Kovaltry

KOVALTRY, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for:

• On-demand treatment and cfont rol of bleeding episodes
• Perioperative management of bleeding
• Routine prophylaxis to reduce the frequency of bleeding episodes

KOVALTRY is not indicated for the treatment of von Willebrand disease.

Mechanism Of Action

KOVALTRY temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

Pharmacodynamics

Plasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT.

Pharmacokinetics

The pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of KOVALTRY are presented in Table 4 (one-stage clotting assay) and Table 5 (chromogenic substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 subjects following 6 to 12 months of prophylaxis).

Table 4: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), One-Stage Clotting Assay

The PK parameters of KOVALTRY for 8 subjects in age group 0 to < 6 years and 10 subjects in age group 6 to < 12 years are shown in Table 5. In general, children < 12 years of age demonstrated lower plasma concentrations when compared to PTP children ≥ 12 years of age.

Table 5: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), Chromogenic Substrate Assay

Incremental Recovery analysis after 6 months of prophylactic treatment yielded comparable results with incremental recovery after the first dose (see Table 6).

Table 6: Incremental Recovery in PTPs

Clinical Studies

The safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A ( < 1% Factor VIII) was evaluated in three international (including U.S.) clinical studies. Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤ 1%) and no history of Factor VIII inhibitors were eligible for the trials.

Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥ 12 years to < 65 years) PTPs ( ≥ 150 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week in which the dosing frequency was assigned by the investigator based on the subject's individual requirements.

Study 2: a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age ≥ 12 years to < 65 years) PTPs ( ≥ 150 EDs) evaluated the superiority of prophylaxis over on-demand treatment with KOVALTRY over a one-year treatment period (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 30 IU/kg two times per week or 30 to 40 IU/kg three times per week and the treatment group was assigned by randomization.

Study 3: a multi-center, open-label, uncontrolled study in pediatric (age ≤ 12 years) PTPs ( ≥ 50 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 8). The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours following previous prophylaxis infusion. ABR during prophylaxis, independent of time of infusion, was also analyzed. The prophylactic regimen was 25 to 50 IU/kg at frequencies of either 2 times per week, 3 times per week or every other day and could be adapted to individual subject's need by the investigator.

In all studies, treatments of breakthrough bleeds and perioperative management were at the investigator's discretion based on standard of care.

A total of 204 subjects were enrolled in the completed clinical trials, 153 subjects ≥ 12 years of age and 51 subjects < 12 years of age. One hundred-forty (140) subjects were treated for at least 12 months, and 43 of these subjects were treated for 24 months.

Table 7: Overview of Study 1 (Prophylaxis Treatment Phase) and Study 2

Table 8: Overview of Study 3

On-demand Treatment And Control Of Bleeding Episodes

A total of 1892 bleeding episodes in 110 subjects were treated with KOVALTRY in Study 1 and Study 2 (see Table 9). The majority of the bleeding episodes were spontaneous, localized in joints, and mild to moderate in severity.

In Study 1 and Study 2, the treatment responses in a total of 1859 treated bleeds were assessed by the subjects compared to their previous treatment experience.

Table 9: On-demand Treatment and Control of Bleeding Episodes in Adolescents and Adults Treated with KOVALTRY

A total of 97 bleeding episodes in 28 pediatric subjects were treated with KOVALTRY. Majority (96.9%) of the bleeds were mild to moderate in severity. Fifty-nine (72.8%) bleeds were trauma related. During the 6 month treatment period, the median dose of KOVALTRY for the treatment of breakthrough bleeds was 36.94 IU/kg per infusion (range 20.8–71.6 IU/kg).

Assessment of response to treatment of bleeds was as follows:

Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no additional infusion administered; Good: Definite pain relief and/or improvement in signs of bleeding but possibly requiring more than one infusion for complete resolution; Moderate: Probable or slight improvement in signs of bleeding with at least one additional infusion for complete resolution; Poor: No improvement at all between infusions or condition worsens.

The hemostatic efficacy in on-demand treatment of bleeds was assessed as either “good” or “excellent” in 90.1% of cases (97.8% in the younger age group and 81.0% in the older age group). Majority of bleeds (89.7%) were successfully treated with ≤ 2 infusions. Response to treatment was similar for children aged 0 to < 6 compared to 6 to 12 years of age (see Table 10).

