Version May 2024
An increased incidence of mortality was seen in brincidofovir-treated subjects compared to placebo-treated subjects in a 24-week clinical trial when brincidofovir was evaluated in another disease.
Nonvariola orthopoxvirus infection (eg, mpox [monkeypox]) (alternative agent) (off-label use): Note: Reserve use for patients with or at risk for severe disease. Use in combination with tecovirimat; only use as monotherapy in patients who have a contraindication to tecovirimat use (Ref).
Oral: Limited data available: 200 mg once weekly for 2 doses (Ref).
Smallpox: Oral:
10 to <48 kg: 4 mg/kg once weekly for 2 doses (days 1 and 8).
≥48 kg: 200 mg once weekly for 2 doses (days 1 and 8).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
Hepatic impairment prior to treatment: Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.
Hepatic impairment during treatment: Consider discontinuation if ALT levels remain persistently >10 × ULN. Do not administer second (final) dose on day 8 if ALT elevation is accompanied by clinical signs and symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR.
GI adverse effects: If severe GI adverse events occur, including diarrhea and dehydration, consider discontinuing therapy.
Refer to adult dosing.
(For additional information see "Brincidofovir (United States: Availability via FDA emergency investigational drug [e-IND] protocol): Pediatric drug information")
Smallpox (variola virus infection): Infants, Children, and Adolescents:
<10 kg: Oral suspension: Oral: 6 mg/kg once weekly for 2 doses (on day 1 and day 8).
10 to <48 kg: Oral suspension: Oral: 4 mg/kg once weekly for 2 doses (on day 1 and day 8).
≥48 kg: Oral suspension or tablet: Oral: 200 mg once weekly for 2 doses (on day 1 and day 8).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents: Oral:
Altered kidney impairment: No dosage adjustment needed for any degree of renal impairment (including end-stage renal disease).
Hemodialysis: No dosage adjustment needed.
Hepatic impairment prior to initiation (baseline): Infants, Children, and Adolescents: Oral:
Mild, moderate, or severe impairment: No dosage adjustment necessary.
Hepatotoxicity during treatment:
ALT persistently >10 × ULN: Consider not administering second dose.
ALT elevation with increased direct bilirubin, alkaline phosphatase, INR, or clinical signs of liver inflammation: Discontinue; do not administer second dose.
GI effects, including abdominal pain, diarrhea, nausea, and vomiting, sometimes requiring discontinuation of therapy, have been reported. GI effects can be severe; may resolve with discontinuation of therapy.
Onset: Varied; has been reported within the first 2 weeks of therapy.
Increased serum alanine aminotransferase (ALT), increased serum aspartate aminotransferase (AST), and increased serum bilirubin have been reported, including cases of concurrent increases in ALT and bilirubin. Severe hepatic events (eg, hepatic sinusoidal obstruction syndrome, hepatitis (acute), hyperbilirubinemia, liver steatosis) have been reported rarely. Hepatotoxicity is generally reversible and treatment discontinuation may or may not be required depending on severity of hepatotoxicity.
