POLIDOCANOL: 1,302 Adverse Event Reports & Safety Profile

VARITHENA injectable foam contains the sclerosant, polidocanol. It is intended for intravenous use only. Chemically, polidocanol is polyoxyl lauryl ether. The structural formula is represented below: Polidocanol has the molecular formula CH 3 (CH 2 ) 11 (OCH 2 CH 2 ) n OH and a molecular weight of 582.9 when the average ethylene glycol moieties is nine (n=9). Polidocanol is a white to almost white, waxy, hygroscopic solid that is soluble in water and alcohol and melts at temperatures above 20°C. VARITHENA is a sterile, injectable foam of an aqueous polidocanol solution (1%) containing the following inactive ingredients: alcohol (4.2% w/w, purity 96% v/v) disodium hydrogen phosphate dihydrate (0.24% w/w), and potassium dihydrogen phosphate (0.085% w/w) with a pH of 6.0-7.5. The injectable foam is generated after activation of the polidocanol canister with oxygen from a second aluminum canister, resulting in a final gas mixture of oxygen:carbon dioxide in a ratio of 65:35 with low (<0.8%) nitrogen content. At the time of use, VARITHENA is generated as an injectable foam of controlled density and bubble size. The foam is then transferred to a syringe through the VARITHENA transfer unit. The injectable foam has 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. polidocanol Structural Formula

AND USAGE VARITHENA (polidocanol injectable foam) 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. VARITHENA (polidocanol injectable foam) is a sclerosing agent 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. ( 1 ).

AND ADMINISTRATION For intravenous use only. VARITHENA is intended for intravenous injection using ultrasound guidance, administered via a single cannula into the lumen of the target incompetent trunk veins or by direct injection into varicosities. Use up to 5 mL per injection and no more than 15 mL per session. Physicians administering VARITHENA must be experienced with venous procedures and be trained in the administration of VARITHENA. Activate VARITHENA using the VARITHENA oxygen canister and polidocanol canister ( see Instructions for Use ). 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. Administer the injectable foam within 75 seconds of extraction from the canister to maintain injectable foam properties. Use a new sterile syringe after each injection. Use a new VARITHENA transfer unit for each treatment session. 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. 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. When treating the proximal GSV, stop the injection when VARITHENA 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, while being monitored. Maintain compression for 2 weeks after treatment. Repeat treatment may be necessary if the size and extent of the veins to be treated require more than 15 mL of VARITHENA. Separate treatment sessions by a minimum of 5 days. Retained coagulum may be removed by aspiration (microthrombectomy) to improve comfort and reduce skin staining. Incompetent great saphenous or accessory saphenous veins: Use Varithena 1% (CEAP Class 2-6 Disease). ( 2 ). For intravenous use which should be performed under ultrasound guidance when treating the GSV. Use up to 5 mL per injection and 15 mL per treatment session. ( 2 ) Separate treatment sessions by a minimum of 5 days. ( 2 )

The use of VARITHENA is contraindicated in patients with: known allergy to polidocanol [see Warnings and Precautions ( 5.1 )] acute thromboembolic disease Known allergy to polidocanol ( 4 ) Acute thromboembolic disease ( 4 )

REACTIONS In clinical trials, the most common related adverse events (occurring in ≥3% of patients treated with VARITHENA) were pain/discomfort in extremity, infusion site thrombosis (retained coagulum), injection site hematoma or pain, thrombophlebitis superficial, and extravasation.( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocompatibles, Inc. at 1-855-971-VEIN (1-855-971-8346) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of VARITHENA cannot be directly compared to rates in the clinical trials of other drugs or procedures and may not reflect the rates observed in practice. A total of 1333 patients with GSVI 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%, including 437 patients treated with VARITHENA in placebo-controlled clinical trials. Adverse reactions occurring in 3% more patients receiving VARITHENA 1% than receiving placebo are shown in Table 1 . a Retained coagulum. b Common femoral vein thrombus extension (non-occlusive thrombi starting in the superficial vein and extending into the common femoral vein).

Table

1: Treatment-emergent adverse reactions (3% more on VARITHENA 1% than on placebo) through Week 8 (n=588)

Adverse Reaction

Placebo (N=151) VARITHENA 1.0% (N=149) Pain in extremity 14 (9.3) 25 (16.8) Infusion site thrombosis b 0 24 (16.1) Contusion/injection site hematoma 9 (6.0) 23 (15.4) Limb discomfort 5 (3.3) 18 (12.1) Tenderness/injection site pain 5 (3.3) 16 (10.7) Venous thrombosis limb c 0 12 (8.1) Thrombophlebitis superficial 2 (1.3) 8 (5.4) Deep vein thrombosis 0 7 (4.7) In VARITHENA-treated patients, 80% of pain events in the treated extremity resolved within 1 week. Proximal symptomatic venous thrombi occurred in <1% of patients treated with VARITHENA. Approximately half of patients with thrombi received treatment with anticoagulants. 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. Neurologic adverse events (cerebrovascular accident, migraines) have been reported in patients following administration of physician compounded foam sclerosants. None of the 1333 patients in the VARITHENA trials experienced clinically important neurological or visual adverse events suggestive of cerebral gas embolism. The incidence of neurologic and visual adverse events within 1 day of treatment in the placebo-controlled studies was 2.7% in the pooled VARITHENA group and 4.0% in the placebo groups. Skin discoloration adverse events were reported in 1.1% of the pooled VARITHENA group and 0.7% of the placebo group in the placebo-controlled studies.

AND PRECAUTIONS Be prepared to treat anaphylaxis. ( 5.1 )

Venous

Thrombosis and Pulmonary Embolism. ( 5.2 )

Arterial

Embolism. ( 5.3 ) Tissue ischemia and necrosis: Do not inject intra-arterially. ( 5.4 )

5.1 Anaphylaxis Severe allergic reactions have been reported following polidocanol use, including anaphylactic reactions, some of them fatal. Severe reactions are more frequent with use of larger volumes (&gt; 3 mL). Minimize the dose of polidocanol. Be prepared to treat anaphylaxis appropriately. Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, take care in intravenous needle placement and use the smallest effective volume at each injection. After the injection session is completed, apply compression with a stocking or bandage, and have the patient walk for 15-20 minutes. Keep the patient under supervision during this period to treat any anaphylactic or allergic reaction <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> .

5.2 Venous Thrombosis and Pulmonary Embolism Asclera can cause venous thrombosis and subsequent pulmonary embolism or other thrombotic events. Follow administration instructions closely and monitor for signs of venous thrombosis after treatment. Patients with reduced mobility, history of deep vein thrombosis or pulmonary embolism, or recent (within 3 months) major surgery, prolonged hospitalization or pregnancy are at increased risk for developing thrombosis.

5.3 Arterial Embolism Stroke, transient ischemic attack, myocardial infarction, and impaired cardiac function have been reported in close temporal relationship with polidocanol administration. These events may be caused by air embolism when using the product foamed with room air (high nitrogen concentration) or thromboembolism. The safety and efficacy of polidocanol foamed with room air has not been established and its use should be avoided.

5.4 Tissue Ischemia and Necrosis Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene. Take care in intravenous needle placement and use the smallest effective volume at each injection site. After the injection session is completed, apply compression with a stocking or bandage and have patients walk for 15-20 minutes. If intra-arterial injection of polidocanol occurs, consult a vascular surgeon immediately.

INTERACTIONS No specific drug interaction studies have been performed. There are no known drug interactions with VARITHENA. There are no known drug interactions with VARITHENA. ( 7 )