The Food and Drug Administration (FDA) has changed the therapeutic equivalence rating for Accord Healthcare’s generic tacrolimus oral capsules from AB to BX making it no longer recommended as automatically substitutable for the brand name drug, Prograf (tacrolimus) oral capsules.

Tacrolimus is indicated for the prevention of organ rejection in adults with allogeneic kidney, liver, heart, or lung transplants, in combination with other immunosuppressants. The FDA’s decision was based on new data from several FDA-funded studies that assessed concerns from the transplant community regarding the substitutability of FDA-approved generic tacrolimus oral capsules that were approved before 2012. 

According to study findings, Accord Healthcare’s tacrolimus oral capsules may deliver elevated peak blood concentrations compared with the brand name drug leading to an increased risk for toxicity. However, no significant differences were observed in the trough blood levels, indicating no increased risk for organ rejection. The FDA is not aware of any postmarketing issues regarding the product’s safety or efficacy.

While the therapeutic equivalence rating for Accord Healthcare’s tacrolimus oral capsules has been changed, the product is still approved and can be prescribed. The change means that the data are insufficient to show that the product provides the same therapeutic effect as Prograf. Patients currently being treated with Accord Healthcare’s tacrolimus oral capsules should not make changes to their treatment without consulting their health care provider. 

Generic tacrolimus oral capsules manufactured by other companies are not impacted by this issue. Other tacrolimus dosage forms are also not affected.

Adverse events or quality problems should be reported to the FDA’s MedWatch program.

The Food and Drug Administration (FDA) has granted Fast Track designation to AntiBKV, an investigational antibody therapeutic that targets BK polyomavirus (BKV) infection in kidney transplant recipients.

BKV infection can pose a significant threat to immunocompromised individuals such as renal transplant patients, resulting in impaired graft function and premature transplant loss.

The Fast Track designation for AntiBKV  was supported by data from a phase 1 study (ClinicalTrials.gov Identifier: NCT05358106) evaluating the safety, tolerability and pharmacokinetics of the neutralizing antibody in healthy participants. No relevant adverse events were reported in the trial, even with the highest doses.

Memo Therapeutics is currently recruiting patients for a phase 2/3 study (ClinicalTrials.gov Identifier: NCT05769582), which will assess the safety and efficacy of AntiBKV in kidney transplant recipients. Patients will be randomly assigned to receive 4 doses of AntiBKV by intravenous infusion every 4 weeks or placebo. The primary endpoint of the trial is the proportion of patients without detectable BK virus in the blood at day 92.

“Receiving Fast Track designation from the FDA is a significant achievement for Memo, validating the potential of AntiBKV and expediting its development,” said Dr Karsten Fischer, Chief Executive Officer of Memo Therapeutics AG. “We believe AntiBKV could be a first- and best-in-class treatment option for kidney transplant patients suffering from BKV infection.”

Based on results from the pivotal trial, the Company anticipates filling a Biologics License Application with the FDA in 2024. “We hope then to be able to offer patients a much needed therapeutic option by 2025 at the latest,” added Fischer.

Novartis is recalling 2 lots of Sandimmune^® Oral Solution (cyclosporine oral solution), 100mg/mL due to crystal formation observed in some bottles that may lead to incorrect dosing. 

Sandimmune Oral Solution is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants, in combination with corticosteroids. It may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressants.

The affected products include lot numbers FX001500 (expiration date 09/2024) and FX001582 (expiration date 09/2024), which were distributed nationwide starting in January 2022 and September 2022, respectively. Sandimmune Oral Solution is packaged in 50mL bottles. 

This most recent issue was identified during an investigation of crystallization in a different lot of Sandimmune Oral Solution. Crystallization can lead to underdosing or overdosing due to nonuniform distribution of cyclosporine in the product. This may result in lower exposure of the drug and reduced efficacy, potentially leading to graft rejection or loss in transplant patients. Higher than intended dosages could lead to possible cyclosporine toxicity. To date, the Company has not received any reports of adverse events related to this recall.

For more information about this recall contact Novartis at 888-669-6682. Adverse events or quality issues should be reported to the FDA’s MedWatch Adverse Event Reporting program, as well as to the Company (https://www.novartis.com/report or usdrugsafety.operations@novartis.com).

Tony Whitehouse, MD, from the Queen Elizabeth Hospital in Birmingham, England, and colleagues examined the efficacy and safety of landiolol in a randomized trial involving 126 adults with tachycardia and established septic shock treated for at least 24 hours with continuous norepinephrine in 40 UK intensive care units. The patients were randomly assigned to usual care (63 patients) or landiolol infusion (63 patients).