Onset: Varied; has been reported within the first 2 weeks of therapy.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Cardiovascular: Peripheral edema (<2%)
Dermatologic: Skin rash (<2%, including maculopapular rash and pruritic rash)
Gastrointestinal: Abdominal pain (3%) (table 1), decreased appetite (<2%), diarrhea (8%) (table 2), dysgeusia (<2%), nausea (5%), vomiting (4%) (table 3)
|
Drug (Brincidofovir) |
Placebo |
Population |
Number of Patients (Brincidofovir) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
3% |
2% |
Adults |
392 |
208 |
|
Drug (Brincidofovir) |
Placebo |
Population |
Number of Patients (Brincidofovir) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
8% |
3% |
Adults |
392 |
208 |
|
Drug (Brincidofovir) |
Placebo |
Population |
Number of Patients (Brincidofovir) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
4% |
1% |
Adults |
392 |
208 |
Hepatic: Increased serum alanine aminotransferase (grades 2/3: 2% to 7%) (table 4), increased serum aspartate aminotransferase (grades 2/3: 1% to 2%) (table 5), increased serum bilirubin (grades 2/3: 1% to 3%)
|
Drug (Brincidofovir) |
Placebo |
Population |
Number of Patients (Brincidofovir) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
7% |
N/A |
Adults |
392 |
N/A |
>3 x ULN during the first 2 weeks of therapy |
|
Grade 2: 3% |
2% |
Adults |
392 |
208 |
>3 to 5 x ULN |
|
Grade 3: 2% |
1% |
Adults |
392 |
208 |
>5 to 20 x ULN |
|
Drug (Brincidofovir) |
Placebo |
Population |
Number of Patients (Brincidofovir) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
Grade 2: 2% |
1% |
Adults |
392 |
208 |
>3 to 5 x ULN |
|
Grade 3: 1% |
0% |
Adults |
392 |
208 |
>5 to 20 x ULN |
Nervous system: Myasthenia (<2%)
<1%:
Hepatic: Hepatic sinusoidal obstruction syndrome, hepatitis (acute), hyperbilirubinemia, liver steatosis
Renal: Increased serum creatinine
Frequency not defined: Gastrointestinal: Dyspepsia, enteritis
There are no contraindications listed in the manufacturer's labeling.
Concurrent drug therapy issues:
• Cidofovir: Do not coadminister with IV cidofovir; brincidofovir is a lipid-linked derivative of cidofovir that is intracellularly converted to cidofovir.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Oral:
Tembexa: 10 mg/mL (65 mL) [contains sodium benzoate; lemon-lime flavor]
Tablet, Oral:
Tembexa: 100 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carm) aluminum lake]
No
Suspension (Tembexa Oral)
10 mg/mL (per mL): $0.00
Tablets (Tembexa Oral)
100 mg (per each): $0.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Tembexa is not available for general public use. Supplies are owned by the US federal government. For treatment of smallpox, additional information is available at https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/smallpox-preparedness-and-response-updates-fda. For treatment of mpox (monkeypox), a single-patient investigational new drug request may be submitted at https://erequest.navigator.reaganudall.org/#/home/presignup?emergency=monkeypox.
Note: Due to carcinogenic potential, avoid direct contact with broken or crushed tablets and oral suspension. If contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water.
Oral:
Tablets: Administer on an empty stomach or with a low-fat meal. Swallow tablet whole; do not crush or divide.
Suspension: Administer on an empty stomach. Shake oral suspension before use. For patients who cannot swallow, oral suspension can be administered by enteral tube (following administration, refill the catheter-tip syringe with 3 mL of water, shake, and administer contents via tube to ensure full dose is administered); flush tube with water before and after enteral administration.
Oral:
Note: Due to carcinogenic potential, avoid direct contact with broken or crushed tablets and oral suspension. If contact with skin or mucous membranes occur, wash thoroughly with soap and water, and rinse eyes thoroughly with water.
Tablets: Administer on empty stomach or with low-fat meal (~400 calories with ~25% calories from fat). Swallow tablets whole; do not crush or divide.
Suspension: Administer on empty stomach. Shake well. Use oral syringe to accurately measure prescribed dose. Discard unused portion after 2 doses.
Enteral feeding tube: Flush enteral feeding tube with water prior to administration; may administer via tube using a catheter tip syringe, then refill syringe with 3 mL of water, shake, and administer to ensure all drug administered. Flush with water again following administration.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Brincidofovir may cause carcinogenicity, reproductive toxicity, and has a structural and/or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Smallpox: Treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates.
Limitations of use: Not indicated for the treatment of diseases other than human smallpox disease. Effectiveness for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug's efficacy is not ethical. Efficacy may be reduced in immunocompromised patients based on studies in immune deficient animals.
Nonvariola orthopoxvirus infection (eg, mpox [monkeypox])
Brincidofovir may be confused with cidofovir.
