Accutane

Name: Accutane

Accutane Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Bone or joint pain
  • burning, redness, itching, or other signs of eye inflammation
  • difficulty with moving
  • nosebleeds
  • scaling, redness, burning, pain, or other signs of inflammation of the lips
  • skin infection or rash
Rare
  • Abdominal or stomach pain (severe)
  • attempts at suicide or thoughts of suicide (usually stops after medicine is stopped)
  • back pain
  • bleeding or inflammation of the gums
  • blurred vision or other changes in vision
  • changes in behavior
  • decreased vision after sunset or before sunrise (sudden or may continue after medicine is stopped)
  • diarrhea (severe)
  • headache (severe or continuing)
  • mental depression
  • nausea and vomiting
  • pain or tenderness of the eyes
  • pain, tenderness, or stiffness in the muscles (long-term treatment)
  • rectal bleeding
  • yellow eyes or skin
Incidence not known
  • Black, tarry stools
  • bloating
  • bloody cough
  • bloody or cloudy urine
  • bone pain, tenderness, or aching
  • burning or stinging of the skin
  • chest pain
  • confusion
  • constipation
  • convulsions
  • cough or hoarseness
  • dark-colored urine
  • decrease in height
  • difficulty breathing
  • difficulty speaking
  • difficulty swallowing
  • discharge from the eyes
  • dizziness
  • double vision
  • ear pain
  • excessive tearing
  • fainting
  • fast, irregular, pounding, or racing heartbeat or pulse
  • fever with or without chills
  • fractures and/or delayed healing
  • heartburn
  • high blood pressure
  • hives or skin rash
  • inability to move the arms, legs, or facial muscles
  • inability to speak
  • indigestion
  • inflamed tissue from infection
  • irregular yellow patch or lump on the skin
  • irritation
  • joint pain, redness, stiffness, or swelling
  • lack or slowing of normal growth in children
  • loosening of the fingernails
  • loss of appetite
  • loss of bladder control
  • loss or change in hearing
  • muscle cramps, spasms, or weakness
  • pain in the ribs, arms, or legs
  • pain or burning in the throat
  • pain or tenderness around the eyes and cheekbones
  • painful cold sores or blisters on the lips, nose, eyes, or genitals
  • painful or difficult urination
  • pains in the chest, groin, or legs, especially calves of the legs
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pale skin
  • pinpoint red spots on the skin
  • redness or soreness around the fingernails
  • redness, soreness, or itching skin
  • sensitivity of the eyes to sunlight
  • sneezing
  • sores, ulcers, or white spots on the lips or tongue or inside the mouth
  • stuffy or runny nose
  • sudden loss of consciousness
  • sudden loss of coordination
  • sudden onset of severe acne on the chest and trunk
  • sudden onset of slurred speech
  • swelling of the eyelids, face, lips, hands, lower legs, or feet
  • swollen, painful or tender lymph glands in the neck, armpit, or groin
  • tightness in the chest
  • unusual bleeding or bruising
  • unusual weight gain or loss
  • use of extreme physical or emotional force
  • watery or bloody diarrhea

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Crusting of the skin
  • difficulty in wearing contact lenses (may continue after medicine is stopped)
  • dryness of the eyes (may continue after treatment is stopped)
  • dryness of the mouth or nose
  • dryness or itching of the skin
  • headache (mild)
  • increased sensitivity of the skin to sunlight
  • peeling of the skin on palms of the hands or soles of the feet
  • stomach upset
  • thinning of the hair (may continue after treatment is stopped)
Incidence not known
  • Abnormal menstruation
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feeling
  • changes in fingernails or toenails
  • continuing ringing or buzzing, or other unexplained noise in the ears
  • dandruff
  • darkening of the skin
  • flushing
  • hair abnormalities
  • hair loss
  • increased hair growth, especially on the face
  • lightening of normal skin color
  • lightening of treated areas of dark skin
  • nervousness
  • oily skin
  • redness of the face
  • severe sunburn
  • skin rash, encrusted, scaly and oozing
  • stomach burning
  • sweating
  • trouble sleeping
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
  • unusually warm skin of the face
  • voice changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Accutane - Clinical Pharmacology

