Pifeltro

Pifeltro

doravirine

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Doravirine.
Description
Each tablet contains 100 mg doravirine.
PIFELTRO is a film-coated tablet containing doravirine for oral administration.
Chemistry: The chemical name for doravirine is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile.
It has a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75.
Doravirine is practically insoluble in water.
Excipients/Inactive Ingredients: Each tablet includes the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and carnauba wax. The tablets are film coated with a coating material containing the following inactive ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin.
Action
Therapeutic Class: HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).
Pharmacology: Mechanism of Action: PIFELTRO is an antiviral drug [see Pharmacodynamics as follows].
Pharmacodynamics: Effects on Electrocardiogram: At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the maximum approved dose, doravirine does not prolong the QT interval to any clinically relevant extent.
Clinical Studies: Treatment-Naïve Adult Subjects: The efficacy of PIFELTRO is based on the analyses of 48-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials, (DRIVE-FORWARD and DRIVE-AHEAD) in antiretroviral treatment-naïve, HIV-1 infected subjects (n=1494).
In DRIVE-FORWARD, 766 subjects were randomized and received at least 1 dose of either PIFELTRO once daily or DRV+r 800/100 mg once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years, 16% were female, 27% were non-white, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC and 87% received FTC/TDF; these characteristics were similar between treatment groups.
In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either DELSTRIGO or EFV/FTC/TDF once daily. At baseline, the median age of subjects was 31 years, 15% were female, 52% were non-white, 3% had hepatitis B or C co-infection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm3; these characteristics were similar between treatment groups.
Week 48 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 1. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
In DRIVE-FORWARD, PIFELTRO demonstrated consistent efficacy across demographic and baseline prognostic factors, including gender, race, ethnicity, NRTI background therapy, baseline HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ T-cell count, and viral subtypes. Mean CD4+ T-cell counts in the PIFELTRO and DRV+r groups increased from baseline by 193 and 186 cells/mm3, respectively.
In DRIVE-AHEAD, DELSTRIGO demonstrated consistent efficacy across demographic and baseline prognostic factors, including gender, race, ethnicity, baseline HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ T-cell count, and viral subtypes. Mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 198 and 188 cells/mm3, respectively. (See Table 1.)

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P007 was a Phase 2b trial in antiretroviral treatment-naïve HIV-1 infected adult subjects (n=340). In Part I, subjects were randomized to receive one of 4 doses of PIFELTRO or EFV, each in combination with FTC/TDF. After Week 24, all subjects randomized to receive PIFELTRO were switched to (or maintained on) PIFELTRO 100 mg. Additional subjects were randomized in Part II to receive either PIFELTRO 100 mg or EFV, each in combination with FTC/TDF. In both parts of the trial, PIFELTRO and EFV were administered as blinded-therapy and FTC/TDF was administered open-label.
At Week 48, the proportion of subjects with HIV-1 RNA less than 50 copies/mL was 79% (85/108) and 82% (89/108) for PIFELTRO 100 mg and EFV, respectively (FDA Snapshot Approach). At Week 96, the proportion of subjects with HIV-1 RNA less than 50 copies/mL was 76% (82/108) and 76% (82/108) for PIFELTRO 100 mg and EFV, respectively. At Week 48, mean CD4+ T-cell counts in the PIFELTRO 100 mg and EFV groups increased from baseline by 192 and 195 cells/mm3, respectively. At Week 96, mean CD4+ T-cell counts in the PIFELTRO 100 mg and EFV groups increased from baseline by 259 and 264 cells/mm3, respectively.
Pharmacokinetics: The pharmacokinetics of doravirine were studied in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Steady state is generally achieved by Day 2 of once daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC0-24, Cmax, and C24. Doravirine steady state pharmacokinetics following administration of 100 mg once daily to HIV-1 infected subjects, based on a population pharmacokinetic analysis, are provided as follows. (See Table 2.)

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Absorption: Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has an absolute bioavailability of approximately 64% for the 100 mg tablet.
Distribution: Based on administration of an IV microdose, the volume of distribution of doravirine is 60.5 L. Doravirine is approximately 76% bound to plasma proteins.
Metabolism: Based on in vitro data, doravirine is primarily metabolized by CYP3A.
Elimination: Doravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism. Excretion of unchanged drug via urinary excretion is minor. Biliary excretion of unchanged drug is not expected to be significant.
Effect of Food on Oral Absorption: The administration of a single PIFELTRO tablet with a high-fat meal to healthy subjects resulted in a 16% and 36% increase in doravirine AUC and C24, respectively, while Cmax was not significantly affected.
Special Populations: Renal Impairment: Renal excretion of doravirine is minor: approximately 6% of the administered dose is excreted unchanged in urine. In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. No dose adjustment is required in patients with mild, moderate or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis [see Renal Impairment under Precautions].
Hepatic Impairment: Doravirine is primarily metabolized and eliminated by the liver. There was no clinically relevant difference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 subjects without hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Hepatic Impairment under Precautions].
Pediatric: The pharmacokinetics and dosing recommendations of PIFELTRO in patients younger than 18 years of age have not been established [see Use in Children under Precautions].
Elderly: No clinically relevant differences in the pharmacokinetics of doravirine have been identified in subjects at least 65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a population pharmacokinetic analysis [see Use in the Elderly under Precautions].
Race: No clinically relevant racial differences in the pharmacokinetics of doravirine have been identified based on a population pharmacokinetic analysis of doravirine in healthy and HIV-1-infected subjects.
Gender: No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine.
Drug Interaction Studies: Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine.
Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and C24 values of doravirine are summarized in Table 3. The effects of co-administration of doravirine on the Cmax and AUC values of other drugs are summarized in Table 4. [See Interactions.] (See Tables 3 and 4.)

