brincidofovir (Rx)

1-10%

Diarrhea (8%)

Nausea (5%)

Vomiting (4%)

Serum creatinine elevated (>1.5-3x ULN) (4%)

Abdominal pain (3%)

ALT elevated (>3 to 20x ULN) (2-3%)

Total bilirubin elevated (>1.5 to 10x ULN) (1-3%)

AST elevated (>3 to 20x ULN) (1-2%)

<2%

• General and administration site: Peripheral edema
• Metabolism and nutrition: Decreased appetite
• Musculoskeletal and connective tissue: Muscular weakness
• Nervous system: Dysgeusia
• Skin and subcutaneous tissue: Rash (ie, rash, maculopapular rash, pruritic rash)

Contraindications

None

Cautions

Increased mortality if used for longer duration

• Not indicated for use in diseases other than human smallpox
• Increased mortality observed in a randomized, placebo-controlled phase 3 trial when evaluated for another disease (CMV infection)
• Increased risk in mortality is possible if used for a duration longer than at the recommended dosage on Days 1 and 8

Elevated hepatic transaminases and bilirubin

• Elevations in ALT, AST, and total bilirubin observed
• Perform hepatic laboratory testing in all patients before starting and during treatment, as clinically appropriate
• Monitor patients who develop abnormal test results for development of severe hepatic injury
• Consider discontinuing if ALT levels remain persistently >10x ULN
• Do not give second dose if ALT elevation accompanied by clinical signs and symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR

Diarrhea and GI adverse effects

• Diarrhea common during treatment
• Other GI effects include nausea, vomiting, and abdominal pain
• Monitor for dehydration, and if necessary, do not give the second dose

Embryofetal toxicity, carcinogenicity, and male infertility

• Based on findings from animal reproduction studies, may cause fetal harm when administered to pregnant females
• Considered a potential human carcinogen; mammary adenocarcinomas and squamous cell carcinomas occurred in rats at systemic exposures less than the expected human exposure based on the recommended dose
• Based on testicular toxicity in animal studies, may irreversibly impair fertility in males of reproductive potential

Drug interaction overview

• Cidofovir

  • Do not coadminister with IV cidofovir
  • Brincidofovir, a lipid-linked derivative of cidofovir, is intracellularly converted to cidofovir

• OATP 1B1 and 1B3 inhibitors

  • If possible, consider alternant medications that are not OATP1B1 or 1B3 inhibitors
  • If concomitant use is necessary, increase monitoring for adverse reactions associated with brincidofovir (elevations in transaminases and bilirubin, diarrhea, or other GI adverse events) and postpone dosing of OATP1B1 or 1B3 inhibitors for at least 3 hr after brincidofovir administration

• Vaccines

  • No vaccine-drug interaction studies have been performed in humans; clinical impacts unknown
  • Animal studies suggest coadministration of brincidofovir at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine
  • Brincidofovir may reduce immune response to replication-defective smallpox vaccine (modified vaccinia virus Ankara)

Pregnancy

Based on findings from animal reproduction studies, may cause fetal harm when administered to pregnant females

Perform pregnancy testing in individuals of childbearing potential before initiating

Animal studies

• Administration to pregnant rats and rabbits during 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

Contraception

• Females of childbearing potential: Use effective contraception during treatment and for at least 2 months after the last dose
• Males: Advise sexually active individuals with partners of childbearing potential to use condoms during treatment and for at least 4 months after last dose

Male infertility

• Based on testicular toxicity in animal studies, may irreversibly impair fertility in males of reproductive potential

Lactation

• Breastfeeding is not recommended in patients with smallpox
• Data are not available on the presence in human milk, effects on breastfed infants, or on milk production
• Brincidofovir is present in animal milk

Animal studies

• When administered to lactating rats (4 mg/kg/day or 15 mg/kg twice weekly), brincidofovir was detected in milk, but not in the plasma of nursing pups

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Prodrug; brincidofovir effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which then acts to inhibit viral replication

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

Bioavailability: 16.8% (oral suspension); 13.4% (tablet)

Peak plasma time: 3 hr (brincidofovir); 47 hr (cidofovir diphosphate)

Peak plasma concentration: 480 ng/mL (brincidofovir); 9.7 pg/10⁶ cells (cidofovir diphosphate)

AUC: 3400 ng⋅hr/mL(brincidofovir); 1200 pg⋅hr/10⁶ cells (cidofovir diphosphate)

Effect of food

• AUC decreased by 31%
• Peak plasma concentration decreased by 49%

Distribution

Protein bound: >99.9%

Vd: 1230 L

Blood/plasma ratio: 0.48-0.61

Metabolism

Brincidofovir is a prodrug that is converted intracellularly to cidofovir, which is subsequently phosphorylated to cidofovir diphosphate, the active antiviral moiety, following oral administration

Metabolic pathways: Hydrolysis, CYP4F2

Elimination

Half-life: 19.3 hr (brincidofovir); 113 hr (cidofovir diphosphate)

Clearance: 44.1 L/hr

Excretion: 51% (as metabolites) in urine; 40% (as metabolites) in feces

Preparation

Suspected carcinogen: Avoid direct contact with broken or crushed tablets or oral suspension; if contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water

Oral Administration

Tablets

• May take on an empty stomach or with a low-fat meal (~400 calories, with ~25% of calories from fat)
• Swallow tablets whole; do not crush or divide

Suspension

• Take on an empty stomach
• Shake oral suspension before use
• Use an appropriate oral dosing syringe to correctly measure the total prescribed dose
• Discard unused portion after completion of 2 prescribed doses

• Administration via enteral tube

  • Draw up prescribed dose with calibrated catheter-tip syringe, and use this syringe to administer dose via the enteral tube
  • Refill catheter-tip syringe with 3 mL of water, shake, and administer the contents via the enteral tube
  • Flush with water before and after enteral administration

Storage

Store at 20-25ºC (68-77ºF); excursions permitted from 15-30ºC (59-86ºF)

Do not freeze

Handling

• 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