bedaquiline

General

Pronunciation:
bed- ak-wi-leen


Trade Name(s)

  • Sirturo

Ther. Class.

antituberculars

Pharm. Class.

diarylquinolines

Indications

Pulmonary tuberculosis due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid (in combination with ≥3 other drugs).

Action

Inhibits bacterial adenosine 5-triphosphate synthase, which is required for mycobacterial energy production.

Therapeutic Effect(s):

Shortened time to sputum conversion to negativity and resultant decrease in infectiousness and sequelae of tuberculosis.

Pharmacokinetics

Absorption: Absorption following oral administration is doubled by food.

Distribution: Unknown.

Protein Binding: >99.9%.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme; eliminated in feces; negligible renal excretion.

Half-life: 5.5 mo.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown5 hrunknown

Contraindication/Precautions

Contraindicated in:

  • Lactation: Lactation.

Use Cautiously in:

  • Severe hepatic or renal impairment;
  • History of torsades de pointes, congenital long QT syndrome, hypothyroidism, bradyarrhythmias, decompensated HF, hypokalemia, hypomagnesemia, or hypocalcemia (↑ risk of QT interval prolongation and serious arrhythmias);
  • OB:  Safety not established in pregnancy;
  • Pedi:  Children <5 yr (safety and effectiveness not established).

Adverse Reactions/Side Effects

CV: chest pain, QT interval prolongation

Derm: rash

GI: nausea, anorexia, HEPATOTOXICITY

MS: arthralgia

Neuro: headache

Resp: hemoptysis

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • Strong   CYP3A4 inducers, including  rifampin,  rifapentine, and  rifabutin, and moderate   CYP3A4 inducers, including  efavirenz, can ↓ levels and effectiveness; avoid concurrent use.
  • Strong  CYP3A4 inhibitors, including  ketoconazole, can ↑ levels and the risk of toxicity; avoid use for >14 consecutive days, if possible.
  •  Lopinavir/ritonavir  may ↑ levels and risk of toxicity.
  • Other  QT interval prolonging drugs, including  fluoroquinolones  and macrolides , may ↑ risk of serious arrhythmias.
  •  Alcohol  or  hepatotoxic drugs  may ↑ risk of adverse hepatic events.

Route/Dosage

PO (Adults and Children ≥5 yr and ≥30 kg): 400 mg once daily for 2 wk; then 200 mg 3 times weekly (with ≥48 hr between doses) for 22 wk.

PO (Children ≥5 yr and 15–29 kg): 200 mg once daily for 2 wk; then 100 mg 3 times weekly (with ≥48 hr between doses) for 22 wk.

Availability

Tablets: 20 mg, 100 mg

Assessment

  • Assess cardiac status (palpitations, chest pain, syncopal episodes) and vital signs.
  • Obtain an ECG before start of therapy, 2 wk after initiation, during treatment, as clinically indicated, and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs (as applicable). If syncope or palpitations occur, obtain an ECG to detect QTc prolongation. Discontinue therapy if significant ventricular arrhythmia occurs or if QTc interval >500 msec.
  • Assess and monitor for hepatotoxicity (fatigue, anorexia, nausea or vomiting, jaundice, dark urine, liver tenderness and hepatomegaly, stomach pain, fever, weakness, itching, light-colored bowel movements, dark-colored urine, yellowing of skin or white of eyes).

Lab Test Considerations:

Obtain baseline serum potassium, calcium, and magnesium, and monitor throughout treatment. Correct abnormalities.

  • Monitor liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly during therapy, and as needed.  If serum AST and ALT ↑ to 3 times the upper limit of normal (ULN),  repeat test within 48 hr and test for viral hepatitis and other hepatotoxic medications. If symptoms of liver impairment (clinically significant ↑ serum ALT, AST, or bilirubin and/or symptoms of fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) occur, re-evaluate.  If AST and ALT ↑ accompanied by total bilirubin ↑ >2 times ULN, or if AST and ALT ↑ >8 time ULN, or if AST and ALT ↑ >5 times ULN and persist beyond 2 wk,  discontinue bedaquiline.
  • Test patient for viral hepatitis prior to starting therapy.

Implementation

  • Only administer by direct observation therapy.
  • Must be taken in combination with 3–4 other antitubercular drugs.
  • PO Administer with food. Tablets may be split for lower doses.
    • Tablets may be dispersed in water (maximum 5 tablets/5 mL) and administered; dispersed in water and mixed with at least 5 mL of beverage (water, milk products, apple juice, orange juice, cranberry juice, carbonated beverage) or 1 tsp of soft food (yogurt, apple sauce, mashed banana, porridge); or crushed and mixed with soft food or administered through a feeding tube. Administer immediately after mixing. Rinse with beverage or add more soft food to ensure no tablet residue is left in cup. For feeding tube administration, disperse 5 tablets or less in 50 mL noncarbonated water and mix well. Mixture should be white to almost white with visible particles. Administer via NG tube immediately; rinse and flush with 25 mL additional water.
    • Weeks 1–2: Administer 400 mg once daily.
    • Weeks 3–24: Administer two 100 mg tablets 3 times/wk with at least 48 hr between doses for a total of 600 mg/wk.

Patient/Family Teaching

  • Instruct patient to take bedaquiline as directed for the complete 24-wk course of therapy. Do not stop without discussing with health care professional. If a dose is missed during first 2 wk, skip dose and return to usual schedule. If a dose is missed wk 3–24, take missed dose as soon as remembered; then resume 3 times/wk regimen. Emphasize that bedaquiline is always taken with 3–4 other antitubercular medications and these medications should be continued unless discussed with health care professional. Stopping any medications may decrease effectiveness of therapy and may increase risk of mycobacterium resistance and disease becoming untreatable in future. Advise patient to read  Medication Guide  before starting therapy.
  • Caution patient to avoid alcohol during therapy.
  • Advise patient to notify health care professional immediately if signs and symptoms of QT interval prolongation (change in heartbeat, dizziness, fainting) or hepatotoxicity (nausea or vomiting, stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light-colored bowel movements, dark-colored urine, yellowing of skin or white of eyes) occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy.
  • Pedi:  Advise parents to call the doctor if the child has a fast or abnormal heartbeat, dizziness, or passes out.

Evaluation/Desired Outcomes

Shortened time to sputum conversion to negativity and resultant decrease in infectiousness of patient and sequelae of tuberculosis.