Regulatory Decision Summary for Vocarvi

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

foscarnet sodium

Therapeutic area:

Antivirals for Systemic Use

Type of submission:

New Drug Submission

Control number:

233046
What was the purpose of this submission?

 

This New Drug Submission (NDS) was filed as a Submission Relying on Third-Party Data (SRTD) to obtain market authorization for Vocarvi (foscarnet sodium injection) for the following indications: Cytomegalovirus Retinitis

the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS);

combination therapy with foscarnet sodium injection and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug;

Mucocutaneous Acyclovir Resistant Herpes Simplex Virus Infections

the treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients.

Upon review, the second indication for CMV retinitis was revised as follows:

combination therapy with Vocarvi and ganciclovir for the treatment of CMV retinitis in patients with AIDS who have relapsed after monotherapy with either drug.

 

Why was the decision issued?

 

Health Canada considers that the benefit/harm profile of Vocarvi is favourable in the treatment of CMV retinitis infection in patients with AIDS, including in combination with ganciclovir in patients who have relapsed after monotherapy with either drug, and in the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients.

The indication in the treatment of CMV retinitis in patients with AIDS is supported by the results from an open-label, randomized study (SOCA 1992 and 1994) conducted in the United States in 234 patients (107 patients were treated with foscarnet and 127 patients with ganciclovir). The primary efficacy endpoints were time to progression evaluated by the Fundus Photograph Reading Center, clinical evaluation and time to reinduction. The time to first progression as evaluated by the Fundus Photograph Reading Center was similar between the two treatment groups, with a median of 53 days in the foscarnet group and 47 days in the ganciclovir group (p = 0.997). The time to first progression as determined by the clinician was substantially longer than by the Fundus Photograph Reading Center for each group but was similar between the two groups, i.e., 74 days for foscarnet and 84 days for ganciclovir (p = 0.498). Times to second and third progression were also similar between the treatment groups. The median times to reinduction were 113 days in the foscarnet group and 126 days in the ganciclovir group (p = 0.599). The relative risk for progression of CMV retinitis was 0.97 (ganciclovir versus foscarnet; p = 0.833). By 120 days after randomization, progression was observed in 85% of patients in each treatment group. Visual acuity outcomes were similar for both groups; at 6 months after randomization, 88% of the foscarnet patients and 93% of the ganciclovir patients had a best-corrected visual acuity of 20/40 or better in the better eye (p = 0.325). Visual field scores were similar in the two groups; in all eyes affected with CMV retinitis, there was a mean 29°/month loss of visual field in the foscarnet group compared with a 31°/month loss in the ganciclovir group (p = 0.674). Overall survival data showed a survival benefit with foscarnet compared to ganciclovir (median overall survival 12.6 versus 8.5 months, p = 0.007). Excess mortality in the ganciclovir group led the Policy and Data Monitoring Board to recommend suspension of the treatment protocol 19 months after the trial started. At that time, 51% of patients in the ganciclovir group had died compared to 34% in the foscarnet group (relative risk = 1.79). In the foscarnet group, the only subgroup that was identified as having excess mortality were patients with renal impairment at study entry.

The indication for the combination therapy with foscarnet and ganciclovir in AIDS patients with CMV retinitis who have relapsed after monotherapy with either drug is supported by the results from a multicenter, randomized, controlled trial (SOCA 1996). This study was conducted in the United States in 279 patients (89 assigned to the foscarnet group, 94 to the ganciclovir group, and 96 to the combination group). The inclusion criteria required that patients had CMV retinitis despite previous treatment attempts using either ganciclovir or foscarnet within the past 28 days. The primary efficacy endpoints were masked time to first progression, unmasked time to first progression, rate of change in visual field from baseline, time to ≥3-line loss and time to ≥6-line loss. Results of masked grading of the fundus photography indicated that median time to first retinitis progression was significantly longer (p<0.001) in the combination therapy group (4.3 months) relative to the foscarnet (1.3 months) and the ganciclovir (2.0 months) groups. Unmasked grading of the fundus photography had similar results with median time to progression being significantly longer (p≤0.001) in the combination therapy group (5.4 months) compared to the foscarnet (2.0 months) and ganciclovir (3.6 months) groups. Combination therapy was associated with the lowest rate of visual field loss of 16° per month compared to 28° per month for the foscarnet group and 18° per month for the ganciclovir group (p = 0.009). There were no marked differences among the three treatment groups in the rate of loss of visual acuity, whether defined as a 15-letter (3-line) loss (p = 0.79) or a 30-letter (6-line) loss (p = 0.35).

The indication for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients is supported by the results from a randomized controlled trial in 14 patients with AIDS that compared foscarnet and vidarabine (Safrin et al. 1991). This study was designed to recruit 25 patients but the recruitment to the vidarabine group was halted by the Data and Safety Monitoring Board due to lack of efficacy and safety reasons after only 14 randomized patients were recruited (8 patients in the foscarnet group and 6 in the vidarabine group). An additional 11 non-randomized patients were recruited and treated with foscarnet. Therapy ended on day 10 if all lesions had healed completely and continued for up to 42 days if the response was partial (defined as a decrease in the total surface area of the two largest lesions of ≥25%). The primary efficacy endpoint was the complete healing of all lesions after 42 days. The randomized patients who received foscarnet treatment had a significantly shorter time to healing (median 13.5 days) than those receiving vidarabine (median 38.5 days; p = 0.01). Additionally, the lesions in all 8 patients in the foscarnet group healed completely after 10 to 24 days of therapy while vidarabine treatment was discontinued in all 6 patients due to therapeutic failure. Of the 6 randomized patients initially receiving vidarabine, 5 crossed over to receive foscarnet treatment. Two of these patients had complete lesion healing after 15 and 20 days of therapy with foscarnet and the other 3 patients stopped receiving foscarnet therapy after 93%, 96%, and 98% of their lesions had healed on days 24, 32, and 38 of therapy, respectively. Lesion isolates were obtained throughout the study to assess time to virologic cure. The time to virologic cure was significantly shorter in randomized patients receiving foscarnet (median 6 days) compared to vidarabine (median 17 days; p = 0.006). All 7 patients in the foscarnet group who were shedding HSV at entry had a virologic cure compared with only 1 in 5 patients receiving vidarabine. Four patients with viral shedding who crossed over to receive foscarnet therapy had virologic cure after a median of 5.5 days of treatment. In addition to the randomized patients, 11 patients who were exempt from randomization due to discontinuation of vidarabine administration prior to enrollment, received foscarnet therapy for their herpetic lesions. Eight of these patients had complete healing after a median of 12.7 days (range 10 to 42). Mucocutaneous HSV recurred after a median of 14 days after foscarnet was discontinued (range 2 to 117 days). Of the 17 first recurrences that occurred out of 25 enrolled patients, 10 were at the site of the healed lesion (7 susceptible to acyclovir, 3 resistant). Eight patients had second recurrences at the site of the initial lesion, all of which were resistant to acyclovir. The median time to the recurrence of acyclovir-resistant HSV was 41 days (range 2 to 173 days).

The main identified risks associated with foscarnet include renal toxicity, QT prolongation (including cases of Torsades de Pointes), electrolyte disturbances, seizures and hematologic effects. These risks are considered to be manageable through the inclusion of appropriate warnings and cautionary statements in the Vocarvi Product Monograph and through the Risk Management Plan.

Overall, the anticipated benefits of Vocarvi are expected to outweigh its risks under the conditions of use recommended in the Vocarvi Product Monograph at this time.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations