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Oct.06.2021

Brincidofovir

Indications/Dosage

Labeled

  • variola virus (smallpox) infection

Off-Label

    † Off-label indication

    For the treatment of variola virus (smallpox) infection

    Oral dosage (tablets)

    Adults weighing 48 kg or more

    200 mg PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Children and Adolescents weighing 48 kg or more

    200 mg PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Oral dosage (oral suspension)

    Adults weighing 48 kg or more

    200 mg PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Adults weighing less than 48 kg

    4 mg/kg/dose PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Children and Adolescents weighing 48 kg or more

    200 mg PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Children and Adolescents weighing 10 to 47 kg

    4 mg/kg/dose PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Infants and Children weighing less than 10 kg

    6 mg/kg/dose PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Neonates

    6 mg/kg/dose PO once weekly for 2 doses (on Days 1 and 8).[66710]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

      weighing 48 kg or more: 200 mg/week PO.

      weighing less than 48 kg: 4 mg/kg/week PO.

    • Geriatric

      weighing 48 kg or more: 200 mg/week PO.

      weighing less than 48 kg: 4 mg/kg/week PO.

    • Adolescents

      weighing 48 kg or more: 200 mg/week PO.

      weighing less than 48 kg: 4 mg/kg/week PO.

    • Children

      weighing 48 kg or more: 200 mg/week PO.

      weighing 10 to 47 kg: 4 mg/kg/week PO.

      weighing less than 10 kg: 6 mg/kg/week PO.

    • Infants

      6 mg/kg/week PO.

    • Neonates

      6 mg/kg/week PO.

    Patients with Hepatic Impairment Dosing

    No dosage adjustments are needed.[66710]

    Patients with Renal Impairment Dosing

    No dosage adjustments are needed.[66710]

     

    Hemodialysis

    No dosage adjustments are needed for end-stage renal disease patients on dialysis.[66710]

    † Off-label indication
    Revision Date: 10/06/2021, 08:49:49 AM

    References

    66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

    Description/Classification

    Description

    Brincidofovir is an oral antiviral indicated for the treatment of human smallpox disease due to variola virus. It is a nucleotide analog lipid conjugate developed to deliver effective intracellular concentrations of the active antiviral metabolite cidofovir diphosphate. Brincidofovir is approved for use in adult and pediatric patients and is given once weekly for 2 weeks. DO NOT exceed the recommended dosing regimen, as an increased risk in mortality is possible with prolonged use. Verify a negative pregnancy test in females of reproductive potential before initiating treatment. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 months after the last dose. Men are advised to use condoms during treatment and for at least 4 months after the last dose.[66710]

    Classifications

    • General Anti-infectives Systemic
      • Antivirals For Systemic Use
        • Variola Virus (Smallpox) Antivirals
    Revision Date: 06/17/2021, 04:38:33 PM

    References

    66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Route-Specific Administration

    Oral Administration

    • Avoid direct contact with tablets that have been broken or crushed or with the oral suspension as brincidofovir is considered a potential carcinogen. If contact with the skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water.[66710]

    Oral Solid Formulations

    • Administer the tablets on an empty stomach or with a low-fat meal (approximately 400 calories, 25% fat)
    • Swallow each tablet whole. DO NOT crush or divide the tablets.[66710]

    Oral Liquid Formulations

    • Administer the oral suspension on an empty stomach.
    • Shake the suspension before use.
    • Use an appropriate oral dosing syringe to ensure delivery of the prescribed dose.
    • For patients unable to swallow, the oral suspension may be administered via nasogastric or gastrostomy tubes as follows:
      • Draw up the prescribed dose with a calibrated catheter-tip syringe.
      • Administer the dose via the enteral tube.
      • Refill the syringe with 3 mL of water, shake the syringe, and administer the contents of the syringe via the enteral tube.
      • Flush the tube with water before and after enteral administration.
    • Discard any unused portion after completing the 2 prescribed doses.[66710]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 06/04/2021, 03:27:30 PM

      References

      66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

      Adverse Reactions

      Mild

      • abdominal pain
      • diarrhea
      • dysgeusia
      • maculopapular rash
      • nausea
      • rash
      • vomiting
      • weakness

      Moderate

      • elevated hepatic enzymes
      • hepatitis
      • hyperbilirubinemia
      • peripheral edema