On the advice of the independent data monitoring committee, the trial was stopped prematurely as it was considered unlikely to demonstrate benefit and because of potential harm. The researchers found that the mean Sequential Organ Failure Assessment score was 8.8 and 8.1 in the landiolol and standard care groups, respectively (mean difference, 0.75). At day 28 after randomization, mortality was 37.1 and 25.4% in the landiolol and standard care groups, respectively (absolute difference, 11.7%). At 90 days after randomization, mortality was 43.5 and 28.6% in the landiolol and standard care groups, respectively (absolute difference, 15%).

“These results do not support the use of landiolol in the management of patients with tachycardia while receiving norepinephrine undergoing treatment for established septic shock,” the authors write.

Several authors disclosed ties to the biopharmaceutical industry.

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Epiphane Kolla, MD, MPH, from the French National Agency for the Safety of Medicines and Health Products in Paris, and colleagues examined factors associated with severe COVID-19 among solid organ transplant recipients. The analysis included 60,456 participants (median age, 59 years; 63.7% male; 68.6% kidney transplants, 23.9% liver transplants, 8.8% heart transplants, and 4.6% lung transplants).

The researchers found that 12.7% of kidney, 6.4% of liver, 12.9% of heart, and 18.0% of lung transplant recipients were hospitalized for COVID-19. Steroids and mycophenolic acid were associated with a high risk for hospitalization in kidney transplant recipients. Tacrolimus was associated with a decreased risk for hospitalization in liver transplant recipients, while steroids and mycophenolic acid were associated with an increased risk for hospitalizations. Cyclosporine was associated with a decreased risk for hospitalization in heart transplant recipients, while steroids, mycophenolic acid, sirolimus, and everolimus were associated with an increased risk for hospitalization. In lung transplant recipients, only steroids were associated with a high risk for COVID-19 hospitalization.

“Health care professionals should consider these results in treating solid organ transplant recipients with SARS-CoV-2 infection by reducing doses or modifying medications in some cases,” the authors write.

One author disclosed ties to industry.

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The Food and Drug Administration (FDA) has approved Prevymis^® (letermovir) for prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-]).

The approval was supported by data from a phase 3 trial (ClinicalTrials.gov Identifier: NCT03443869) that evaluated the efficacy and safety of letermovir to prevent CMV disease in adult kidney transplant recipients at high risk.

Patients were randomly assigned to receive either letermovir 480mg orally once daily concomitantly with acyclovir (n=289), or valganciclovir 900mg orally once daily concomitantly with a placebo to acyclovir (n=297), within 7 days post-kidney transplant through 28 weeks post-transplant, with follow-up through 52 weeks.

At 52 weeks, treatment with letermovir was found to be effective and noninferior to valganciclovir; 10% of patients in the letermovir arm developed CMV disease vs 12% of patients in the valganciclovir arm (stratum adjusted difference, -1.4 [95% CI, -6.5, 3.8]).

The incidence of CMV syndrome (defined as evidence of CMV in blood by viral isolation, rapid culture, antigenemia, or nucleic acid testing, and ≥2 of the following: 1) fever ≥38°C for at least 2 days, 2) new or increased malaise/fatigue, 3) leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, 4) ≥5% atypical lymphocytes, 5) thrombocytopenia, 6) elevation of ALT or AST to 2x ULN) was 8% and 11% in the letermovir and valganciclovir arms, respectively.

Efficacy was found to be comparable across all subgroups, including those who used or did not use highly cytolytic, antilymphocyte immunotherapy during induction.

Exploratory findings showed that the difference in the incidence of CMV disease through week 28 post-transplant between the letermovir and valganciclovir groups was -1.7% (95% CI, -3.4, 0.1). Through week 28 post-transplant, 5 cases of CMV disease were reported in the valganciclovir group vs no cases in the letermovir group.

The most common adverse reaction reported with letermovir (at a frequency greater than valganciclovir) was diarrhea.

Prevymis is supplied as 240mg and 480mg tablets and in single-dose vials of 240mg/12mL and 480mg/12mL. In the clinical trial, Prevymis was administered either orally or intravenously.

Dosage adjustments are required if Prevymis is coadministered with cyclosporine. Monitoring for CMV reactivation following the completion of Prevymis prophylaxis is recommended.

Prevymis is also indicated for prophylaxis CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant.