Varithena Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

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.

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.

CONTRAINDICATIONS

The use of Varithena™ is contraindicated in patients with:

• Known allergy to polidocanol or any ingredient in the formulation
• Acute thromboembolic disease
• Thrombophilia
• Pregnancy

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Anaphylaxis

Severe allergic reactions have been reported following administration of liquid polidocanol, including anaphylactic reactions, some of them fatal. Observe patients for at least 10 minutes following injection and be prepared to treat anaphylaxis appropriately.

• Tissue Ischemia and Necrosis

Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene. Patients with underlying arterial disease may be at increased risk for tissue ischemia. If intra-arterial injection of polidocanol occurs, consult a vascular surgeon immediately.

• Venous Thrombosis

Varithena™ can cause venous thrombosis (See ADVERSE REACTIONS). Follow administration instructions closely and monitor for signs of venous thrombosis after treatment. Patients with risk factors such as reduced mobility, history of deep vein thrombosis or pulmonary embolism, recent (within 3 months) major surgery, prolonged hospitalization, malignancy, use of hormonal contraceptives, use of hormone replacement therapy, obesity or smoking are at increased risk for developing thrombosis. Benefit-risk needs to be carefully considered in these patients, the same consideration should be applied to those patients who are contraindicated for anticoagulation.

• Ischemic cerebrovascular events

Ischemic cerebrovascular events such transient ischemic attack (TIA) or stroke have been reported rarely for sclerosing agents minutes or days after sclerotherapy. These events have not been reported to date with Varithena™. Factors that may increase the risk of these events after physician-compounded foam sclerotherapy include the use of room air instead of carbon dioxide to prepare the foam, large bubbles size, a presence of patent foramen ovale (PFO), failure to elevate the limb during and after therapy, and any excessive amount of foam used during one session. Because of the potential for arterial gas-emboli to occur, patients with known PFO should be appropriately counselled about this risk with Varithena™ treatment and the risk –benefit of treating these patients with Varithena™ should be carefully considered (See WARNING AND PRECAUTION, Special populations, Patent foramen ovale).

Post-Procedural Period

Physician should monitor patients for signs suggestive of hypersensitivity (redness of the skin and conjunctiva, pruritus, cough) and neurological signs (scotomas, amaurosis, or focal sensory and /or motor deficits).

Advise the patient to keep post-treatment bandages dry and in place for 48 hours and to wear compression stockings on the treated legs continuously for 2 weeks (see DOSAGE AND ADMINISTRATION).

Cardiovascular

Benefit-risk needs to be carefully considered in patients with significant cardiovascular disease, such as recent myocardial infarction, uncontrolled hypertension and heart failure (NYHA Class III or IV), and those with a history of TIA/Stroke because these patients have not been studied in clinical trials.

Special Populations

Patent foramen ovale (PFO): Ischemic adverse events have been reported in clinical trials and in the medical literature a few minutes after injection of polidocanol in liquid or physician-compounded room air-based foam. Physicians should advise patients to avoid any Valsalva manoeuvre or similar activities (such as bending to put on stockings or coughing, etc.) immediately following foam sclerotherapy. The potential for Varithena™-derived bubbles to cause cerebrovascular events was investigated in one study², patients with proven PFO and varicose veins were treated with Varithena™; patients with bubbles demonstrated in the middle cerebral artery were carefully monitored including serial MRI. No significant clinical neurological events or MRI changes were demonstrated (See ACTION AND CLINICAL PHARMACOLOGY).

Pregnant Women: There are no adequate and well-controlled studies of Varithena™ in pregnant women; therefore, use of Varithena™ is contraindicated.

Developmental reproductive toxicity testing was performed in rats and rabbits using intravenous administration of polidocanol solution. In rabbits, dose levels up to 10 mg/kg/day (approximately 12 times the maximum human dose of 15 mL of 1.0% polidocanol injectable foam based on body surface area) did not produce any indication of adverse effects on embryo-fetal mortality, fetal weight, or the incidences of fetal abnormalities and variants. In rats, at dose levels up to 27 mg/kg/day of polidocanol solution (approximately 13.5 times the maximum human dose of 15 mL of 1.0% polidocanol injectable foam based on body surface area), there were no adverse effects on pregnancy performance but there was an increased incidence of supernumerary ribs in fetuses at ≥3 mg/kg/day of polidocanol solution (approximately 1.5 times the maximum human dose of 15 mL of 1.0% polidocanol injectable foam based on body surface area) which slightly exceeded the historic control groups. In a peri-natal and post-natal study in rats, dose levels of polidocanol up to 9 mg/kg/day (approximately 4.5 times the human dose based on body surface area) were without adverse effects on the development of the conceptus and offspring, and at a dose level of 27 mg/kg/day of polidocanol solution (approximately 13.5 times the human dose based on body surface area), adverse effects were confined to an equivocal reduction in body weights of first-generation males, and an associated equivocal delay in the age of preputial separation.

Nursing Women: It is not known whether polidocanol is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, avoid administering Varithena™ to a nursing woman.

Pediatrics (< 18 years of age): Safety and effectiveness in pediatric patients have not been established. Therefore Varithena™ is not recommended.

Geriatrics (> 65 years of age): Of the 1333 subjects treated with Varithena™ in clinical studies, 9.1% (n=121) of subjects were ≥65 years of age. No clinically important differences in safety or efficacy were observed between older and younger patients.

Hepatic and Renal Impairment: The safety and efficacy of Varithena™ treatment in patients with known hepatic impairment, renal impairment or clinically significant proteinuria has not been established and therefore caution is advised with the use of Varithena™ in these patients.

There is no clinical experience in patients undergoing renal dialysis. Use in patients on renal dialysis is not recommended.

Monitoring and Laboratory Tests:

Patients should be monitored during the administration of Varithena™ and for confirmation of venospasm.

No specific laboratory tests are required. Since Varithena™ induces thrombosis in the treated superficial veins, D-dimer is commonly elevated post-treatment and is not useful diagnostically to assess patients for venous thrombus following treatment with Varithena™.

ADVERSE REACTIONS

The Adverse Reactions reported in the clinical trial population are discussed in the section below. Based upon the clinical trial data, the most serious Adverse Reactions that may influence prescribing decisions or that could result in clinical intervention are outlined below and discussed in greater detail in the Warnings and Precautions section.

• Anaphylaxis
• Tissue Ischemia and Necrosis
• Venous Thrombosis

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug or procedure. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

A total of 1333 patients in 12 clinical trials were evaluated for safety when treated with Varithena™ at dose concentrations of 0.125%, 0.5%, 1.0%, or 2.0%; these include 437 patients treated with polidocanol injectable foam in placebo-controlled clinical trials.

In patients treated with Varithena™ 1%, 16 patients experienced 20 serious adverse events: 3 patients died (traffic accident, heart failure, hepatic cirrhosis/acute on chronic renal failure) and 13 patients experienced non-fatal serious adverse events, 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.

The most common (>10%) adverse events in patients treated with Varithena™ 1% include contusion, pain in extremity, headache and skin discoloration.

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

Adverse Reactions that occurred in 2% of patients receiving polidocanol injectable foam 1% or in 1% more than in patients receiving placebo are shown in Table 1. All adverse reactions that occurred in the treatment arms were common or very common in terms of frequency. The event terms venous thrombosis limb and deep vein thrombosis occurred only in the treatment arms of the studies, not in patients who received placebo.

Table 1: Treatment-Emergent Adverse Reactions (2% on Varithena™ [polidocanol injectable foam] or 1% more than on Placebo) Through Week 8

MedDRA preferred terms most appropriate to the condition were selected to identify different thrombotic adverse events

a. Infusion site thrombosis = retained coagulum in treated vein

b. Venous thrombosis limb = Common femoral vein thrombus extension

c. Deep vein thrombosis = thrombosis in the axial deep veins of the leg

d. Thrombosis = thrombosis in small calf veins (gastrocnemius or soleal veins)

In Varithena™-treated patients, 80% of pain events in the treated extremity resolved within 1 week.

In the 1333 patients treated with polidocanol injectable foam, the following venous thrombus adverse events occurred: common femoral vein thrombus extension (2.9%), proximal deep vein thrombosis (DVT) (1.7%), distal DVT (1.1%), and isolated gastrocnemius and soleal vein thrombosis (1.4%) Table 2.

Proximal symptomatic venous thrombi occurred in <1% of patients treated with polidocanol injectable foam. Approximately half (49%) of patients with thrombi received treatment with anticoagulants.

All thrombi that were detected in the deep and muscular calf veins were reported as were all extensions of thrombus from the SFJ into the common femoral vein (common femoral vein thrombus extension; CFVTE). If a thrombus AE was identified:

• Patients underwent an additional duplex scan 1 and 2 weeks later and then monthly until the thrombi stabilized or resolved.
• The patient was evaluated for the presence of symptoms of venous thrombus and of pulmonary embolism.
• Management of the identified thrombi was according to clinical presentation and usual clinical practice.

Table 2: Venous Thrombus Adverse Events (Main Treatment Period, N=1192)

In addition, 1 patient (2.6%) treated with ETA + Placebo had a posterior tibial, asymptomatic venous thrombus AE, and 1 patient (0.8%) treated with non-Varithena™ sclerotherapy had a gastrocnemius, symptomatic venous thrombus AE.

^a 2 patients had serious venous thrombus AEs. In both cases, the event was serious because the investigator, per institutional policy, was required to hospitalize the patient in order to begin treatment with intravenous unfractionated heparin.

None of the 1333 patients treated with polidocanol injectable foam in clinical trials experienced clinically important neurological or visual adverse events suggestive of cerebral gas embolism. In the early clinical trials of Varithena™, product containing up to 10% nitrogen was used. In Study 001, six patients had transient treatment-emergent AEs that might have been attributed to cerebral gas embolism. All of these events were brief; the longest event, which had features of a transient ischemic attack, lasted 20 minutes. The product was subsequently modified to remove all but a trace of nitrogen (<0.8%, 100 times less than room air) and is the current marketed product. As gas emboli occur immediately or shortly after administration, adverse neurological events related to gas embolization would be reported within 1 day.

In all studies, the incidence of possible neurologic adverse events within 1 day of treatment with Varithena™ 1% was 81/837 (9.7%). In contrast, studies using the formulation with up to 10% nitrogen was 13.5% (n=532) compared with 3.4% (n=265) in Varithena™ 1% (current formulation <0.8% nitrogen,) and 4.0% (n=151) in the placebo group.

Less Common Clinical Trial Adverse Reactions

The following additional adverse reactions were reported at incidence of less than 2% and greater than placebo, regardless of causality.

