Updates from FDA
New drugs
RESMETIROM
(Rezdiffra—Madrigal Pharmaceuticals)
Drug class: Rezdiffra is a thyroid hormone receptor-beta (THR-beta) agonist.
Indication: Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Avoid use of Rezdiffra in patients with decompensated cirrhosis.
Recommended dosage and administration: The recommended dosage of Rezdiffra is based on actual body weight. For patients weighing <100 kg, the recommended dosage is 80 mg orally once daily. For patients weighing >100 kg, the recommended dosage is 100 mg orally once daily. Administer Rezdiffra with or without food.
Common adverse effects: The most common adverse reactions with Rezdiffra are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness.
Warnings and precautions: Monitor patients during treatment with Rezdiffra for elevations in liver tests and for the development of liver-related adverse reactions. Discontinue Rezdiffra and continue to monitor the patient if hepatotoxicity is suspected.
Cholelithiasis and cholecystitis were observed more often in patients treated with Rezdiffra. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event such as acute cholecystitis is suspected, interrupt Rezdiffra treatment until the event is resolved. Concomitant use with strong or moderate CYP2C8 inhibitors or OATP1B1 and OATP1B3 inhibitors is not recommended. If used concomitantly with atorvastatin, pravastatin, rosuvastatin, or simvastatin, limit the daily dosage of the statin as recommended. If used concomitantly with CYP2C8 substrates, monitor patients more frequently for substrate-related adverse reactions. Avoid use of Rezdiffra in patients with moderate to severe hepatic impairment.
APROCITENTAN
(Tryvio—Idorsia)
Drug class: Tryvio is an endothelin receptor antagonist.
Indication: Tryvio is indicated for the treatment of hypertension in combination with other antihypertensive drugs, to lower BP in adult patients who are not adequately controlled on other drugs. Lowering BP reduces the risk of fatal and nonfatal CV events, primarily strokes and myocardial infarctions.
Recommended dosage and administration: The recommended dosage of Tryvio is 12.5 mg orally once daily with or without food.
Common adverse effects: The most common adverse reactions are edema and anemia.
Boxed warning: Tryvio can cause major birth defects if used by pregnant patients and is contraindicated during pregnancy. Exclude pregnancy prior to initiation of treatment, monthly during treatment, and for 1 month after stopping Tryvio. Use acceptable contraception prior to initiation of treatment, during treatment, and for 1 month after stopping Tryvio. Tryvio is only available through a restricted distribution program called the Tryvio REMS.
Other warnings and precautions: Tryvio is contraindicated in pregnancy and hypersensitivity. Endothelin receptor antagonists can cause hepatotoxicity and liver failure. Measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and repeat periodically during treatment and as clinically indicated. Fluid retention may require intervention. Decreases in hemoglobin and decreased sperm counts may occur. Patients should be advised not to breastfeed.
GIVINOSTAT
(Duvyzat—Italfarmaco)
Drug class: Duvyzat is a histone deacetylase inhibitor.
Indication: Duvyzat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years and older.
Recommended dosage and administration: Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of Duvyzat. Do not initiate Duvyzat in patients with a platelet count <150 x 109/L.
The dose of Duvyzat is based on the patient’s body weight. Administer orally twice daily with food. Dosage modifications may be needed for decreased platelet counts, diarrhea, increased triglycerides or QTc prolongation.
Common adverse effects: The most common adverse reactions are diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, and pyrexia.
Warnings and precautions: Duvyzat can cause dose-related thrombocytopenia and other signs of myelosuppression, including anemia and neutropenia. Monitor platelets, as dosage adjustment or discontinuation may be needed.
An increase in triglycerides can occur and dosage modification or discontinuation may be needed. Adjust dosage if moderate or severe diarrhea occurs. Antiemetics or antidiarrheal medications may be considered during treatment with Duvyzat. Discontinue if the symptoms persist. Avoid use of Duvyzat in patients who are at an increased risk for ventricular arrhythmias.