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Toxicology: Animal Toxicology: Acute Toxicity: No acute toxicity studies were performed with doravirine.
Chronic Toxicity: In repeat-dose oral toxicity studies, doravirine was very well tolerated in all animal species up to the highest doses tested. There were no adverse effects or target organs of toxicity identified in rats dosed for 6 months with 450 mg/kg/day, or in dogs dosed with 1000 mg/kg/day for 9 months (approximately 7-fold and 18-fold, respectively, above the exposure at the RHD).
Carcinogenesis: Long-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence of carcinogenic potential at exposures up to 6 times (mice) and 7 times (rats) the human exposures at the RHD.
Mutagenesis: Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo rat micronucleus assays.
Reproduction: There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to the highest dose tested. Systemic exposures (AUC) to doravirine were approximately 7 times the exposure in humans at the RHD.
Development: Reproduction studies with orally administered doravirine have been performed in rats and rabbits at exposures approximately 9 (rats) and 8 (rabbits) times the exposure in humans at the RHD with no effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development. Doravirine was administered orally at up to 300 mg/kg/day to pregnant rabbits on gestation days 7 to 20, and up to 450 mg/kg/day to rats on gestation days 6 to 20, and also to rats on gestation day 6 to lactation/postpartum day 20. Studies in pregnant rats and rabbits showed that doravirine is transferred to the fetus through the placenta, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on gestation day 20.
Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14.
Microbiology: Mechanism of Action: Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Antiviral Activity in Cell Culture: Doravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM.
Antiviral Activity in Combination with other HIV Antiviral Agents: The antiviral activity of doravirine was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.
Resistance: In Cell Culture: Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106M, V106I, V108I, F227L, F227C, F227V, H221Y, M230I, L234I, P236L, and Y318F.
In Clinical Trials: The phase 3 studies, DRIVE-FORWARD and DRIVE-AHEAD, including previously untreated patients (n=747) where the following NNRTI substitutions were part of the exclusion criteria: L100I, K101E, K101P, K103N, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, M230I, M230L, P225H, F227C, F227L, F227V.
In the doravirine treatment arms of the treatment-naïve trials DRIVE-FORWARD and DRIVE-AHEAD (n=747), emergent doravirine-associated resistance substitutions were observed in 7 of 30 subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or at early study discontinuation and having resistance data). In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no emergent darunavir-associated resistance substitutions were observed in the 11 subjects in the resistance analysis subset. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), emergent efavirenz-associated resistance substitutions were observed in 12 out of 24 subjects in the resistance analysis subset.
Emergent doravirine associated resistance substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F.
Cross-Resistance: Laboratory strains of HIV-1 harboring the common NNRTI-associated mutations K103N, Y181C, or K103N/Y181C substitutions in RT exhibit less than a 3-fold decrease in susceptibility to doravirine compared to wild-type virus when evaluated in the presence of 100% NHS. Doravirine was able to suppress the following NNRTI-associated substitutions: K103N, Y181C, G190A, and E138K mutants under clinically relevant concentrations.
A panel of 96 diverse clinical isolates containing NNRTI-associated mutations was evaluated for susceptibility to doravirine in the presence of 10% fetal bovine serum. Clinical isolates containing the Y188L substitution or V106 substitutions in combination with A98G, H221Y, P225H, F227C or Y318F showed a greater than 100-fold reduced susceptibility to doravirine.
Treatment emergent doravirine resistance associated substitutions may confer cross resistance to efavirenz, rilpivirine, nevirapine, and etravirine. Of the 7 virologic failures who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 3 had partial resistance to etravirine based on the Monogram Phenosense assay.
Indications/Uses
PIFELTRO is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of viral resistance to NNRTI.
Dosage/Direction for Use
General: PIFELTRO is a tablet containing 100 mg of doravirine.
Adult Patients: The recommended dosage regimen of PIFELTRO in adults is one 100 mg tablet taken orally once daily with or without food.
Missed Dose: If the patient misses a dose of PIFELTRO within 12 hours of the time it is usually taken, the patient should take PIFELTRO as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 12 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not take 2 doses at one time.
Pediatric Patients: Safety and efficacy of PIFELTRO have not been established in patients younger than 18 years of age [see Pharmacology: Pharmacokinetics under Actions].
Elderly Patients: There are limited data available on the use of doravirine in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients [see Use in the Elderly under Precautions, Pharmacology: Pharmacokinetics under Actions]. No dose adjustment of PIFELTRO is needed in elderly patients.
Renal Impairment: No dose adjustment of PIFELTRO is required in patients with mild, moderate or severe renal impairment. PIFELTRO has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients [see Renal Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No dose adjustment of PIFELTRO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PIFELTRO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Hepatic Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Co-administration with Rifabutin: If PIFELTRO is co-administered with rifabutin, one tablet of PIFELTRO should be taken twice daily (approximately 12 hours apart) [see Interactions, Pharmacology: Pharmacokinetics: Drug Interaction Studies under Actions].
Overdosage
There is no known specific treatment for overdose with PIFELTRO. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.
Contraindications
PIFELTRO should not be co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO [see Pharmacology: Pharmacokinetics: Drug Interaction Studies under Actions]. These drugs include, but are not limited to, the following: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin, rifapentine; the cytotoxic agent mitotane; St. John's wort (Hypericum perforatum); lumacaftor.
Special Precautions
Drug Interactions: Caution should be given to prescribing PIFELTRO with drugs that may reduce the exposure of doravirine [see Contraindications, Interactions, and Pharmacology: Pharmacokinetics: Drug Interaction Studies under Actions].
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
Renal Impairment: No dose adjustment of PIFELTRO is required in patients with mild, moderate or severe renal impairment. PIFELTRO has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients [see Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No dose adjustment of PIFELTRO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PIFELTRO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Pharmacology: Pharmacokinetics under Actions].
Use in Children: Safety and efficacy of PIFELTRO have not been established in patients younger than 18 years of age [see Pharmacology: Pharmacokinetics under Actions].
Use in the Elderly: There are limited data available on the use of doravirine in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients [see Pharmacology: Pharmacokinetics under Actions]. No dose adjustment of PIFELTRO is needed in elderly patients.
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: No adequate human data are available to establish whether or not PIFELTRO poses a risk to pregnancy outcomes. Doravirine use in women during pregnancy has not been evaluated.
Reproduction studies performed in rats and rabbits at exposures up to approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose (RHD) did not indicate harmful effects of doravirine with respect to pregnancy or embryofetal development [see Pharmacology: Toxicology: Animal Toxicology under Actions].
Nursing Mothers: Risk Summary: It is unknown whether doravirine is excreted in human milk. Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PIFELTRO.
Animal Data: Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14.
Adverse Reactions
Clinical Trials Experience: Summary of the safety profile: The most frequently reported adverse reactions considered possibly or probably related to doravirine were nausea (6%) and headache (5%).
Tabulated summary of adverse reactions: The adverse reactions with suspected (at least possible) relationship to treatment are listed as follows by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). (See Table 5.)

