TEMBEXA (brincidofovir) tablets, 100 mg, for oral use are immediate release film-coated tablets containing the following inactive ingredients: Colloidal Silicon Dioxide, Crospovidone, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinyl Alcohol, Purified Water, Silicified Microcrystalline Cellulose, Talc and Titanium Dioxide.
TEMBEXA (brincidofovir) oral suspension, 10 mg/mL, is an aqueous based, preserved, orally dosed suspension. The inactive ingredients are: Citric Acid Anhydrous, Lemon Lime Flavor, Microcrystalline Cellulose and Carboxymethyl Cellulose Sodium, Purified Water, Simethicone 30% Emulsion, Sodium Benzoate, Sucralose, Trisodium Citrate Anhydrous, and Xanthan Gum.
Brincidofovir is an orthopoxvirus nucleotide analog DNA polymerase inhibitor and a lipid conjugate of the nucleotide analog cidofovir and is indicated for the treatment of human smallpox disease. The full chemical name is: Phosphonic acid, P-[[(1S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1- (hydroxymethyl)ethoxy]methyl]-, mono[3-(hexadecyloxy)propyl] ester.
The molecular formula of brincidofovir is C27H52N3O7P and the relative molecular mass is 561.70.
Indication and usage
TEMBEXA is an orthopoxvirus nucleotide analog DNA polymerase inhibitor and is indicated for the treatment of human smallpox disease in adult and pediatric patients, including neonates.
Limitations of Use:
- TEMBEXA is not indicated for the treatment of diseases other than human smallpox disease.
- The effectiveness of TEMBEXA for treatment of smallpox disease has not been determined in humans because adequate and wellcontrolled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical.
- TEMBEXA efficacy may be reduced in immunocompromised patients based on studies in immune deficient animals.
Dosage and administration
Testing: Before initiation and during treatment with TEMBEXA perform hepatic laboratory testing and pregnancy testing
- Adult and pediatric patients weighing 48 kg or above: 200 mg (two 100 mg tablets or 20 mL oral suspension for patients who cannot swallow tablets) once weekly for 2 doses.
- Adult and pediatric patients weighing 10 kg to less than 48kg: 4 mg/kg oral suspension once weekly for 2 doses.
- Pediatric patients weighing less than 10 kg: 6 mg/kg oral suspension once weekly for 2 doses.
Mechanism of Action
Brincidofovir is a lipid conjugate of cidofovir, an acyclic nucleotide analog of deoxycytidine monophosphate. The lipid conjugate is designed to mimic a natural lipid, lysophosphatidylcholine, and thereby use endogenous lipid uptake pathways. Once inside cells, the lipid ester linkage of brincidofovir is cleaved to liberate cidofovir, which is then phosphorylated to produce the active antiviral, cidofovir diphosphate. Based on biochemical and mechanistic studies using recombinant vaccinia virus E9L DNA polymerase, 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.
Warnings and precautions
Elevations in Hepatic Transaminases and Bilirubin: May cause increases in serum transaminases (ALT or AST) and serum bilirubin. Monitor liver laboratory parameters before and during treatment.
Diarrhea and Other Gastrointestinal Adverse Events: Diarrhea and additional gastrointestinal adverse events including nausea, vomiting, and abdominal pain may occur. Monitor patients, provide supportive care, and if necessary, do not give the second and final dose of TEMBEXA.
Coadministration with Related Products: TEMBEXA should not be coadministered with intravenous cidofovir.
Embryo-fetal Toxicity: May cause fetal harm. Advise individuals of childbearing potential of the potential risk to the fetus and to use effective contraception.
Carcinogenicity: TEMBEXA should be considered a potential human carcinogen. Do not crush or divide TEMBEXA tablets.
Male Infertility: Based on testicular toxicity in animalstudies, TEMBEXA may irreversibly impair fertility in individuals of reproductive potential.
Common adverse reactions (occurring in at least 2% of TEMBEXA-treated subjects) were diarrhea, nausea, vomiting, and abdominal pain.
Concomitant use with OATP1B1 and 1B3 inhibitors increase TEMBEXA exposure which may increase TEMBEXA-associated adverse reactions. Consider alternative medication that are not OATP1B1 or 1B3 inhibitors. If concomitant use is necessary, increase monitoring for adverse reactions associated with TEMBEXA and postpone the dosing of OATP1B1 or 1B3 inhibitors at least 3 hours after TEMBEXA administration.
Use in specific populations
Pregnancy: Based on findings from animal reproduction studies, TEMBEXA may cause fetal harm when administered to pregnant individuals. Use an alternative therapy to treat smallpox during pregnancy, if feasible. There are no available data on the use of brincidofovir in pregnant individuals to evaluate for a drug-associated risk of major birth defects, miscarriage, and other adverse maternal and fetal outcomes.
In animal reproduction studies, oral administration of brincidofovir to pregnant rats and rabbits during the period of organogenesis resulted in embryotoxicity and structural malformations. These effects occurred in animals at systemic exposures less than the expected human exposure based on the recommended dose of TEMBEXA.
Lactation: Because of the potential for variola virus transmission through direct contact with the breastfed infant, breastfeeding is not recommended in patients with smallpox. There are no data on the presence of brincidofovir in human milk, the effects of the drug on the breastfed infant, or on milk production. Brincidofovir is present in animal milk
Females and Males of Reproductive Potential
Advise individuals of childbearing potential to use effective contraception during treatment and for at least 2 months after the last dose of TEMBEXA.
Advise sexually active individuals with partners of childbearing potential to use condoms during treatment and for at least 4 months after last dose of TEMBEXA.
Based on testicular toxicity in animal studies, TEMBEXA may irreversibly impair fertility in individuals of reproductive potential
Pediatric Use: As in adults, the effectiveness of TEMBEXA in smallpox infected pediatric patients, including neonates, is based solely on efficacy studies in animal models of orthopoxvirus disease. The recommended pediatric dosing regimen is expected to produce brincidofovir exposures that are comparable to those in adults based on a population pharmacokinetic modeling and simulation approach. The dosage for pediatric patients is based on weight
Geriatric Use: Of the 392 subjects in the controlled clinical studies, 21% were ≥65 years of age and 1% were ≥75 years of age. The nature and severity of adverse events was comparable between subjects older and younger than 65 years. No alteration of dosing is recommended for patients ≥65 years of age.
Renal Impairment: No dosage adjustment of TEMBEXA is required for patients with mild, moderate, or severe renal impairment or patients with end stage renal disease (ESRD) receiving dialysis.
Hepatic Impairment: Perform hepatic laboratory testing in all patients before starting TEMBEXA and while receiving TEMBEXA, as clinically appropriate. No dosage adjustment is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C)
There is no clinical experience with overdosage of TEMBEXA. In the event of an overdose, monitor patients for adverse effects and provide appropriate supportive care.
Storage and handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Do not divide, break, or crush the tablets. Avoid direct contact with broken or crushed tablets. If contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water.
Avoid direct contact with oral suspension. If contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water