלב תשוחת בל בצק , תיחטש המישנ וא המישנ יישק .)יטקליפנא קוש לש םינמיס( ריהמ

םיביכ ,םיפירח וא/ו םירזוח םימוהיז ,םיליגר אל םימומידו תולבח ,ןורגבו הפב ,רועבו הפב תומודא תודוקנ תעפוה .השלוח תשוחת ,רועה לש גירח ןורוויח וליא םינימסת היעבל ןמס תווהל םילולע .םדה תכרעמב

.ןהמ תחא ףאמ לובסת אלו

לש הרקמב אפורל דימ תונפל שי

םיפוצפצב תאטבתמה רתי תושיגר אכ ,המישנ יישק ,םיימואתפ ,הזחב םיב וא םייתפשב תוחיפנ ,םייפעפעה תוחיפנ החירפ ,םינפב וא

הזשכ דחוימב(רועב דרג .)ףוגה לכ לע בחרנ

.םוח וא/ו האוצב םד ,ןטב יבאכ ,לושלש וא ךלהמב עיפוהל םילולע וליא םינימסת םהו הקיטויביטנאב לופיט םויס רחאל .יעמב הרומח תקלדמ עובנל םילולע

יפכ ,יטקליפנא קוש םע הפצנש .הצובקה התואמ תורחא תוקיטויביטנא

הפב םיביכ ,םיפירח וא/ו םירזוח םימוהיז

וא/

תולבח ,ןורגב וא

,םיליגר אל םימומיד ו הפב תומודא תודוקנ תעפוה וא/

,רועב .השלוח תשוחת ,רועה לש גירח ןורוויח היעבל ןמס תווהל םילולע וליא םינימסת .םדה תכרעמב

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