Table 10: On-demand Treatment and Control of Bleeding Episodes in Children Treated with KOVALTRY

Perioperative Management

A total of 14 major and 46 minor surgeries were performed in 44 previously treated subjects (43 adults and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY dose administered was 2500 IU (108.7 IU/kg).

The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood loss similar to the non-hemophilic patient).

Routine Prophylaxis

A total of 140 subjects were treated with KOVALTRY for at least 12 months with median (range) 157 EDs (25-178) in Study 1, [305 EDs (25-355) inclusive of extension phase], and 153 EDs (103-187) in Study 2 (see Table 11). In both studies, subjects in the Intent-to-Treat (ITT) population received 95% to 100% of the prescribed number of prophylaxis infusions.

Table 11: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment Exposure

The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, respectively. In Study 2, comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference (p < 0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as compared to subjects receiving prophylaxis (2 bleeds per year). In Study 2, mean ABR in subjects receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis.

Table 12: ABR in Adolescent and Adult Subjects

The ABR for subjects (n=21) receiving on-demand therapy in Study 2 [median (IQR Q1; Q3)] for all bleeds: 60 (41.7; 76.3); spontaneous bleeds: 42.1 (24.3; 61.3); joint bleeds: 38.8 (24.3; 60.0).

A total of 51 PTPs were treated with KOVALTRY for at least 6 months with median (range) 73 EDs (37-103) (see Table 13). Subjects received > 95% of the prescribed number of prophylaxis infusions.

Table 13: Prophylaxis Treatment with KOVALTRY in Children 12 Years of Age or Younger – Treatment Exposure

In children 12 years of age and younger (n=51), the median (IQR Q1; Q3) ABR within 48 hours after prophylactic infusion was 0 (0; 4) for all bleeds, and 0 (0; 0) for spontaneous and joint bleeds. The median (IQR Q1; Q3) ABR during prophylactic treatment independent of time of infusion was 1.9 (0; 6) for all bleeds, 0 (0; 0) for spontaneous bleeds and 0 (0; 2) for joint bleeds. The mean ABR within 48 hours after prophylactic infusion was 2.04 ± 2.91. The mean ABR at any time during the prophylaxis regimen was 3.75 ± 4.98.

In both age groups (0 to < 6 years and 6 to 12 years), the ABR for spontaneous bleeds and joint bleeds within 48 hours after prophylactic treatment [ABR median (IQR Q1; Q3)] was 0 (0; 0). The median (IQR Q1; Q3) annualized number of spontaneous bleeds during prophylactic treatment independent of time of infusion was 0 (0; 0). The median (IQR Q1; Q3) annualized number of joint bleeds during prophylactic treatment independent of time of infusion was 0 (0; 1.9) in 0 to < 6 years age group and 0 (0; 2.1) in 6 to 12 years age group (see Table 14).

The majority (32/53) of bleeds that occurred within 48 hours after a previous prophylaxis infusion were trauma related. Twenty-three (45.1%) subjects reported no bleeds during the six-month prophylaxis period.

Table 14: ABR in Children 12 Years of Age or Younger

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© Kovaltry Patient Information is supplied by Cerner Multum, Inc. and Kovaltry Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Kovaltry is a prescription medicine used to replace clotting factor (Factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally. 

Your healthcare provider may give you Kovaltry when you have surgery. Kovaltry can reduce the number of bleeding episodes in adults and children with hemophilia A when used regularly (prophylaxis).

Kovaltry is not used to treat von Willebrand Disease.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Bayer HealthCare LLC - Consumer Care

No drug interactions have been reported by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

All products:

• Irritation where the shot is given.
• Headache.

Nuwiq:

• Back pain.
• Dry mouth.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

All products:

• If this medicine is given at home, store unopened containers at room temperature or in the refrigerator. Do not freeze.
• Store in original container.
• If stored at room temperature, make a note of the date it was placed at room temperature.
• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Kovaltry and Novoeight:

• If stored at room temperature, throw away any unused vials after 12 months or after the expiration date, whichever comes first.
• Do not put Kovaltry back in the refrigerator after it has been stored at room temperature.

Nuwiq:

• If stored at room temperature, throw away any unused vials after 3 months or after the expiration date, whichever comes first.
• Do not put Kovaltry back in the refrigerator after it has been stored at room temperature.