Blood and Lymphatic System Disorders: Anaemia, Microcytic Anaemia

Cardiac Disorders: Arrhythmia, Cardiomegaly, Palpitations, Sick Sinus Syndrome, Ventricular Extrasystoles

Ear and Labyrinth Disorders: Ear Pain, Tympanic Membrane Perforation, Vertigo

Endocrine Disorders: Hyperthyroidism, Hypothyroidism

Eye Disorders: Blindness, Conjunctival Haemorrhage, Conjunctivitis, Eye Pain, Eye Swelling, Vision Blurred, Visual Acuity Reduced, Visual Impairment

Gastrointestinal Disorders: Abdominal Discomfort, Abdominal Distension, Abdominal Pain, Abdominal Pain Upper, Constipation, Dry Mouth, Dyspepsia, Flatulence, Gastrointestinal Disorder, Gastrooesophageal Reflux Disease, Haematemesis, Haemorrhoids, Lip Ulceration, Oral Discomfort, Oral Pain, Sensitivity of Teeth, Tongue Ulceration, Toothache, Vomiting

Immune System Disorders: Allergy to Arthropod Sting, Hypersensitivity, Seasonal Allergy

Injury, Poisoning and Procedural Complications: Animal Bite, Arthropod Sting, Clavicle Fracture, Corneal Abrasion, Face Injury, Injury, Meniscus Lesion, Mountain Sickness Acute, Procedural Complication, Procedural Pain, Road Traffic Accident, Sunburn, Therapeutic Agent Toxicity, Thermal Burn, Wrist Fracture

Investigations: Alanine Aminotransferase Abnormal, Alanine Aminotransferase Increased, Arthroscopy, Aspartate Aminotransferase Increased, Blood Alkaline Phosphatase Increased, Blood Cholesterol Abnormal, Blood Cholesterol Increased, Blood Creatine Phosphokinase Increased, Blood Pressure Increased, Blood Pressure Systolic Increased, End-Tidal Co2 Abnormal, End-Tidal Co2 Decreased, Gamma-Glutamyltransferase Abnormal, Gamma-Glutamyltransferase Increased, Hepatic Enzyme Abnormal, Progesterone Decreased, Prothrombin Time Abnormal, Prothrombin Time Prolonged, Ultrasound Doppler Abnormal

Metabolism and Nutrition Disorders: Hypercholesterolaemia

Neoplasms Benign, Malignant and Unspecified (Cysts and Polyps): Skin Papilloma

Nervous System Disorders: Burning Sensation, Lethargy, Sciatica, Sensory Disturbance, Somnolence, Speech Disorder, Visual Field Defect

Pregnancy, Puerperium and Perinatal Conditions: Abortion Spontaneous

Psychiatric Disorders: Anxiety Disorder, Depression

Renal and Urinary Disorders: Glycosuria, Haematuria, Renal Colic

Reproductive System and Breast Disorders: Dysmenorrhoea, Menopausal Symptoms, Menorrhagia

Respiratory, Thoracic and Mediastinal Disorders: Cough, Dry Throat, Dysphonia, Dyspnoea, Epistaxis, Oropharyngeal Pain, Rhinitis Allergic, Rhinorrhoea

Skin and Subcutaneous Tissue Disorders: Acne, Alopecia, Blister, Blood Blister, Dermatitis, Dermatitis Allergic, Dermatitis Contact, Drug Eruption, Dry Skin, Ecchymosis, Eczema, Erythema, Night Sweats, Pigmentation Disorder, Skin Discomfort, Skin Tightness, Skin Ulcer, Stasis Dermatitis, Swelling Face, Urticaria

Surgical and Medical Procedures: Dermabrasion, Haematoma Evacuation, Inguinal Hernia Repair, Thrombectomy

In all studies, the incidence of skin discolouration adverse events in patients treated with Varithena™ 1% was 32.1%. When excluding Study 001 in which events were solicited rather than spontaneously reported, skin discolouration was reported in 12.3% of patients treated with Varithena™ 1% compared to 0.7% of patients treated with placebo in placebo-controlled studies.

No anaphylaxis or life-threatening hypersensitivity reactions were reported in any of the 1333 patients treated with polidocanol injectable foam in clinical trials.

Post-Market Adverse Drug Reactions

As of 19 June 2015, approximately 1581 patients have been treated with Varithena™, and a small number of adverse events have been received from the market place. Adverse events are very rare with the product (reported in less the 1% of the treatment population) and all of the adverse events received with Varithena™ to date have been non-serious. The Adverse Events that have been reported with post-market use of Varithena™ are as follows:

General disorders and administration site conditions: Injection site erythema, Injection site vesicles, Medical device site irritation, Medical device site vesicles, Pyrexia, Injection site pain, Infusion site thrombosis.

Immune system disorders: Device allergy.

Infections and infestations: Cellulitis.

Vascular disorders: Deep vein thrombosis, Thrombophlebitis, Thrombophlebitis Superficial, Venous thrombosis, Phlebitis, Venous thrombosis limb.

Musculoskeletal and connective tissue disorders: Pain in extremity.

Skin and Subcutaneous Tissue Disorders: Dermatitis Contact.

DRUG INTERACTIONS

No specific drug interaction studies have been performed. There are no known drug interactions with polidocanol injectable foam.

Drug-Drug Interactions

Interactions with other drugs have not been established.

Drug-Food interactions

Interactions with food have not been established.

Drug-Herb interactions

Interactions with herbal products have not been established.

Drug-laboratory test interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Varithena™ is intended for intravenous injection only, as the activated foam, using ultrasound guidance and is administered via a single cannula into the lumen of the target incompetent trunk veins or by direct injection into varicosities.

See the attached Instruction of Use leaflet for detailed instructions on activation and preparation of the product.

Maintain the sterile bi-canister assembly within the Tyvek pouch until immediately prior to activation

Recommended Dose and Dosage Adjustment

Use no more than 15 mL per patient treatment session administered in aliquots of 5 mL or less. Depending on the extent and diameter of the varicose veins to be treated, additional treatment sessions may be needed. Separate each treatment session by a minimum of 5 days.

Administration

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 Varithena™.

Local anesthetic may be administered prior to cannula insertion but neither tumescent anesthesia nor patient sedation is required. Cannulate the vein to be treated using ultrasound guidance to confirm venous access.

Occlude the treated vein distal to the cannula using finger pressure and inject freshly-generated Varithena™ injectable foam slowly (approximately 1 mL/second in the GSV and 0.5 mL/second in accessory veins or varicosities) while monitoring using ultrasound. Confirm venospasm of the treated vein using ultrasound. Special care must be employed if a perforator is present, to minimize the risk of foam entering the deep venous system.

When treating the proximal GSV, stop the injection when Varithena™ (polidocanol injectable foam) is 3-5 cm distal to the saphenofemoral junction (SFJ).

Apply compression bandaging and stockings and have the patient walk for at least 10 minutes following treatment. Maintain compression for 2 weeks after treatment. Following treatment, advise the patient to avoid heavy exercise for 1 week and extended periods of inactivity for 1 month.

Retained coagulum may be removed by aspiration (microthrombectomy) to improve comfort and reduce skin staining.

Generation of Foam

Activate Varithena™ using the Varithena™ oxygen canister and polidocanol canister [see the attached Instructions for Use leaflet]. Once a Varithena™ transfer unit is in place, foam can be generated and transferred to a syringe. Discard the syringe contents if there are any visible bubbles.

Once activated, the canister of Varithena™ should be stored at room temperature in the upright position, and used within 30 days

Administer the injectable foam within 75 seconds of extraction from the canister to maintain injectable foam properties. If the foam has not been used within 75 seconds discard and generate new foam, as the foam quality will begin to deteriorate.

Use a new sterile syringe after each injection.

Use a new Varithena™ transfer unit for each treatment session.

See Instructions for Use

OVERDOSAGE

In clinical studies, total volumes of up to 60 mL of Varithena™ (polidocanol injectable foam) per treatment session have been administered. There are no known cases of overdosage with Varithena™.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

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. Varithena™ is intended to act as follows:

(1) the foam displaces blood from the vein to be treated, and

(2) the foam scleroses the endothelium.

The active pharmaceutical ingredient of Varithena™ is polidocanol, a non-ionic surfactant sclerosing agent. The hydrophobic pole of the polidocanol molecule attaches to the lipid cell membrane of the venous endothelium, resulting in disruption of the osmotic barrier, destruction of the venous endothelium, and vasospasm. Following exposure to polidocanol, the interior surface of the vein becomes thrombogenic, which leads to thrombus formation and venous occlusion. The occluded vein is eventually replaced by fibrous connective tissue. Polidocanol is deactivated upon contact with blood, thus limiting the sclerosant action to the endothelium near the site of injection.

Gas absorption

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Transient neurologic adverse events such as visual disturbance, migraine like-headache, dizziness or paresthesia have been reported following use of unapproved physician-compounded room air foam sclerotherapy, as a result of presumed passage of bubbles through a patent foramen ovale and temporary occlusion of the cerebral microvasculature.

Blood at ambient pressure is saturated with nitrogen and has no capacity to absorb gaseous nitrogen (similar to the Bends). For this reason Varithena™ excludes all but a trace of nitrogen (<0.8%), and is made of readily absorbable gasses carbon dioxide and oxygen (injected into venous blood containing desaturated hemoglobin). Absorption of Varithena™ gases into human blood is complete within 2 minutes, in contrast foam made with nitrogen does not absorb (80% in air). In another study air based foam was shown to completely occlude the microvasculature of the rat whereas Varithena™ even at 8x the dose did not¹.

In one study investigating the safety of Varithena™, 82 patients with varicose veins were enrolled, including 61 screened for presence of patent foramen ovale². Patients were treated with up to 20 mL Varithena™ 1% (current product with <0.8% nitrogen). Patients were monitored by transcranial Doppler ultrasound for bubbles in the middle cerebral artery (MCA) during and up to one hour post treatment; 60 patients had at least one MCA bubble (mean=22; maximum=382). Patients were hospitalized and monitored for 24 hours, including pulse oximetry); patients with MCA bubbles had neurological examinations, visual field testing, Troponin and ECG, and serial diffusion-weighted MRI within 6 hours and again at 24 hours, 7 days and 28 days. One patient complained of ‘twinkly lights’ which lasted for 20 seconds; ophthalmologic and neurological examinations, visual field assessments and diffusion-weighted MRI performed immediately after this incident were normal.

No patient had any clinical or subclinical neurological signs or symptoms; in particular, there were no changes in the 24 hour MRI diffusion weighted sequence, which would have demonstrated changes in edema in small volumes of cerebral tissue^2,3.

Pharmacodynamics

Polidocanol had a concentration dependent sclerosant effect when injected either as a foam or solution in the marginal ear vein of the rabbit.