      Gastrointestinal (GI) adverse events experienced by recipients of brincidofovir during the safety clinical trials (n = 392) included diarrhea (8%), nausea (5%), vomiting or retching (4%), and abdominal pain (3%). Diarrhea was a composite term that included irregular bowel movements, defecation urgency, fecal incontinence, and frequent bowel movements. Abdominal pain was a composite term that included abdominal discomfort, distention, pain, and tenderness. All reported GI adverse events started within the first 2 weeks of treatment. Of the 392 patients who received brincidofovir, treatment was stopped in 9 due to diarrhea, 3 due to nausea, 1 due to vomiting, 1 due to enteritis, and 1 due to dyspepsia; all GI adverse events resolved upon treatment discontinuation.[66710]

      Brincidofovir has been associated with elevated hepatic enzymes, increased total bilirubin, and in rare cases (less than 1%) severe hepatobiliary adverse events (e.g., hyperbilirubinemia, acute hepatitis, hepatic steatosis, veno-occlusive hepatic disease). Treatment-emergent liver function test abnormalities reported during the brincidofovir safety clinical trials (n = 392) included Grade 2 and 3 increases in ALT (3% and 2%, respectively), Grade 2 and 3 increases in AST (2% and 1%, respectively), and Grade 2 and 3 increases in total bilirubin (3% and 1%, respectively). Most of the elevations in the liver function tests were reversible and did not require treatment discontinuation; however, 1 patient discontinued treatment due to an ALT greater than 10-times the upper limit of normal. The ALT concentration normalized upon treatment discontinuation. Other treatment-emergent laboratory abnormalities reported during the safety trial included Grade 2 and 3 increases in serum creatinine (4% and less than 1%, respectively).[66710]

      Clinically significant adverse reactions reported in less than 2% of brincidofovir recipients during the safety clinical trials included peripheral edema, decreased appetite, dysgeusia, muscle weakness, and rash (includes generalized rash, maculopapular rash, and pruritic rash).[66710]

      Revision Date: 10/05/2021, 05:54:33 PM

      References

      66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • breast-feeding
      • contraception requirements
      • dehydration
      • diarrhea
      • hepatotoxicity
      • immunosuppression
      • infertility
      • mortality
      • pregnancy
      • pregnancy testing
      • reproductive risk
      • secondary malignancy

      Based on in vitro data, the conversion of brincidofovir to cidofovir and cidofovir diphosphate (the active moiety) may be reduced in patients with acid sphingomyelinase deficiency; however, the clinical relevance of this finding is unknown.[66710]

      Brincidofovir was associated with an increase in mortality during a Phase 3 clinical trial in which the drug was being evaluating for cytomegalovirus prevention. In this trial, patients were randomized to receive either brincidofovir 100 mg twice weekly or a matching placebo for up to 14 weeks. At Week 24, the all-cause mortality in the brincidofovir group was 16% compared to 10% in the placebo group. Brincidofovir is not indicated for use in any disease other than human smallpox. DO NOT exceed the recommended dosing regimen of 1 dose per week for 2 weeks.[66710]

      Data from immune deficient animals suggest the efficacy of brincidofovir may be reduced in patients with immunosuppression.[66710]

      Perform liver function testing (LFT) on all patients before and during treatment with brincidofovir, as clinically appropriate. Brincidofovir has been associated with hepatotoxicity including elevated hepatic enzymes and severe hepatobiliary adverse events (e.g., hyperbilirubinemia, acute hepatitis, hepatic steatosis, veno-occlusive hepatic disease). Most of the elevations in the LFTs are reversible and do not require treatment discontinuation; however, treatment discontinuation should be considered in patients with ALT concentrations that remain persistently higher than 10-times the upper limit of normal (ULN). DO NOT give the second and final dose on Day 8 if ALT elevations are accompanied by clinical signs of hepatic inflammation or increasing direct bilirubin, alkaline phosphatase, or INR.[66710]

      Monitor brincidofovir treated patients for gastrointestinal (GI) adverse events including diarrhea and dehydration; provide supportive care, and if necessary, do not give the second and final dose on Day 8. During the clinical trials, recipients of brincidofovir experienced diarrhea, nausea, vomiting, and abdominal pain; some of these GI adverse events required treatment discontinuation.[66710]