Substrate of OATP1B1/1B3 (SLCO1B1/1B3); Inhibits MRP2
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Asciminib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Risk C: Monitor therapy
Cidofovir: Brincidofovir may enhance the adverse/toxic effect of Cidofovir. Risk X: Avoid combination
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Corticosteroids (Systemic): May diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Immunosuppressants (Cytotoxic Chemotherapy): May diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Immunosuppressants (Miscellaneous Oncologic Agents): May diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Immunosuppressants (Therapeutic Immunosuppressant Agents): May diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Leniolisib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Methotrexate: May diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors: May increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification
Pretomanid: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Smallpox and Monkeypox Vaccine (Live): Brincidofovir may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Risk C: Monitor therapy
Smallpox Vaccine Live: Brincidofovir may diminish the therapeutic effect of Smallpox Vaccine Live. Risk C: Monitor therapy
Trofinetide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider therapy modification
Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Food decreases the brincidofovir oral tablet AUC and Cmax by 31% and 49%, respectively. The effect of food on brincidofovir oral suspension has not been studied. Management: Take brincidofovir tablets on an empty stomach or with a low-fat meal. Take brincidofovir oral suspension on an empty stomach.
Pregnancy testing is recommended prior to use in patients who may become pregnant.
Patients who may become pregnant should use effective contraception during therapy and for at least 2 months after the last brincidofovir dose. Patients with partners who may become pregnant should use condoms during therapy and for at least 4 months after the last dose of brincidofovir.
Maternal toxicity and adverse pregnancy outcomes were observed in animal reproduction studies with doses less than the expected human exposure. Based on data from animal reproduction studies, in utero exposure to brincidofovir may cause fetal harm.
Smallpox infection during pregnancy is associated with adverse events. Contracting smallpox while pregnant increases the risk of severe maternal disease (including hemorrhagic smallpox) and death; the fatality rate in unvaccinated pregnant patients can be up to 70% (CDC [Petersen 2015]).
Alternative therapy to treat smallpox infection in pregnant patients should be used if available. Brincidofovir is not recommended as an alternative therapy to treat patients with mpox (monkeypox) during the first trimester (CDC 2022a).
It is not known if brincidofovir is present in breast milk.
Lactating patients with smallpox infection have the potential to transmit the virus via direct contact to a breastfed infant. Therefore, breastfeeding is not recommended. In addition, brincidofovir is not recommended as an alternative therapy to treat lactating patients with mpox (monkeypox) (CDC 2022a).
Tablet: Take on an empty stomach or with a low-fat meal (~400 calories, with ~25% of calories from fat).
Oral suspension: Take on an empty stomach.
LFTs (at baseline and during therapy as clinically appropriate); GI adverse effects (eg, diarrhea, dehydration); pregnancy testing prior to initiation in individuals of childbearing potential.
Brincidofovir is a lipid conjugate that is converted intracellularly to cidofovir, which is subsequently phosphorylated to an active metabolite, cidofovir diphosphate. Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis
Absorption: Administration of oral tablet with a low-fat meal resulted in decreases in AUC (31%) and Cmax (49%) relative to administration under fasted conditions. The effect of food on oral suspension absorption was not studied.
Distribution: Vd: 1,230 L.
Protein binding: >99.9 % bound to human plasma proteins.
Metabolism: Hydrolyzed to cidofovir, then phosphorylated to form cidofovir diphosphate (active metabolite).
Bioavailability: Tablet: 13.4%; oral suspension: 16.8%.
Half-life elimination: Brincidofovir: 19.3 hours; cidofovir diphosphate (active metabolite): 113 hours.
Time to peak: Brincidofovir: 3 hours (range: 2 to 8 hours); cidofovir diphosphate (active metabolite): 47 hours (range: 23 to 311 hours).
Excretion: Urine (51%, as metabolites); feces (40%, as metabolites).
Pediatric: Recommended pediatric dosing regimen is expected to result in similar exposures to adults, based on population pharmacokinetic modeling and simulation.
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