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Accutane, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 × 40 mg capsules) of Accutane under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Accutane given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Accutane capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74
Accutane
2 × 40 mg Capsules
AUC0-∞
(ng∙hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2
(hr)
* Eating a standardized high-fat meal
Fed* 10,004 (22%) 862 (22%) 5.3 (77%) 21 (39%)
Fasted 3,703 (46%) 301 (63%) 3.2 (56%) 21 (30%)
Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of Accutane to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Accutane to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received Accutane for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Table 3 Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N=38*
Parameter Isotretinoin
(Single Dose)
Isotretinoin
(Steady-State)
* The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2. † Median (range)
Cmax (ng/mL) 573.25 (278.79) 731.98 (361.86)
AUC(0-12) (ng∙hr/mL) 3033.37 (1394.17) 5082.00 (2184.23)
AUC(0-24) (ng∙hr/mL) 6003.81 (2885.67)
Tmax (hr)† 6.00 (1.00-24.60) 4.00 (0-12.00)
Cssmin (ng/mL) 352.32 (184.44)
T1/2 (hr) 15.69 (5.12)
CL/F (L/hr) 17.96 (6.27)

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

Accutane Dosage and Administration

Accutane should be administered with a meal (see PRECAUTIONS: Information for Patients).

The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2.0 mg/kg/day, as tolerated. Failure to take Accutane with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with Accutane has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Accutane, even in low doses, has not been studied, and is not recommended. It is important that Accutane be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Accutane on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).

Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS).

Table 4 Accutane Dosing by Body Weight (Based on Administration With Food)
Body Weight Total mg/day
kilograms pounds 0.5 mg/kg 1 mg/kg 2 mg/kg*
* See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1.0 mg/kg/day.
40 88 20 40 80
50 110 25 50 100
60 132 30 60 120
70 154 35 70 140
80 176 40 80 160
90 198 45 90 180
100 220 50 100 200

INFORMATION FOR PHARMACISTS

Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to obtain an authorization and the "do not dispense to patient after" date. Accutane must only be dispensed in no more than a 30-day supply.

REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.

An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as required by law. This Accutane Medication Guide is an important part of the risk management program for the patient.

Side Effects of Accutane

Serious side effects have been reported with Accutane. See “Accutane Precautions” section.

Common side effects of Accutane may include the following:

  • dry skin
  • chapped lips
  • dry eyes
  • dry nose that may lead to nosebleeds

Call your doctor if you get any side effect that bothers you or that does not go away.

Accutane Interactions

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Accutane and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take:

  • Vitamin A supplements. Vitamin A in high doses has many of the same side effects as Accutane. Taking both together may increase your chance of getting side effects.
  • tetracycline antibiotics such as doxycycline, tetracylcine, or minocycline (Minocin).
  • progestin-only birth control pills (mini-pills) such as Camilla, Norethindrone, and Orvette.
  • dilantin (phenytoin).
  • corticosteroids such as dexamethasone, hydrocortosine, or fludrocortisone (Florinef).
  • St. John’s wort.

These medicines should not be used with Accutane unless your doctor tells you it is okay.

Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.

Accutane and Lactation

Accutane should not be used by women who are breastfeeding. It is not known if Accutane is excreted in human breast milk or if it will harm your nursing baby. Tell your doctor if you are breastfeeding before you receive Accutane.

What is isotretinoin (amnesteem, claravis, sotret)?

Isotretinoin is a form of vitamin A. It reduces the amount of oil released by oil glands in your skin, and helps your skin renew itself more quickly.

Isotretinoin is used to treat severe nodular acne that has not responded to other treatments, including antibiotics.

Isotretinoin may also be used for purposes not listed in this medication guide.

What happens if i miss a dose (amnesteem, claravis, sotret)?

Skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Side effects

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of Accutane (isotretinoin) , and the postmarketing experience. The relationship of some of these events to Accutane (isotretinoin) therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane (isotretinoin) are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)

Gastrointestinal

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms

Hematologic

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).

Neurological

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness

Psychiatric

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

abnormal menses

Respiratory

bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

Skin and Appendages

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

Special Senses

Hearing - hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision- corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Laboratory

Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

Read the entire FDA prescribing information for Accutane (Isotretinoin)

Read More »

Important information

Accutane can cause severe, life-threatening birth defects. Never use Accutane if you are pregnant.