      It is recommended to use an alternative to brincidofovir, if feasible, for the treatment of smallpox during pregnancy. No human pregnancy data are available to evaluate for a drug-associated risk of major birth defects, miscarriages, or other maternal or fetal outcomes. In animal reproductive studies, brincidofovir administered orally to pregnant rats and rabbits during organogenesis resulted in embryotoxicity, decreased fetal survival, and structural malformations at systemic exposures less than the expected human exposure based on the recommended dose.[66710]

      It is recommended that patients with smallpox avoid breast-feeding, as transmission of the variola virus to the breast-fed infant can occur through direct contact with the mother. There are no data on the presence of brincidofovir in human milk, the effects on the breast-fed infant, or on milk production.[66710]

      Based on data from animals, brincidofovir may be associated with reproductive risk. Verify the pregnancy status in females of reproductive potential with pregnancy testing before initiating treatment with brincidofovir. Discuss contraception requirements with the patients. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 months after the last dose. Men are advised to use condoms during treatment and for at least 4 months after the last dose.[66710]

      Based on testicular toxicity data from animal studies, treatment with brincidofovir may result in irreversible infertility in male drug recipients. In monkeys, twice weekly doses of brincidofovir for 9 months caused atrophy of the seminiferous tubules and hypospermia in the epididymides. After 6 months, these findings showed a trend toward recovery. In rats, twice weekly doses for 13 weeks caused decreased testes weight, depletion of spermatogenesis, and hypospermia. Recovery was not observed in rats after a 12-week post-dosing period. Drug exposures in both the monkeys and rats were less than exposure observed in humans following the recommended 200 mg dose.[66710]

      Avoid direct contact with tablets that are broken or crushed or with the oral suspension as brincidofovir is considered a potential human carcinogen. If contact with the skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water. In animal studies, secondary malignancy (i.e., mammary adenocarcinomas and squamous cell carcinomas) was observed in rats with systemic exposures less than the expected human exposure based on the recommended dose.[66710]

      Revision Date: 06/17/2021, 03:39:41 PM

      References

      66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

      Mechanism of Action

      Brincidofovir is an orthopoxvirus nucleotide analog DNA polymerase inhibitor indicated for the treatment of human smallpox disease caused by the variola virus. The drug is a lipid conjugate of cidofovir, an acyclic nucleotide analog of deoxycytidine monophosphate, that was created to increase intracellular delivery of cidofovir. The lipid conjugate mimics lysophosphatidylcholine (a natural lipid) to use the endogenous lipid uptake pathways. Once inside cells, the lipid ester linkage of brincidofovir is cleaved to release cidofovir, which is then phosphorylated to produce the active moiety, cidofovir diphosphate. Cidofovir diphosphate blocks viral replication by selectively inhibiting orthopoxvirus DNA polymerase-mediated synthesis of viral DNA.

       

      Data from cell cultures show the median 50% effective concentration (EC50) of brincidofovir against variola virus to be 0.11 micromolar (range: 0.05 to 0.21 micromolar) across 5 viral strains. The median EC50 against rabbitpox, ectromelia, vaccinia, and monkeypox viruses were 1.1 micromolar (0.5 to 1.89 micromolar), 0.33 micromolar (0.12 to 0.51 micromolar), 0.17 micromolar (0.004 to 1.2 micromolar), and 0.074 micromolar (0.023 to 0.12 micromolar), respectively. There are no known examples of naturally occurring brincidofovir resistant orthopoxviruses; however, brincidofovir treatment-emergent resistance may develop under drug selection. Certain amino acid substitutions in the target viral DNA polymerase protein can confer reductions in brincidofovir antiviral activity. Cross-resistance with tecovirimat is not expected.[66710]

      Revision Date: 06/17/2021, 04:03:06 PM

      References

      66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

      Pharmacokinetics

      Brincidofovir is administered orally. Once in systemic circulation, the drug is more than 99.9% bound to human plasma proteins and has a volume of distribution of 1,230 L; the blood-to-plasma ratio is between 0.48 and 0.61. Brincidofovir is a prodrug that is hydrolyzed intracellularly by acid sphingomyelinase to cidofovir, which is then phosphorylated to cidofovir diphosphate (the active moiety). Brincidofovir is also metabolized by CYP4F2 to form the inactive metabolites CMX103 (3-hydroxyproply ester of cidofovir) and CMX064 (4-(3-propoxy)butanoic acid ester of cidofovir). Radiolabeled doses of brincidofovir showed excretion of the metabolites occurred through the urine (51%) and feces (40%). The apparent clearance is 44.1 L/hour and the mean terminal half-life is 19.3 hours.[66710]

       

      Affected cytochrome P450 isoenzymes and transporters: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP4F2, BCRP, MRP2, BSEP, OATP1B1, OAT1, OAT3

      In vitro studies show brincidofovir inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP4F2. The drug also inhibits the following transporters: breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporting polypeptides 1B1 (OATP1B1), and organic anion transporters 1 and 3 (OAT1 and OAT3). Brincidofovir is a substrate for CYP4F2. Further, data from a drug interaction study suggests brincidofovir is also a substrate for OATP1B1 and OATP1B3, as administration with an OATP1B1/3 inhibitor increased the mean exposure and maximum plasma concentration of brincidofovir by 374% and 269%, respectively.[66710]

      Route-Specific Pharmacokinetics

      Oral Route

      The oral bioavailability of the brincidofovir tablet and suspension are 13.4% and 16.8%, respectively. Under fasted conditions, the time to reach maximum plasma concentration (Tmax) is 3 hours (range: 2 to 8 hours). Administration of the tablet formulation with a low-fat meal (i.e., 400 calories, 25% fat) decreases brincidofovir exposure (AUC) and maximum plasma concentration (Cmax) by 31% and 49%, respectively; however, there are no clinically relevant changes in the intracellular cidofovir diphosphate concentration. The effects of food on the pharmacokinetics of the oral suspension have not been evaluated. In healthy adults, administration of a single dose resulted in a brincidofovir AUC of 3,400 ng x hour/mL and Cmax of 480 ng/mL; the AUC and Cmax of cidofovir diphosphate was 1,200 pg x hour/106 cells and 9.7 pg/106 cells.[66710]

      Special Populations

      Hepatic Impairment

      No clinically relevant differences in the pharmacokinetics of brincidofovir have been observed based on hepatic function.[66710]

      Renal Impairment

      No clinically relevant differences in the pharmacokinetics of brincidofovir have been observed based on renal function, including patients with end-stage renal disease not on dialysis. Exposures (AUC) and maximum plasma concentrations (Cmax) of brincidofovir and cidofovir are comparable in patients requiring hemodialysis whether on- or off-dialysis.[66710]

      Pediatrics

      No clinically relevant differences in the pharmacokinetics of brincidofovir have been observed based on age. Doses of the oral suspension are predicted to provide pediatric patients, including neonates, with exposures comparable to those observed in adults who receive the oral tablets.[66710]

      Geriatric

      No clinically relevant differences in the pharmacokinetics of brincidofovir have been observed based on age.[66710]

      Gender Differences

      No clinically relevant differences in the pharmacokinetics of brincidofovir have been observed based on gender.[66710]

      Ethnic Differences

      No clinically relevant differences in the pharmacokinetics of brincidofovir have been observed based on ethnicity.[66710]

      Revision Date: 06/17/2021, 04:36:42 PM

      References

      66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

      Pregnancy/Breast-feeding

      pregnancy

      It is recommended to use an alternative to brincidofovir, if feasible, for the treatment of smallpox during pregnancy. No human pregnancy data are available to evaluate for a drug-associated risk of major birth defects, miscarriages, or other maternal or fetal outcomes. In animal reproductive studies, brincidofovir administered orally to pregnant rats and rabbits during organogenesis resulted in embryotoxicity, decreased fetal survival, and structural malformations at systemic exposures less than the expected human exposure based on the recommended dose.[66710]

      breast-feeding

      It is recommended that patients with smallpox avoid breast-feeding, as transmission of the variola virus to the breast-fed infant can occur through direct contact with the mother. There are no data on the presence of brincidofovir in human milk, the effects on the breast-fed infant, or on milk production.[66710]

      Revision Date: 06/17/2021, 03:39:41 PM

      References

      66710 - Tembexa (brincidofovir) package insert. Whippany, NJ: Cambrex Whippany, Inc; 2021 Aug.

      Interactions

      No information is available regarding drug interactions associated with Brincidofovir - refer to Brincidofovir prescribing information.
      Revision Date: 06/05/2021, 02:29:00 AM

      References

      Monitoring Parameters

      • LFTs
      • pregnancy testing

      US Drug Names

      • Tembexa
      ;