Closely monitor when Duvyzat is used in combination with an oral CYP3A4 sensitive substrate or a sensitive substrate of the OCT2 transporter, for which a small change in substrate plasma concentration may lead to serious toxicities.
Avoid concomitant use with other drugs that prolong the QTc interval and monitor ECG if concomitant use cannot be avoided. Based on animal data, use in pregnancy may cause fetal harm. In hepatic impairment, exposure to givinostat is expected to be increased.
New dosage forms
RILPIVIRINE
(Edurant PED—Janssen)
Drug class: Edurant PED is an HIV-1 specific, non-nucleoside reverse transcriptase inhibitor (NNRTI).
Indication: Edurant PED is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naive patients 2 years and older and weighing at least 14 kg with HIV-1 RNA ≥100,000 copies/mL.
Recommended dosage and administration: The recommended dosage of Edurant PED is based on body weight for pediatric patients 2 years and older and weighing ≥14 kg to ≤25 kg. Edurant PED tablets must be dispersed in drinking water and taken with a meal.
Common adverse effects: The most common adverse reactions to Edurant PED were depressive disorders, headache, insomnia, and rash.
Warnings and precautions: Coadministration of Edurant PED is contraindicated with drugs for which significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance.
Severe skin and hypersensitivity reactions have been reported. Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develop, and closely monitor clinical status including hepatic serum biochemistries. Hepatic adverse events have been reported in patients with underlying liver disease, including hepatitis B or C virus coinfection, or in patients with elevated baseline transaminases. Monitor liver function tests before and during treatment with Edurant PED in patients with underlying hepatic disease or marked elevations in transaminase.
Also consider monitoring liver functions tests in patients without pre-existing hepatic dysfunction or other risk factors. Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. Patients may develop immune reconstitution syndrome. Consider alternatives to Edurant PED when it would be coadministered with drugs with a known risk of torsade de pointes. Edurant PED should not be used in combination with NNRTIs.
Coadministration with drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine. Coadministration with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine. Total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period.
New combinations
MACITENTAN AND TADALAFIL
(Opsynvi—Actelion)
Drug class: Opsynvi is a combination of macitentan, an endothelin receptor antagonist, and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor.
Indication: Opsynvi is indicated for chronic treatment of pulmonary arterial hypertension in adult patients of WHO functional class II–III. Macitentan reduces the risk of clinical worsening events and hospitalization. Tadalafil improves exercise ability.
Recommended dosage and administration: The recommended dosage is one 10 mg/20 mg or 10 mg/40 mg tablet taken orally once daily with or without food.
Common adverse effects: The most common adverse reactions are edema, anemia, and headache/migraine.
Other warnings and precautions: Opsynvi is contraindicated in pregnancy, hypersensitivity, concomitant organic nitrates, and concomitant guanylate cyclase stimulators.
Endothelin receptor antagonists cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated. Vasodilatory effects may cause hypotension in susceptible patients. Decreases in hemoglobin may occur. Worsening pulmonary veno-occlusive disease may occur so if pulmonary edema is confirmed, discontinue treatment.
Sudden loss of vision could be a sign of nonarteritic ischemic optic neuropathy and may be permanent. Cases of sudden decrease or loss of hearing have been reported in patients taking tadalafil. Fluid retention may require intervention. Avoid use with other PDE5 inhbitors. Decreases in sperm count have been observed in patients taking endothelin receptor antagonists. Advise patients to seek emergency treatment if an erection lasts more than 4 hours.
Avoid concomitant use with strong CYP3A4 inducers and inhibitors and moderate dual or combined CYP3A4 and CYP2C9 inhibitors. Advise patients not to breastfeed during treatment. Avoid use in patients with creatinine clearance of 15 mL/min to 29 mL/min. Do not initiate in patients with severe hepatic impairment. ■