Regulatory Decision Summary for Varithena

In Canada, varicose veins are managed by either invasive procedures, such as surgery and stripping of saphenous veins or minimally-invasive treatment such as laser and sclerotherapy. Each of these methods of treatment has important risks and limitations.

Varithena is an injectable foam sclerosing agent that is the first product in a new class, and it is supplied in a package as two connecting sterile canisters. Varithena injectable foam is produced by mixing a polidocanol solution (in one canister) and a gas phase consisting of oxygen: carbon dioxide (65:35) with low nitrogen content of less than 1% (in another canister). A sterile foam transfer unit is incorporated with the two canisters to produce foam at a concentration of 1.0% weight/volume, with controlled density and bubble size (median size <100 micrometres (µm) and no bubbles >500 µm). The advantage of foam is to effectively ablate veins with a relatively small amount of active sclerosant.

Varithena can be administered as an office procedure by a physician trained in the required technique. The fundamental objective of the treatment is to ablate the varicose veins by injecting the foam directly into the incompetent veins and related varicosities of the great saphenous system (GSV), using ultrasound guidance. The volume of foam to be injected depends on the size and extent of the veins to be treated. The maximum recommended volume per treatment session is 15 mL, comprising individual injections up to 5 mL each.

Clinical studies have shown that Varithena injectable foam can effectively treat the varicosities of GSV and associated tributaries. The results of the 2 pivotal studies showed that treatment with Varithena resulted in statistically significant improvements in patient-reported symptoms (primary efficacy endpoint) and appearance of varicose veins as assessed by both the patient and an independent panel of expert clinicians blinded to study treatment (co-secondary efficacy endpoints). Varithena also showed statistically significant elimination of reflux using duplex ultrasound. The efficacy was consistent across subgroups, and there was no subgroup identified that did not benefit from treatment with Varithena. However, data submitted did not allow the evaluation of time to recurrence, progression to chronic complication (such as ulceration or progression to deep vein thrombosis or pulmonary embolism) and varicose hemorrhage.

The adverse events most commonly observed in the clinical studies of Varithena were manageable events that would be expected in patients undergoing a minimally-invasive medical procedure for the treatment of GSV incompetence. These included retained coagulum, injection site hematoma, bruising, pain in extremity, limb discomfort, superficial thrombophlebitis and headache. The majority of adverse events were mild or moderate in severity.

The serious risks of Varithena are deep venous thromboembolisms (DVTs), which have the potential to lead to pulmonary embolism (PE), and ischemic cerebrovascular conditions such as stroke or transient ischemic attack (TIA). With the creation of a thrombus in the target superficial vein, there is a risk of causing thrombosis in a non-target, perforating and/or deep vein. About 7% of patients in the Varithena clinical studies experienced a venous thrombus adverse event, with 2.7% classified as deep vein thrombosis (DVT). Most venous thrombus AEs detected were asymptomatic and resolved or stabilized on average within one month, with or without anticoagulation treatment. No patient was diagnosed with a PE. The DVTs occurred no more frequently with the use of Varithena than with the use of other treatment modalities for varicose veins [that is (i.e.) surgery, laser ablation].

Ischemic cerebrovascular events such as TIA or stroke have been reported rarely for sclerosing agents minutes or days after sclerotherapy (foam or liquid form). The cause is believed to be the nitrogen content in the air (normally 80%) resulting in the creation of large bubbles when foam is prepared in the office. None of the 1,333 patients treated with Varithena in clinical trials experienced clinically important neurological or visual adverse events suggestive of cerebral gas embolism.

While all patients treated with sclerosant foam will have bubbles circulating in the venous system, they are normally filtered out by the lung. However in the presence of a right to left cardiac shunt, [for example (e.g.) patent foramen ovale (PFO)], bubbles can pass into the arterial circulation and then to the brain. Because of the role played by nitrogen in the formation of bubbles, the product was subsequently modified to remove all but a trace of nitrogen in the proposed product. Preclinical data showed that the current gas mixture contained in Varithena foam is rapidly absorbed, thus minimizing the risk of gas embolism. In addition, the potential for Varithena-derived bubbles to cause cerebrovascular events was investigated in a study in patients with proven PFO and varicose veins. Patients with bubbles demonstrated in the middle cerebral artery were carefully monitored including serial magnetic resonance imaging (MRI). No significant clinical neurological events, MRI changes or visual disturbances were demonstrated.

To mitigate the risk of DVT and the potential ischemic adverse events, the Varithena Product Monograph has been revised extensively to instruct physicians on product specific risk mitigation strategies in the Warnings and Precautions, Dosage and Administration and the Instructions for Use. In addition, physicians who are planning to use the product must be adequately trained in order to mitigate the pre- and post-procedural risks of Varithena.

Varithena injectable foam 1% was selected as the proposed dose for marketing on the basis of providing the best balance of benefit and risk for patients. Overall, Varithena was shown in the clinical studies to be a safe, effective and minimally invasive treatment option for patients with varicose veins.

For more information on Health Canadas decision, please view the Summary Basis of Decision.