Pharmacokinetics

The pharmacokinetics of polidocanol injectable foam (as a weighted sum of 4 oligomers: E5, E9, E12 and E14) were evaluated at two concentrations (1.0% and 2.0%) randomly assigned within gender in 20 patients with GSV incompetence.

When administered as an intravenous injectable foam as 2 fixed 5 mL doses separated by 10 minutes, polidocanol was rapidly detected in plasma, reaching maximum concentration of drug in the body after dosing (C_max) within 15 minutes of the first injection and within 5 minutes of receiving the second injection of polidocanol injectable foam 1.0% or polidocanol injectable foam 2.0%. The mean volume of distribution (Vd) of polidocanol ranged from 35 to 82 L.

Mean systemic clearance (CL) of polidocanol ranged from 0.2 to 0.4 L/min. The clearance of E5 was significantly greater than that of longer oligomers. Mean terminal elimination half-life (t_1/2) ranged from 102 to 153 minutes, with most plasma samples below the limit of quantitation (BLQ) at the end of the 8-hour collection period. The increase in plasma polidocanol concentrations was less than proportional with increasing polidocanol injectable foam concentration. Weight-normalized data demonstrated no consistent differences in C_max or area under the concentration-time curve (AUC) between males and females.

Table 3: Summary of Pharmacokinetic Parameters of Polidocanol following

Administration of Polidocanol Injectable Foam 1.0% in Patients with Incompetence of the SFJ Associated with Incompetence of the GSV or Other Major Accessory Veins

* n = 4 females for Ae and Ae% following Varithena™ 1.0%.

AUC_[0-t] where t = 300 min

Ae: amount excreted in urine; Ae% percent excreted in urine;

ng = nanogram; min = minute; mL = milliliter; L = Liter; NC = Not calculable, no polidocanol detected in urine; SD = standard deviation

Absorption: Total polidocanol was rapidly detected in plasma following injection into the incompetent GSV (or major accessory). For Varithena™ 1.0%, C_max was reached within 14 min and increased with dose (along with AUC) in a less than proportional manner. Overall exposure (C_max and AUC) was higher in females when compared to males; this was accounted for by differences in body weight.

Distribution: Vd ranged from 34.9 L to 82.4 L and was considered similar between males (41.8 L) and females (34.9 L) following administration of Varithena™ 1.0% and between males (82.4 L) and females (48.0 L) following administration of Varithena™ 2.0%.

Metabolism: The data suggest that, since there is no significant renal excretion of intact polidocanol oligomers E5, E9, E12, and E14, metabolism is likely the major route of elimination of polidocanol. In-vitro metabolism studies have demonstrated a time-dependent metabolism of [¹⁴C]- polidocanol following incubation with rat, dog and human liver microsomal and S9 fractions. Qualitative analysis suggested metabolism to be more extensive in human than animal species, and microsomal metabolism was greater than S9 for each species. In rat and dog in-vivo studies, following intravenous administration, [14C]-polidocanol was mainly metabolised to polar metabolites that were rapidly eliminated, predominantly via the renal route and to a lesser extent via the biliary route and in expired air.

Excretion: Terminal t_1/2 ranged from 102.0-153.4 min and was considered similar between males (102.0 min) and females (105.5 min) administered Varithena™ 1.0% and males (153.4 min) and females (114.1 min) administered Varithena™ 2.0 %. CL ranged from 0.236 L/min to 0.351 L/min and was considered similar between males (0.288 L/min) and females (0.236 L/min) administered Varithena™ 1.0 % and males (0.351 L/min) and females (0.291 L/min) administered Varithena™ 2.0 %. Approximately 0.02% of total polidocanol was excreted in the urine following Varithena™ 1.0% and approximately 0.01% of total polidocanol was excreted in the urine following Varithena™ 2.0%, with low renal clearance (≤ approximately 0.05 mL/min), suggesting metabolism is likely the major route of elimination of polidocanol.

Visual inspection of polidocanol injectable foam AUC and C_max values suggests that the increase in AUC and C_max values was modestly less than proportional to increasing dose. The lack of a consistent dose-dependent change in half-life, CL, and Vd suggests that polidocanol injectable foam pharmacokinetics are linear over the dose range studied.

STORAGE AND STABILITY

Contains gas under pressure: May explode if heated. Store in a well-ventilated place. Store the canisters away from sources of heat, including strong light conditions.

Pressurized Oxygen: May cause or intensify fire; oxidiser. Store away from combustible materials.

Maintain the sterile bi-canister assembly within the Tyvek pouch until immediately prior to activation.

Once activated, the canister of Varithena™ must be used within thirty (30) days. The activated Varithena™ canister should always be stored with a Varithena™ transfer unit in place in the upright position at 20-25°C with excursions permitted to 15 and 30°C.

Discard aerosol canisters after use in accordance with local requirements.

SPECIAL HANDLING INSTRUCTIONS

Always write the activation date and time on the canister and verify that the product has not expired prior to use. Do not shake Varithena™ canisters. Avoid contact with eyes.

As the foam fills the syringe and before injecting, inspect the syringe full of foam for any visible bubbles. If visible bubbles are present, the foam should be emptied into the Varithena™ transfer unit waste chamber and the syringe refilled.

A new Varithena™ transfer unit must be used for each treatment session. Use a new sterile syringe after each injection. Do not fill a syringe until just before the foam is required for administration.