Women of child-bearing potential must agree in writing to use two specific forms of birth control and have regular pregnancy tests before, during, and after taking isotretinoin.

Accutane is available only under a special program called iPLEDGE. It is dangerous to try and purchase Accutane on the Internet or from vendors outside of the United States.

Do not take vitamin supplements containing vitamin A while you are taking isotretinoin. Do not donate blood while taking Accutane and for at least 30 days after you stop taking it.

What should I discuss with my healthcare provider before taking Accutane?

Accutane is available only under a special program called iPLEDGE. You must be registered in the program and sign documents stating that you understand the dangers of this medication and that you agree to use birth control as required by the program. Ask your doctor or call the drug maker if you have questions about the program or the written requirements.

It is dangerous to try and purchase Accutane on the Internet or from vendors outside of the United States. The sale and distribution of Accutane outside of the iPLEDGE program violates the regulations of the U.S. Food and Drug Administration for the safe use of this medication.

Do not use this medication if you are allergic to isotretinoin or to parabens, or if you are pregnant or may become pregnant.

To make sure you can safely take Accutane, tell your doctor if you have any of these other conditions:

  • a personal or family history of depression or mental illness;

  • heart disease, high cholesterol or triglycerides;

  • osteoporosis or other bone disorders;

  • an intestinal disorder such as inflammatory bowel disease, ulcerative colitis, or Crohn's disease;

  • diabetes;

  • asthma;

  • an eating disorder (anorexia nervosa); or

  • liver disease.

Accutane can cause severe, life-threatening birth defects if the mother takes the medication during pregnancy. Even one dose of Accutane can cause major birth defects of the baby's ears, eyes, face, skull, heart, and brain. Never use Accutane if you are pregnant.

For Women: Unless you have had your uterus and ovaries removed (total hysterectomy with oophorectomy) or have been in menopause for at least 12 months in a row, you are considered to be of child-bearing potential.

Even women who have had their tubes tied are required to use birth control while taking Accutane.

You must have a negative pregnancy test 30 days before you start taking Accutane. A pregnancy test is also required before each prescription is refilled, right after you take your last dose of Accutane, and again 30 days later. All pregnancy testing is required by the iPLEDGE program.

You must agree in writing to use two specific forms of birth control beginning 30 days before you start taking Accutane and ending 30 days after you stop taking it. Both a primary and a secondary form of birth control must be used together.

Primary forms of birth control include:

  • tubal ligation (tubes tied);

  • vasectomy of the male sexual partner;

  • an IUD (intrauterine device);

  • estrogen-containing birth control pills (not mini-pills); and

  • hormonal birth control patches, implants, injections, or vaginal ring.

Secondary forms of birth control include:

  • a male latex condom plus spermicidal foam or gel;

  • a diaphragm plus spermicidal foam or gel;

  • a cervical cap plus spermicidal foam or gel; and

  • a vaginal sponge containing spermicide.

Stop using Accutane and call your doctor at once if you have unprotected sex, if you quit using birth control, if your period is late, or if you think you might be pregnant. If you get pregnant while taking Accutane, call the iPLEDGE pregnancy registry at 1-866-495-0654.

It is not known whether isotretinoin passes into breast milk. Do not take Accutane without first talking to your doctor if you are breast-feeding a baby.

What should I avoid?

Do not take vitamin supplements containing vitamin A while you are taking Accutane.

Do not donate blood while taking Accutane and for at least 30 days after you stop taking it. Donated blood that is later given to pregnant woman could lead to birth defects in her baby if the blood contains any level of Accutane.

Do not use wax hair removers or have dermabrasion or laser skin treatments while you are taking Accutane and for at least 6 months after you stop taking it. Scarring may result.

Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds). Accutane can make your skin more sensitive to sunlight and sunburn may result. Accutane may impair your vision, especially at night. Be careful if you drive or do anything that requires you to see clearly.

What other drugs will affect Accutane?

Before taking Accutane, tell your doctor if you are also taking:

  • steroids (prednisone and others);

  • seizure medication such as phenytoin (Dilantin); or

  • a tetracycline antibiotic such as demeclocycline (Declomycin), doxycycline (Doryx, Vibramycin), minocycline (Minocin), or tetracycline (Brodspec, Sumycin, Tetracap).

This list is not complete and other drugs may interact with Accutane. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

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