Summary Basis of Decision for Varithena

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Varithena is located below.

Recent Activity for Varithena

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Varithena

Updated:

2023-01-11

The following table describes post-authorization activity for Varithena, a product which contains the medicinal ingredient polidocanol. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN):

DIN 02444267 - 1.3 mg polidocanol/mL foam, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DIN 02444267 reported as dormant Not applicable
2020-02-28

The manufacturer reported the DIN as dormant as per section C.01.014.71 and subsection C.01.014.5(1)(a)(ii) of the Food and Drug Regulations.
SNDS # 211101 2017-11-20 Issued NOC
2018-11-15		 Submission filed as a Level I - Supplement to seek approval for a change in the drug product specifications. The data were reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02444267) market notification Not applicable Date of first sale:
2016-11-30		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 203344 2017-03-01 Issued NOC
2017-10-20		 Submission filed as a Level I - Supplement to extend the drug product in-use period from the current 7 days to 30 days. In-use data, including testing to product specifications and microbial ingress testing, has been submitted to demonstrate the product to meet all specifications and be acceptable for use following storage for up to 30 days at the label storage conditions and according to the labelled instructions for use. The information was reviewed and considered acceptable. An NOC was issued.
SNDS # 190714 2016-01-27 Issued NOC
2016-09-01		 Submission filed as a Level I - Supplement to add a terminal sterilization site with a new sterilization process for the Varithena fully assembled units. The proposed site is the current approved site used for manufacture and testing of the drug product. The sterilization process and performance qualification and validation results demonstrate the process to be robust and consistent in producing product with acceptable characteristics. The information was reviewed and considered acceptable. An NOC was issued.
NDS # 177359 2014-08-20 Issued NOC
2015-08-04		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Varithena

Date SBD issued: 2015-09-18

The following information relates to the new drug submission for Varithena.

Polidocanol, 1.3 mg polidocanol/mL, foam, intravenous

Drug Identification Number (DIN):

  • 02444267

Provensis Ltd.

New Drug Submission Control Number: 177359

 

On August 4, 2015, Health Canada issued a Notice of Compliance to Provensis Ltd. for the drug product, Varithena.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Varithena is favourable for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein (GSV) system, above and below the knee. Varithena is intended for use in adults with clinically significant venous reflux as diagnosed by duplex ultrasound.

1 What was approved?

Varithena, a sclerosing agent, was authorized for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein (GSV) system, above and below the knee. Varithena is intended for use in adults with clinically significant venous reflux as diagnosed by duplex ultrasound.

Physicians administering Varithena must be experienced with venous procedures, possess a detailed working knowledge of the use of the duplex ultrasound in venous disease, and be trained in the administration of the product.

Varithena is contraindicated in patients who are pregnant or have a known allergy to polidocanol or any ingredient in the formulation. Varithena is also contraindicated in patients with acute thromboembolic disease or thrombophilia. Varithena was approved for use under the conditions stated in the Varithena Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Varithena (1.3 mg polidocanol/mL foam) is a sterile, injectable foam of an aqueous polidocanol solution (1%) combined with carbon dioxide and oxygen, containing the following inactive ingredients: ethanol, disodium hydrogen phosphate dehydrate, and potassium dihydrogen phosphate, with pH in the range 6.0-7.5.

Polidocanol solution, 180 mg/18 mL (10 mg/mL) must be activated before use. Once activated, Varithena injectable foam delivers a 1% polidocanol solution. Each millilitre of Varithena injectable foam contains 1.3 mg of polidocanol. One canister of Varithena generates 90 mL of foam, which following purging instructions in the Instructions for Use, is sufficient to yield 45 mL of usable foam for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Varithena Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Varithena approved?

Health Canada considers that the benefit/risk profile of Varithena is favourable for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein (GSV) system, above and below the knee. Varithena is intended for use in adults with clinically significant venous reflux as diagnosed by duplex ultrasound.