For more information, please refer to the Instruction for Use.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Varithena™ is a sterile, injectable foam of an aqueous polidocanol solution (1%) combined with carbon dioxide and oxygen, containing the following inactive ingredients: ethanol (4.2% w/w), disodium hydrogen phosphate dihydrate (0.24% w/w), and potassium dihydrogen phosphate (0.085% w/w) with pH in the range 6.0-7.5.

Polidocanol solution, 180 mg/ 18 mL (10mg/mL) must be activated before use. Once activated, Varithena™ injectable foam delivers a 1% polidocanol solution. Each 1 mL of Varithena™ injectable foam contains 1.3 mg of polidocanol (0.13%). 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.

Varithena™ is supplied as two connecting sterile canisters in a Tyvek^® pouch containing:

• Canister 1- Polidocanol solution, 180 mg/18 mL (10 mg/mL) in carbon dioxide atmosphere
• Canister 2 – Oxygen

The two canisters must be connected and the oxygen added to the polidocanol solution. The foam is then generated after activation [see Product Monograph Administration Section and Instructions For Use].

The injectable foam generated after activation of the polidocanol canister with oxygen from a second aluminum canister, results in a final gas mixture of oxygen:carbon dioxide in a ratio of 65:35 with low (<0.8%) nitrogen content.

The foam is then transferred to a syringe through the Varithena™ transfer unit. The injectable foam thus generated presents controlled density and bubble size and a liquid-to-gas ratio of approximately 1:7 by volume. The median bubble diameter is less than 100 µm and no bubbles are greater than 500 µm.

Varithena™ (polidocanol injectable foam) product is supplied as two commercial presentations:

• Varithena™ Bi-Canister

  o A Tyvek^® pouch containing two sterile, connected 303 mL aluminum alloy canisters: one containing polidocanol solution, 180 mg/18 mL (10 mg/mL) (1% polidocanol), under a carbon dioxide atmosphere, the second containing pressurized oxygen at approximately 5.4 bar absolute pressure. The connector joins the two canisters and allows activation of the product.

  o Product Monograph

  o Patient Medication Information

  o Instructions for Use

• Varithena™ Administration Pack

  o One Varithena™ transfer unit to generate and dispense foam

  o Instructions for Use

  o Patient ancillary components:

  • Three 10 mL silicone-free Luer syringes
  • One 51 cm manometer tube
  • Two compression pads

Varithena™ is also supplied in a Convenience Box that contains:

• A Tyvek^® pouch containing two sterile, connected 303 mL aluminum alloy canisters, as above:
• Product Monograph
• Patient Medication Information
• Instructions for Use
• Three Varithena™ transfer units to dispense injectable foam;

• Three Ancillary Packs each containing:

  o Three 10 mL silicone-free Luer syringes

  o One 51 cm manometer tube

  o Two compression pads

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance Proper name: polidocanol, macrogol lauryl ether, BP/Ph.Eur., polyoxyl lauryl ether, USP

Chemical name: α-dodecyl-ω-hydroxypoly(oxyethylene), oxypolyethoxydodecane, macrogol lauryl ether, polyoxyl lauryl ether, polyethylene glycol monolauryl ether

Molecular formula and molecular mass:

Polidocanol structural formula – 9-mole adduct

O

O

O

O

O

O

O

O

O

OH

C12H25 C18H37O10

= C30H62O10

Foam Liquid Phase 1.0% solution of (CH₃(CH₂)₁₁(OCH₂CH₂)_nOH)_x where n = an average of nine (9)

Foam Gas Phase (CO₂)_y.(O₂)_z where Y:Z = 35:65; Nitrogen content <0.8%

Liquid Phase: Gas Phase = 1:7

Physicochemical properties:

(a) Physical description (e.g., appearance, colour, physical state):

Polidocanol is a white/almost white waxy solid at 15-20°C, as referenced in the Ph.Eur monograph on Macrogol Lauryl Ether (Ph.Eur 01/2008:1124)

(b) Physical form (e.g., polymorphic form, solvate, hydrate):

Polidocanol is a heterogeneous controlled oligomeric compound which has an average polymer length of 9 ethoxy units. It is a waxy solid in appearance and texture, which does not melt at a specific single point due to its heterogeneous nature. The drug substance exhibits no crystallinity and therefore there is no potential for polymorphism.

(c) Solubilities (e.g., in common solvents, aqueous/nonaqueous solubility profile):

Polidocanol is hygroscopic, soluble in water and alcohol, and practically insoluble in light petroleum.

(d) pH and pKa values:

To obtain an accurate and meaningful value for pKa or log P the compound needs to be a single homogenous entity. As polidocanol is a mixture of oligomers, values for pKa and log P are not useful or meaningful measurements.

(e) Other (e.g., partition coefficients, melting or boiling points, optical rotation, refractive index (for a liquid), hygroscopicity, UV absorption maxima and molar absorptivity):

Table 4: Additional Properties of Polidocanol

^a Differential scanning calorimetry ^b Phosphate-buffered saline

CLINICAL TRIALS

Study demographics and trial design: Varithena™ was evaluated in two randomized, blinded, multicenter clinical trials designed to assess the efficacy and safety 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. These trials were conducted in patients with saphenofemoral junction (SFJ) incompetence as evidenced by reflux of the 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. Patients with history of deep vein thrombosis or pulmonary embolism; inability to comply with post-treatment compression due to severe peripheral arterial disease or leg obesity; incompetence of the small saphenous vein or deep venous reflux as a major source of reflux; or reduced mobility, major surgery, pregnancy, or prolonged hospitalization within 3 months were excluded. Patients were randomized in an equal distribution to each treatment group; the primary time point for analyses of the primary, secondary, and tertiary efficacy endpoints was Week 8.

In these clinical trials, the maximum volume of injectable foam or placebo to be 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 1 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.

At each study visit after the initial treatment, AEs, concomitant medications and procedures were recorded. One week after each study treatment (initial or optional additional treatment), patients had a follow-up visit for safety using duplex ultrasound.

Of the 519 patients randomized in VANISH-1 and VANISH-2, a total of 511 were treated with Varithena™ 0.5% (n=111), 1.0% (n=110), or 2.0% (n=63), Varithena™ 0.125% as control (n=114), or placebo (n=113). 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-fourths of the patients were women. The mean 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.

Study results: In VANISH 1 and VANISH 2, Varithena™ was demonstrated to improve the symptoms of superficial venous incompetence and the appearance of visible varicosities. The primary efficacy endpoint in both clinical trials was improvement in patient symptoms, as measured by the change from baseline to Week 8 in the 7-day average electronic daily diary 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. VVSymQ™ scores range from 0 to 25, where 0 represents no symptoms and 25 represents all 5 symptoms experienced all of the time. Results are shown in Table 5.

Table 5: Improvement in Symptoms of Varicose Veins as Measured by VVSymQ™ at

Week 8, VANISH-1 and VANISH-2

*VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.

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 improvement in appearance of visible varicosities from baseline to Week 8 as measured by 1) patients scoring the appearance of their varicose veins in the medial view of their study leg (PA-V³ score) from “Not at all noticeable” (a score of 0) to “Extremely noticeable” (a score of 4); and 2) an independent photography review panel rating the severity of the patient’s varicose vein appearance in standardized digital photographs of the medial view of each patient’s study leg (IPR-V³ score) from “None” (a score of 0) to “Very severe” (a score of 4). Results are shown in Table 6.

Table 6: Improvement in Appearance of Visible Varicosities as Measured by IPR-V³ and PA-V³ at Week 8, VANISH-1 and VANISH-2

*VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.

**IPR-V3 assessed at Week 8 only.

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.

The physiological response to treatment, as measured by duplex ultrasound (duplex response), was defined as elimination of reflux through the SFJ and/or complete occlusion of all incompetent GSV and major accessory veins at baseline. The primary comparison for duplex response in both studies was the pooled Varithena™ groups versus the Varithena™ 0.125% (control) group. Results are shown in Table 7.

Table 7: Response to Treatment as Measured by Duplex Ultrasound at Week 8,

VANISH-1 and VANISH-2

*VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.

**In VANISH-1, a significant dose-response trend was evident between the percent of responders and the dose concentration of Varithena™ (P<0.0001).

VCSS is a clinician rating of severity of chronic venous insufficiency ranging from 0 to 30, where higher scores indicate more severe venous disease. In VANISH-1 and VANISH-2, the adjusted mean changes 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 (Table 8). In both studies, the differences between these improvements were statistically significant (P<0.0001).

Table 8: Improvement in VCSS at Week 8, VANISH-1 and VANISH-2

* VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.

VEINES-QOL is a disease-specific quality of life instrument, with scores ranging from 0 (worst possible quality of life) to 100 (best possible quality of life). 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 are statistically significant (P<0.0001).

The efficacy of Varithena™ was consistent across age, sex, BMI (up to 48 kg/m²), 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.

DETAILED PHARMACOLOGY

Animal Studies

Safety Pharmacology

An extensive package of in vitro and in vivo safety pharmacology studies has been performed with polidocanol solution and foam.

At 10 mg/kg intravenous dose of polidocanol solution, blood in the urine was noted at 6 hours after dosing in male rats but this effect was no longer evident 24 hours after dosing. The 10 mg/kg dose is approximately 5 times the maximum human dose of 15 mL of Varithena™ 1.0% polidocanol on the basis of body surface area.

Intravenous administration of polidocanol solution at 20 mg/kg in the anesthetized dog slightly increased diastolic and mean blood pressure and increased P-Q and QRS interval. The NOAEL for cardiovascular effects in this study was 15 mg/kg (approximately 25 times the maximum human dose of 15 mL of Varithena™ 1.0% polidocanol on the basis of body surface area).

In a further cardiovascular pharmacology study conducted with a once weekly, for four weeks, intravenous bolus injection of Varithena™ in the conscious dog, dose levels of up to 8.0 mL/kg (approximately 17 times the human dose of 15 mL of Varithena™ 1.0% polidocanol based on body surface area) to beagle dogs caused only a transient, but consistent, effect on respiration, evidenced by a decrease in tidal volume and RMV at 15 minutes post-dose, resolving by one hour post-dose. Histopathology of the lung at the end of the 3 month follow-up period showed no abnormalities.

Clinical Pharmacokinetics

In one dedicated pharmacokinetics study, all patients were treated with the current, low-nitrogen formulation of Varithena™ that was used in the pivotal US Phase 3 studies and is planned for marketing. The Study was a 5-week, single-center, open-label, randomly assigned within gender, parallel-group study in which a 10 mL dose of two concentrations of Varithena™ (1.0% and 2.0%) was evaluated. Patients were assigned to receive either Varithena™ 1.0% (3 males and 6 females) or Varithena™ 2.0% (6 males and 6 females).

