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.