Varicose veins are enlarged, bulging veins that most often occur in the leg's GSV system. Varicose veins are usually visible and can cause uncomfortable symptoms such as swelling and achiness. They occur when the tiny valves inside the veins become weaker, causing blood to back up and make the veins swell. Chronic venous insufficiency (CVI) is common, affecting up to 25% of the adult population. The most severe form of varicose veins is leg ulceration. Leg ulcerations are difficult to manage medically, and have a major negative impact on quality of life. Untreated CVI can also result in hemorrhage, thrombophlebitis, edema, changes in skin pigmentation, varicose eczema, and lipodermatosclerosis. 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 have risks and limitations. Varithena is an injectable foam sclerosing agent. The advantage of foam is to effectively ablate veins with a relatively small amount of active sclerosant. In the past, sclerosant foam therapy was used off-label in Canada, and neither polidocanol nor foam polidocanol formulations were approved by Health Canada. Most of the physicians used a homemade foam with a variety of techniques to generate foam.

Varithena has been shown to be efficacious in patients with saphenofemoral junction (SFJ) incompetence as evidenced by reflux of the GSV or major accessory veins. The market authorization was based on two randomized, blinded, multicentre, pivotal studies. 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 haemorrhage.

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 were mild or moderate in severity.

Serious risks of concern include 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. Approximately 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 adverse events were asymptomatic and resolved or stabilized on average within one month, with or without anticoagulation treatment. None of the patients were diagnosed with a PE. Deep venous thrombosis occurs 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 room air (normally 80%) resulting in the creation of large bubbles when the foam is prepared in the office. None of the 1,333 patients treated with Varithena in the clinical studies 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 amount of nitrogen (<0.8%, 100 times less than room air). This modification was made to the product for market authorization. Non-clinical data showed that the current gas mixture contained in Varithena foam was rapidly absorbed, thus minimizing the risk of gas embolism. In addition, the potential for Varithena-derived bubbles to cause cerebrovascular events was investigated in one study in patients with proven PFO and varicose veins. Patients with bubbles 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. However, it is unclear whether foam sclerotherapy is causally related to neurological events, or patients with PFO were shown to be associated with a higher incidence of cryptogenic stroke/TIA or other unexplained neurological events such as migraine with aura.

To mitigate the risk of DVT and the potential ischemic adverse events, the Varithena Product Monograph instructs physicians on product specific risk mitigation strategies in the Warnings and Precautions, Dosage and Administration, and the Instructions for Use for professionals. 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.

The major safety issues of potential anaphylaxis, tissue ischemia and necrosis, venous thrombosis, and potential ischemic cerebrovascular events have been described in a Serious Warnings and Precautions box in the Varithena Product Monograph.

A Risk Management Plan (RMP) for Varithena was submitted by Provensis Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and, when needed, to describe measures that will be put in place to minimize risks associated with the product.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Varithena therapy are considered to outweigh the potential risks. 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. Varithena was shown in the clinical studies to be a safe, effective and minimally invasive treatment option for patients with varicose veins. With the market authorization of Varithena, physicians and patients will have the option of using a sclerosing foam approved by Health Canada for varicose vein treatment.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Varithena?

Submission Milestones: Varithena

Submission Milestone Date
Pre-submission meeting: 2014-04-16
Submission filed: 2014-08-20
Screening  
Screening Acceptance Letter issued: 2014-10-08
Review  
Quality Evaluation complete: 2015-07-30
Clinical Evaluation complete: 2015-07-31
Labelling Review complete: 2015-07-31
Notice of Compliance issued by Director General: 2015-08-04

The Canadian regulatory decision on the non-clinical and clinical review of Varithena was based on a critical assessment of the Canadian data package. The foreign reviews completed by United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Varithena?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Varithena is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

 

Clinical Pharmacology

Varithena (polidocanol injectable foam) is a drug/device combination product that generates injectable foam. The injectable foam is composed of a liquid and gas phase, both of which are necessary to have its therapeutic effect. The foam is intended to displace blood from the vein to be treated, and scleroses the endothelium.

The data from the submitted clinical pharmacology studies are considered sufficient and there are no major concerns to prevent the market authorization of Varithena for the specified indication.

For further details, please refer to the Varithena Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Varithena was evaluated in two Phase III randomized, blinded, multicentre, clinical studies (VANISH-1 and VANISH-2) designed to assess the efficacy of Varithena 0.5%, 1.0%, and 2.0% (VANISH-1) and Varithena 0.5% and 1.0% (VANISH-2) compared with placebo in the treatment of both symptoms and appearance of varicose veins. These studies were conducted in patients with saphenofemoral junction (SFJ) incompetence as evidenced by reflux of the great saphenous vein (GSV) or major accessory veins. In both studies, a Varithena 0.125% treatment group was included as a control for blinding of the duplex ultrasound assessment. The maximum volume of injectable foam or placebo administered per treatment session was 15 mL.

In VANISH-1, patients received one blinded treatment and in VANISH-2, patients received one blinded treatment with an option for a second blinded treatment one week later. In VANISH-2, patients in the Varithena 1.0% treatment group received an average of 1.4 blinded treatments. All patients received post-procedure compression therapy for 14 days following treatment.

One week after each study treatment (initial or optional additional treatment), patients had a follow-up visit for safety using duplex ultrasound.

In VANISH-1 and VANISH-2, of the 511 patients that were randomized for treatment, 111 patients were treated with Varithena 0.5%, 110 patients with Varithena 1.0%, 63 patients with Varithena 2.0%, 114 patients with Varithena 0.125% as a control, and 113 patients were treated with placebo. Ninety-nine percent of the patients in VANISH-1 and VANISH-2 completed the blinded treatment period.

In the Varithena 1.0% group in VANISH-2, 23 of 58 patients received an additional blinded treatment. Two of these patients had retreatment of veins treated in the initial treatment session. The remaining 21 patients received treatment for additional veins not treated in the initial treatment session.

In VANISH-1 and VANISH-2, the mean age was approximately 50 years and approximately three-quarters of the patients were women. The mean body mass index (BMI) was similar in VANISH-1 and VANISH-2, at 28 kg/m2 (range 16 to 44 kg/m2) and 30 kg/m2 (range 17 to 48 kg/m2), respectively. The mean baseline GSV diameter was also similar in VANISH-1 and VANISH-2, at 7.6 mm (range 1.5 to 25.9 mm) and 8.7 mm (range 3.1 to 19.4 mm), respectively. Overall, 22% of patients in VANISH-1 and 25% of patients in VANISH-2 reported one or more prior varicose vein procedures in the leg to be treated.

The primary efficacy endpoint in both clinical studies was improvement in patient symptoms, as measured by the change from baseline to Week 8 in the 7-day average electronic daily diary Varicose Veins Symptoms Questionnaire (VVSymQ) score. The VVSymQ score is a patient-reported outcome measure based on daily patient assessment of the duration of varicose vein symptoms determined to be most important to patients: heaviness, achiness, swelling, throbbing, and itching. The scores range from 0 to 25, where 0 represents no symptoms and 25 represents all 5 symptoms experienced all of the time.

In both VANISH-1 and VANISH-2, treatment with Varithena 1.0% was superior to placebo in improving symptoms as measured by VVSymQ. These findings were consistent when duration-based and intensity-based scales were used to measure patients' symptoms.

The co-secondary endpoints in VANISH-1 and VANISH-2 were the improvements in appearance of visible varicosities from baseline to Week 8 as measured by patient scoring and an independent photography review. In both endpoints, Varithena resulted in statistically greater improvement appearance compared to placebo (p<0.0001).

Tertiary endpoints in VANISH-1 and VANISH-2 included response to treatment as determined by duplex ultrasound, by change from baseline in Venous Clinical Severity Score (VCSS), and by change from baseline in Venous Insufficiency Epidemiologic and Economic Study - Quality of Life (VEINES-QOL) score.

For the duplex ultrasound endpoint, the comparison for both studies was between the pooled Varithena groups versus the Varithena 0.125% (control) group. For VANISH-1 and VANISH-2, patients that met the criteria for response to treatment were 80% and 86% of patients respectively, compared with 42% of patients and 60% of patients, respectively, in the 0.125% (control) groups. These differences were statistically significant (p≤0.0002).

In VANISH-1 and VANISH-2, the adjusted mean reductions from baseline in VCSS at Week 8 in the Varithena 1.0% treatment groups were 3.70 and 5.05, respectively, compared with 0.75 and 1.52 points, respectively, in the placebo groups. In both studies, the differences between these improvements were statistically significant (p<0.0001).

In VANISH-1 and VANISH-2, the adjusted mean changes from baseline in VEINES-QOL in the pooled Varithena treatment groups were 21.2 and 21.6, respectively, at Week 8 compared with 7.7 and 7.4 points in the placebo groups, respectively. For both studies, the differences between these improvements were statistically significant (p<0.0001).

The efficacy of Varithena was consistent across age, sex, BMI (up to 48 kg/m2), Clinical-Etiology-Anatomical-Pathophysiology (CEAP) clinical class, GSV diameter and VCSS subgroups for each efficacy endpoint evaluated. Treatment with Varithena led to clinically meaningful improvements in primary and secondary endpoints.

Varithena injectable foam 1% was selected as the proposed dose for marketing, to provide the best balance of benefit and risk for patients. Regarding efficacy, Varithena 0.5%, 1% and 2% dose concentration were not substantially different from one another with regard to improvement in symptoms or appearance. The results of the primary and secondary endpoints suggest that the 0.5% and 1.0% foam dose concentrations were generally comparable and the dose response for these endpoints appeared to be monotonic. However for the duplex ultrasound endpoint, Varithena 1.0% was notably more effective compared to Varithena 0.5%. In addition, the percentage of patients requiring additional open-label treatment was lower in the Varithena 1.0% group compared to the 0.5% group and comparable to the 2.0% dose group. In terms of safety, Varithena injectable foam 1% was associated with the lowest frequency of venous thrombosis adverse events.

The original proposed indication by the sponsor for Varithena in the New Drug Submission (NDS) was: "Varithena is indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins and visible varicosities of the great saphenous vein (GSV) system above and below the knee. Varithena improves the symptoms of superficial venous incompetence and the appearance of visible varicosities."

Following the review of the submission, Health Canada revised the indication to: "Varithena is indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein (GSV) system, above and below the knee. Varithena is intended for use in adults with clinically significant venous reflux as diagnosed by duplex ultrasound."

Health Canada also added the statement, "Physicians administering Varithena must be experienced with venous procedures, possess a detailed working knowledge of the use of the duplex ultrasound in venous disease, and be trained in the administration of the product."

In conclusion, Varithena showed consistent, statistically significant elimination of reflux and clinically meaningful improvement in symptoms (such as pain and discomfort) and appearance in the GSV system for patients with SFJ incompetence.

For more information, refer to the Varithena Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety database included results from 12 clinical studies of Varithena; four placebo/vehicle-controlled Phase III studies, one randomized open-label active-controlled Phase III study, one open-label study of clinical pharmacology and safety, and six open-label Phase II studies. The safety population included 1,333 patients treated with Varithena at dose concentrations of 0.125%, 0.5%, 1%, or 2%, of which 907 patients were followed for ≥3 months, 527 for ≥6 months and 483 for ≥1 year.

Of the 797 patients treated with Varithena 1%, 16 patients experienced 20 serious adverse events (SAEs). Three patients died (traffic accident, heart failure, hepatic cirrhosis/acute renal failure) and 13 patients experienced non-fatal SAEs, including facial injury, venous thrombosis limb (2 cases), appendicitis, angina pectoris, grand mal convulsion, spinal osteoarthritis, tracheobronchitis, bronchitis, influenza, bronchopneumopathy, cellulitis, sick sinus syndrome, gastric obstruction, diverticulitis and pneumonia.

In patients treated with Varithena 1%, excluding the 3 patients who died, 9 patients were discontinued due to adverse events (AEs), including venous thrombosis limb (3 cases; 2 were SAEs), spinal osteoarthritis (SAE), extravasation (2 cases), superficial thrombophlebitis, foam entering the deep venous system and injection site pain.

The most common (>10%) AEs in patients treated with Varithena 1% include contusion, pain in extremity, headache and skin discoloration. Fifty-six of these patients (7%) had one or more SAE. The SAEs that occurred in more than one patient in the Varithena 1.0% treatment group were pain in extremity (26 patients, 3.3%), headache (10 patients, 1.3%), muscle spasms (4 patients, 0.5%),venous thrombosis limb (3 patients, 0.4%), inflammation, tenderness, paraesthesia, pruritus, and vein pain (2 patients, or 0.3% each).

All studies were used to evaluate the incidence of AEs of special interest in Varithena- treated patients [(that is (i.e.), venous thrombosis, ischemic cerebrovascular events, and skin disorders].

Venous thrombosis

With the creation of a thrombus in the target superficial vein, there is also a risk of causing thrombosis in a non-target, perforating and/or deep vein. Thus, all minimally invasive treatments for venous insufficiency may give rise to the presence of thrombi in the deep and/or calf muscle veins.

A total of 94 Varithena-treated patients had venous thrombus AEs during the main or optional open-label treatment periods of their respective studies. These 94 patients represented 7.1% of the 1,333 Varithena-treated patients. Seventy-one patients (6.1%) treated with Varithena 1% had venous thrombus AEs. Of the 94 patients who had venous thrombus AEs, the percentage of patients with venous thrombus AEs was lowest in the Varithena 0.125% group, similar in the 0.5% and 1% groups, and highest in the Varithena 2% group.

The most common type of venous thrombus was asymptomatic and non-occlusive; 2.9% of the 1,333 Varithena-treated patients (39 patients) had common femoral vein thrombus extensions from the treated GSV in the Varithena group. The second type of venous thrombosis by vein location was the isolated gastrocnemius and soleal vein thrombosis (IGSVT) which were observed in 1.4% of the 1,333 Varithena-treated patients (19 patients) during detailed duplex ultrasound evaluations of the calf, and caused no symptoms.

Deep vein thrombosis (DVT) was detected by ultrasound in 38 of 1,333 (2.8%) Varithena-treated patients, distal DVTs in 1.1%, and proximal DVTs in 1.7%. One percent of 1,333 Varithena-treated patients had proximal, symptomatic thrombi. Fifty-one of 97 patients with venous thrombus AEs were treated with anticoagulants. About 70% of patients with proximal DVT (thrombus in femoral vein or popliteal) received anticoagulants; the median time to stabilization or resolution was 87 days. Most patients with DVT (79%) or IGSVT (84%) did not receive anticoagulants; half of the patients with common femoral vein thrombus extensions were managed with ultrasound observation and did not receive anticoagulants. With the exception of 3 patients (1 patient with proximal DVT and 2 with IGSVT), the venous thrombus AEs resolved or stabilized rapidly (median of 29 days) irrespective of whether or not the patients were treated with anticoagulants.

All patients with venous thrombus events were assessed for signs and symptoms of pulmonary embolism (PE). None of the patients in the clinical studies were diagnosed with a PE. Two Varithena-treated patients with venous thrombus AEs experienced signs or symptoms that might be attributed to a PE.

Overall, DVT occurs no more frequently with the use of Varithena than with the use of other treatment modalities for varicose veins such as surgery or laser ablation.

Ischemic cerebrovascular events

Injection of gas or air into the circulatory system creates bubbles that can potentially lead to embolism in the heart, lungs, or brain, with subsequent clinical sequelae. While all patients with sclerosant foam will have bubbles circulating in the venous system, they are normally filtered out by the lung. However, bubbles can pass into the arterial circulation and then to the eye or brain in the presence of a right to left cardiac shunt [e.g. patent foramen ovale (PFO)] or in patients with lung diseases.

Ischemic cerebrovascular events such as transient ischemic attack (TIA) or stroke have been reported rarely for sclerosant agents minutes or days after sclerotherapy. These events have not been reported to date with Varithena.

Certain transient neurologic AEs such as visual disturbance, headaches, dizziness or paresthesia have been reported more frequently with Varithena compared to placebo. The immediate post-treatment visual disturbances all resolved without sequelae. Factors that may increase the risk of these events include the use of room air instead of carbon dioxide to prepare the foam, large bubble size, the presence of PFO, failure to elevate the limb during and after therapy, and any excessive amount of foam used during one session. However, it is unclear whether foam sclerotherapy is causally related to neurological events, or whether patients with PFO were shown to be associated with a higher incidence of cryptogenic stroke/TIA or other unexplained neurological events such as migraine with aura. In the general population, about 25-30% of patients are thought to have a PFO of which most of them are asymptomatic. The benefit/risk profile of Varithena treatment for patients with known PFO must be carefully considered.

In all studies, the incidence of possible neurologic AEs within 1 day of treatment with Varithena 1% was 9.7% and 4% with placebo.

Skin disorders

Severe allergic reactions have been reported following administration of liquid polidocanol, including anaphylactic reactions, some of them fatal. Such reactions were more frequent in patients treated with larger volumes (i.e., >3 mL) of the product in liquid form. These events have not been reported to date with Varithena injectable foam.

Safety Conclusion

In conclusion, the safety analysis demonstrated that Varithena was well-tolerated with manageable adverse events. Appropriate warnings and precautions are in place in the approved Varithena Product Monograph to address the identified safety concerns. The major safety issues of anaphylaxis, venous thrombosis and ischemic cerebrovascular events have been described in a Serious Warnings and Precautions box in the Varithena Product Monograph. A warning of tissue ischemia and necrosis was also included as intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene.

Overall, the safety profile of Varithena is acceptable and manageable for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the GSV system, above and below the knee.

For more information, refer to the Varithena Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical efficacy of polidocanol, the medicinal ingredient of Varithena, was evaluated in rabbits where it had a concentration-dependent sclerosant effect when injected either as a foam or solution in the marginal ear vein. These results supported the clinical development of Varithena as a sclerosant agent.

The non-clinical safety of Varithena was evaluated in safety pharmacology and toxicology studies performed with polidocanol as a solution and/or foam. Varithena was considered to have an overall acceptable safety profile for its subsequent use in clinical studies. The results of the non-clinical studies, as well as the potential risks to humans, have been included in the Varithena Product Monograph.

In a rat embryo-fetal development study, there was an increased incidence of supernumerary ribs in fetuses at approximately 1.5 times the maximum human dose of Varithena 1.0% based on body surface area which slightly exceeded the historic control groups. No abnormalities were seen in the rabbit embryo-fetal development study up to approximately 12 times the maximum human dose of Varithena 1.0% based on body surface area. The clinical relevance of the finding of supernumerary ribs in rats is unknown, particularly as this finding only slightly exceeded the historic control groups, but the potential risk is considered to be adequately mitigated by the fact that the use of Varithena is contraindicated in pregnancy.

Overall, the non-clinical programme for Vartihena was adequate to support the approval of this product. Appropriate warnings and precautionary measures are in place in the Varithena Product Monograph to address the identified safety concerns.

For more information, refer to the Vartihena Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Vartihena has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life of seven days once activated is acceptable.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

The excipients used in the drug product formulation are not of animal or human origin.

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