FDA Approves Once-Weekly Dosing And Revised Safety Information For Kyprolis

The U.S. Food and Drug Administration (FDA) has approved the addition of a once-weekly dosing regimen to the official prescribing information for Kyprolis.
In addition, the FDA approved revisions in the prescribing information related to two safety issues: the risk of heart-related side effects due to Kyprolis, and the risk of birth defects or miscarriage in women taking or exposed to Kyprolis during pregnancy.
The once-weekly dosing of Kyprolis is approved for use in combination with dexamethasone (Decadron) in multiple myeloma patients who have relapsed after one to three prior lines of therapy.
Previously, the only dosing regimens approved by the FDA were twice-weekly. The twice-weekly dosing is still included in the prescribing information, or "label," as it often is called. The twice-weekly dosing is listed as an option for Kyprolis in combination with Revlimid (lenalidomide) and dexamethasone, or for Kyprolis administered by itself, for the treatment of relapsed myeloma patients.
Kyprolis is not approved by the FDA for use in newly diagnosed myeloma patients, either as a single agent or in combination with other drugs.
The revisions to the heart-related safety warnings in the Kyprolis label mainly involve shifting important safety-related trial results out of a key summary area of the label to less frequently read parts of the label. Although some new information has been added to the key summary area, the label changes as a whole are likely to diminish a bit the perceived risk of the serious, sometimes fatal, heart-related side effects Kyprolis can cause.
The changes in the prescribing information related to the risk of birth defects and miscarriage, on the other hand, are more substantial, involving additional information and more detailed warnings. Thus, the net effect of these changes is likely to be heightened, rather than diminished, awareness of this class of potential Kyprolis side effects.
Amgen, the company that markets Kyprolis globally, is hoping the latest changes in the drug’s U.S. label will help reinvigorate sales of the myeloma therapy. Competition from newer myeloma drugs, concerns about Kyprolis’s safety, and the drug’s twice weekly dosing have caused U.S. prescribing of Kyprolis to be essentially unchanged the past four quarters (2017:Q3-2018:Q2) compared to the previous four quarters (2016:Q3-2017:Q2). Overseas sales of Kyprolis also have been flat the past two quarters (2018:Q1-Q2) once one adjusts for clinical trial-related purchases.
Significance Of A Drug’s Prescribing Information
A drug's prescribing information, or “label,” is a document that describes the drug’s approved uses, dosing, efficacy, safety, and other pertinent information. In the United States and other countries, the contents of the prescribing information dictate what companies that sell a drug can legally say about it in sales discussions and in advertising.
In addition, in most countries, “off-label” prescribing of a drug is not permitted. When that’s the case, it means, for example, that a myeloma drug cannot be used to treat newly diagnosed patients if it is only approved for use in relapsed patients.
“Off-label” prescribing is permitted in the United States and is widely practiced. The language of a drug’s prescribing information still has an effect on its use, however, partly through its effect on marketing and physician perceptions, and partly through its influence on insurance coverage.
Once-Weekly Dosing Regimen
The newly approved once-weekly dosing of Kyprolis is for a single dose of the drug at 70 mg/m2 once per week for three weeks out of a four-week (28-day) cycle.
The once-a-week dosing is for use when the drug is combined with dexamethasone for the treatment of myeloma patients with one to three prior lines of therapy. The approved dexamethasone dose for this combination is 40 mg once each week for every week of the four-week cycle.
The Kyprolis dose used during the once-weekly dosing regimen, 70 mg/m2, is higher than the dose originally approved for the drug. The original recommended Kyprolis dosing was twice per week at 20 mg/m2 for the first cycle of therapy, and then twice per week at a dose of 27 mg/m2, if tolerated, for all subsequent cycles.
Since the drug's initial approval, additional dosing regimens have been tested and eventually approved by the FDA. However, all approved dosing regimens had been for twice-a-week administration until the approval of the new once-weekly dosing.