Patients had SFJ incompetence, incompetence of the GSV or other major accessory veins, and an expected need for treatment with at least 10 mL of Varithena™ to complete treatment of the incompetent GSV and tributaries. A standardized, fixed volume of Varithena™ was administered (i.e., two 5 mL injections 10 minutes apart).

Patients randomized to receive Varithena™ 2.0% in received approximately 25% more polidocanol than is contained in the anticipated marketed maximum dose, 15 mL of Varithena™ 1.0% per treatment session.

The primary objective of this study was to determine the pharmacokinetic parameters of polidocanol, including maximum concentration (C_max), time to peak plasma concentration (T_max), area under the concentration-time curve (AUC), clearance (CL), terminal rate constant (K_el), volume of distribution (Vd) and elimination half-life (T_½) after administration of Varithena™ 1.0% or 2.0%. The absolute amount and percent of polidocanol eliminated unchanged in urine (Ae and Ae%) were also determined.

Blood was obtained to determine the plasma concentrations of the 4 major polidocanol oligomers (E5, E9, E12 and E14 oligomers) and total polidocanol concentrations pre-dose and 1, 4, 5, 7, 9, 11, 14, 15, 17, 20, 25, 30, 60, 120, 180, 240, 300, 360 and 480 minutes following the initial injection of study drug. The mean plasma concentration-time curves for total polidocanol (linear scale) is presented by treatment and gender in Figure 1 (see also Table 3).

Figure 1: Mean Plasma Concentration-time Curves for Total Polidocanol by

Treatment and Gender, Linear Scale (PK)

Polidocanol was rapidly detected in plasma following injection of Varithena™ into the incompetent GSV (or major accessory vein), reaching a peak within 4-5 minutes of the first injection, and reaching C_max within 15 minutes following the initial dose of Varithena™ and within 5 minutes of administration of the second injection.

Plasma polidocanol increased with increasing dose. Overall exposure following administration of Varithena™ as measured by C_max and AUC tended to be higher in the female patients, but weight-normalized data demonstrate no consistent gender differences.

Polidocanol appears in the plasma within 1 minute of injection and the majority was eliminated within 120 minutes, with most plasma samples below the LLOQ at the end of the 8-hour collection period. Approximately 19% of the dose was excreted in the urine in patients treated with Varithena™ 1.0%, and approximately 7% was excreted in the urine in

Serial electrocardiogram (ECG) measurements were obtained in triplicate pre-dose and at 4, 7, 9, 14, 17, 20, 25, 30, 60, 120, 240, 360 and 480 minutes following the initial injection of study drug. These ECGs were analyzed centrally for heart rate (HR) and for PR, QRS, QT, QT interval corrected according to the method of Fridericia (QTcF) and QT interval corrected according to the method of Bazett (QTcB) intervals. A pharmacokinetic/ pharmacodynamic (PK/PD) analysis using a mixed linear effects modeling approach was performed for all patients who had paired ECG and plasma concentrations of polidocanol and the 4 polidocanol oligomers.

The results of the PK/PD analysis showed a slight increase in heart rate 4-6 hours after dosing. There was no signal of any effect on atrioventricular (AV) conduction or cardiac repolarization as measured by the PR and QRS interval durations. There was no significant effect on cardiac repolarization as measured by the lack of a significant change in QTcF and the slightly positive slope for polidocanol and its constituents in the PK/PD model. This ECG analysis showed no evidence of a dose-related effect of Varithena™ on QTcF.

MICROBIOLOGY

Not applicable

TOXICOLOGY

Polidocanol solution, rather than foam, was used in a number of studies because of limitations on the volume of foam that could be injected and because of effects of the foam on the vein independent of the polidocanol. Bridging studies comparing polidocanol foam and polidocanol solution were performed, where applicable. Genotoxicity and reproductive toxicity studies were performed using polidocanol solution.

General Toxicity

Substantial multiples of the clinical dose could not be administered in repeat-dose toxicology studies due to dose-limiting local reactions at the injection site. The principal target organs for toxicity identified in the general toxicity studies were the cardiovascular and the respiratory systems. These results are presented in the DETAILED PHARMACOLOGY section (under Safety Pharmacology).

Genotoxicity

The genotoxicity of polidocanol was investigated in the standard battery of tests. Polidocanol solution was not mutagenic, clastogenic or an inducer of micronuclei in rodent hemopoietic cells. While polidocanol solution was shown to have a weak mutagenic effect in the mouse lymphoma tk mutation assay, this was only seen at highly toxic concentrations and in the presence of the metabolic activation system.

Carcinogenicity

No carcinogenicity studies were performed.

Effect on Fertility

There was no adverse effect on fertility in both male and female rats at 27 mg/kg/day. This dose level is approximately 13.5 times the maximum human dose of 15 mL of Varithena™ 1.0% based on body surface area.

Immunotoxicity

In the guinea pig study, there were no antigenic effects associated with administration of polidocanol solution up to 30 mg/kg (approximately 15 times human exposure at the maximum therapeutic dose of 15 mL of Varithena™ 1.0% based on body surface area).

Local Tolerance

The paravenous injection of 0.5 ml of 2% polidocanol and 2% polidocanol foam around the marginal ear vein of rabbits produced evidence of a local irritant effect which was less marked for polidocanol foam compared to polidocanol solution.

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