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Drug Interactions
Established and Other Potentially Significant Drug Interactions: Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of PIFELTRO and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine and reduce the therapeutic effect of doravirine [see Contraindications, Precautions, and Pharmacology: Pharmacokinetics: Drug Interaction Studies under Actions]. Co-administration of PIFELTRO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.
Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of drugs metabolized by CYP enzymes.
Table 6 shows the established and other potentially significant drug interactions with PIFELTRO but is not inclusive. (See Table 6.)

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Drugs with No Observed or Predicted Interactions with PIFELTRO: Drug-drug interactions with PIFELTRO and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see Pharmacology: Pharmacokinetics: Drug Interaction Studies under Actions]: aluminum hydroxide/magnesium hydroxide/simethicone-containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, midazolam, sofosbuvir/ledipasvir, elbasvir/grazoprevir, dolutegravir, lamivudine, or tenofovir DF.
No clinically relevant drug-drug interaction is expected when PIFELTRO is co-administered with abacavir, emtricitabine, enfuvirtide, raltegravir, maraviroc, tenofovir alafenamide, buprenorphine, naloxone, daclatasvir, simeprevir, diltiazem, verapamil, rosuvastatin, simvastatin, canagliflozin, liraglutide, sitagliptin, lisinopril, or omeprazole.
Lactose: The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Storage
Store PIFELTRO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant.
Store PIFELTRO below 30°C.
MIMS Class
ATC Classification
J05AG06 - doravirine ; Belongs to the class of non-nucleoside reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
FC tab 100 mg (white, oval-shaped, debossed with the corporate logo and 700 on one side and plain on the other side) x 30's.
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