Approval Based On Results Of “ARROW” Clinical Trial
The FDA approval of the once-weekly regimen is based on results of the Phase 3 “ARROW” clinical trial. It compared two different Kyprolis-dexamethasone treatment regimens in myeloma patients who have had two or three prior therapies.
One group of patients in the trial got Kyprolis once a week at a high (70 mg/m2) dose, while a second group of patients got Kyprolis twice a week at a standard (27 mg/m2) dose at each infusion.
More patients in the once-weekly, higher-dose group responded to treatment, and the once-weekly patients also had longer remissions.
More details about the results of the ARROW trial can be found in the Beacon’s recent news article about it.
Updated Heart-Related Safety Information
Section 5.1 of the newly approved prescribing information for Kyprolis contains the following important summary of the heart-related risk associated with the drug:
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function. In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% ...
The last sentence in the above paragraph – the with the "8%" statistics – is new. Previously, instead of the new sentence, there were two sentences with safety information from key Kyprolis clinical trials. Those sentences were as follows:
In a randomized, open-label, multicenter trial evaluating Kyprolis in combination with lenalidomide and dexamethasone (KRd) versus / dexamethasone (Rd), the incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm. In a randomized, open-label, multicenter trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd), the incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm ...
In the recently updated prescribing information, the information in these two sentences is still present, but it is relegated to less frequently read sections of the label summarizing results of specific clinical trials.
Thus, the fact that patients in a key trial were almost four times as likely to experience heart failure if taking Kyprolis-dexamethasone instead of Velcade-dexamethasone (11% versus 3%) is no longer in the heart-related safety summary of the label. Instead, it is at the very end of a paragraph in the label listing many safety-related results of the Kyprolis-dexamethasone versus Velcade-dexamethasone head-to-head trial.
As a result, the net effect of the label changes is likely to be a diminished recognition of the heart-related side effects that can occur when patients are treated with Kyprolis.
Updated Fetal Safety Information
The safety information in the recently revised Kyprolis label also includes changes related to the risk of birth defects or miscarriage associated with Kyprolis. The new summary of "embryo-fetal toxicity" information (section 5.16 of the label) reads as follows:
Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m 2 based on body surface area caused post-implantation loss and a decrease in fetal weight ...
Females of reproductive potential should avoid becoming pregnant while being treated with Kyprolis. Advise females of reproductive potential that they must use contraception during treatment with Kyprolis and for 6 months following the final dose. Advise males with female sexual partners of reproductive potential that they must use contraception during treatment with Kyprolis and for 3 months following the final dose. If Kyprolis is used during pregnancy or if the patient becomes pregnant during Kyprolis treatment, the patient should be apprised of the potential risk to the fetus ...
This information is noticeably more extensive and more detailed than the language in the previously approved Kyprolis label, which was as follows:
Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Kyprolis.
Advise females of reproductive potential to avoid becoming pregnant while being treated with Kyprolis. Advise males of reproductive potential to avoid fathering a child while being treated with Kyprolis. Advise women who use Kyprolis during pregnancy or become pregnant during treatment with Kyprolis of the potential hazard to the fetus ...
Additional Information
For further information related to the new dosing and revised safety information in the Kyprolis label, see the updated prescribing information for the drug, the previous prescribing information, and the Amgen press release related to the prescribing information changes.
Related Articles:
- Once-Weekly High-Dose Kyprolis Yields Deeper Responses And Longer Remissions Than Twice-Weekly Kyprolis (ASCO & EHA 2018)
- ASCO 2018 Update – Expert Perspectives On The Key Multiple Myeloma-Related Oral Presentations
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Common Measures Of Heart And Blood Vessel Health May Predict Risk Of Heart-Related Side Effects During Treatment With Kyprolis
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
Thanks for the interesting article about Kyprolis. Just having to go for an infusion once a week would be better for quality of life, even though the dosage is more than twice the amount (70 cf. to 27 cf). Would one of the criteria of a patient having 1 - 3 prior lines of therapy include that person having first tried Velcade?