itor 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.

nnula 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 )

lacebo-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.

kground risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data developmental reproductive toxicity testing was performed in rats and rabbits using intravenous administration of polidocanol solution. in rabbits, dose levels up to and including 10 mg/kg/day (approximately 12 times the proposed maximum human dose of 15 ml of 1% varithena 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 administered 27 mg/kg/day of polidocanol solution (approximately 13.5 times the human dose based on body surface area), there were no adverse effects on pregnancy performance or fetal development. 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 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), 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. 8.2 lactation risk summary there are no data on the presence of polidocanol in human milk, the effects on the breastfed infant, or the effects on milk production. a lactating woman may consider interrupting breastfeeding and pumping anddiscarding breast milk up to 8 hours after varithena administration in order to minimize exposure to a breastfed infant. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use of the 1333 subjects in clinical studies treated with varithena, 9.1% (n=121) were ≥65 years of age. no clinically important differences in safety or efficacy were observed between older and younger patients in all studies.

loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data developmental reproductive toxicity testing was performed in rats and rabbits using intravenous administration of polidocanol solution. in rabbits, dose levels up to and including 10 mg/kg/day (approximately 12 times the proposed maximum human dose of 15 ml of 1% varithena 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 administered 27 mg/kg/day of polidocanol solution (approximately 13.5 times the human dose based on body surface area), there were no adverse effects on pregnancy performance or fetal development. 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 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), 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.

miting the sclerosant action to the endothelium near the site of injection. 12.2 pharmacodynamics the active pharmaceutical ingredient in varithena is polidocanol. polidocanol damages the endothelium of blood vessels. 12.3 pharmacokinetics the pharmacokinetics of varithena (as a weighted sum of 4 oligomers: e5, e9, e12 and e14) were evaluated at two concentrations (1% and 2%) randomly assigned within gender in 20 patients with gsv incompetence. when administered as an intravenous injectable foam as two 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 varithena 1% or varithena 2%. 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 varithena concentration. weight-normalized data demonstrated no consistent differences in c max or auc between males and females.

e in plasma polidocanol concentrations was less than proportional with increasing varithena concentration. weight-normalized data demonstrated no consistent differences in c max or auc between males and females.

t dose tested (10 mg/kg) hematuria occurred in 67% of animals. this dose is 5 times higher than the proposed maximum human dose based on body surface area. blood was no longer detectable in urine 24 hours after dosing. in the 28-day repeated dose toxicity study in rat blood, pigments were noted in the urine for animals in all treatment groups, including male controls, at the end of the 4-week treatment period with up to 27 mg polidocanol/kg/day. following the 2-week recovery period, there was still evidence that blood pigments were present in the urine but the incidence and severity was decreased when compared to the main study animals. there were no histopathological findings in the urinary bladder in any study animals. in a cardiovascular pharmacology study in the anesthetized dog at 20 mg/kg (approximately 33 times the human dose based on body surface area), statistically significantly higher values for p-q interval were measured before and during dosing and at all time points up to 30 minutes after dosing. an increase in qrs interval was also measured after dosing of 20 mg/kg and at 5 and 10 minutes after dosing. this effect was short lived and was no longer seen at 15 minutes after dosing. in addition, there was an increase in diastolic pressure with increasing dose of polidocanol. this increase became significantly greater (p<0.05) than baseline before injection of the final and highest dose (20 mg/kg). 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 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.

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. of the 519 patients randomized into vanish-1 and vanish-2, a total of 511 were treated with either 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% 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. 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/m 2 (range 16 to 44 kg/m 2 ) and 30 kg/m 2 (range 17 to 48 kg/m 2 ), 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. for both clinical trials, the primary efficacy endpoint 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 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 2 . for both vanish-1 and vanish-2, treatment with 1.0% was superior to placebo in improving symptoms as measured by vvsymq ® , when either a duration or an intensity scale was used to measure patients’ symptoms. *percent of patients who reported their symptoms had "moderately improved" or "much improved" compared with baseline. table 2: improvement in symptoms of varicose veins as measured by vvsymq ® at week 8, vanish-1 and vanish-2 vvsymq ® vanish-1 vanish-2 placebo varithena 1.0% placebo varithena 1.0% n 55 50 54 57 baseline score, mean 8.60 8.82 9.26 7.82 adjusted mean change from baseline at week 8 -2.13 -4.87 -2.00 -5.06 clinically meaningful improvement in symptoms at week 8 * 5.4% (n=56) 64.7% (n=51) 19.6% (n=56) 75.9% (n=58) comparison vs. placebo at week 8, p -value, adjusted mean change <0.0001 <0.0001 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-v 3 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-v 3 score) from "none" (a score of 0) to "very severe" (a score of 4). results are shown in table 3 . † percent who reported the appearance of varicose veins had “moderately improved” or “much improved” compared with baseline. table 3: improvement in appearance of visible varicosities as measured by ipr-v 3 and pa-v 3 at week 8, vanish-1 and vanish-2 vanish-1 vanish-2 placebo varithena 1.0% placebo varithena 1.0% ipr-v 3 n 55 49 56 57 baseline score, mean 1.82 1.98 2.18 2.02 adjusted mean change from baseline at week 8 -0.01 -0.76 -0.07 -0.83 clinically meaningful improvement in appearance at week 8 † 8.9% (n=56) 70.6% (n=51) 0 (n=56) 70.7% (n=58) comparison vs. placebo, p -value at week 8, adjusted mean change <0.0001 <0.0001 pa-v 3 n 55 50 56 57 baseline score, mean 3.49 3.46 3.30 3.49 adjusted mean change from baseline at week 8 -0.15 -1.60 -0.32 -1.79 clinically meaningful improvement in appearance at week 8 † 3.6% (n=56) 54.9% (n=51) 7.1% (n=56) 69.0% (n=58) comparison vs. placebo, p -value at week 8, adjusted mean change <0.0001 <0.0001 tertiary endpoints in vanish-1 and vanish-2 included response to treatment as determined by change from baseline in venous clinical severity score (vcss), by duplex ultrasound, and by change from baseline in venous insufficiency epidemiologic and economic study – quality of life/symptoms (veines-qol) score. 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 in the 1% varithena treatment groups were 3.70 and 5.05, respectively, at week 8 compared with 0.75 and 1.52 points in the placebo groups, respectively. for both studies, the differences between these improvements are statistically significant ( p <0.0001). 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 4 . *in vanish-1, a significant dose-response trend was evident between the percent of responders and the dose concentration of varithena ( p< 0.0001). table 4: response to treatment as measured by duplex ultrasound at week 8, vanish-1 and vanish-2 parameter treatment group, % placebo varithena 0.125% (control) varithena 1.0% responders, vanish-1 * 5.4% (n=56) 42.1% (n=57) 80.4% (n=51) responders, vanish-2 1.8% (n=56) 59.6% (n=57) 86.2% (n=58) veines-qol is a disease-specific quality of life instrument, 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). for efficacy endpoints, varithena treatment effects were consistent across subgroups of age, sex, bmi (up to 48 kg/m 2 ), ceap clinical class, gsv diameter (up to 25.9 mm), and vcss.

as 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; oxidizer. store away from combustible materials. once activated, the canister of 180 mg/18 ml (10 mg/ml) varithena must be used within thirty (30) days. once activated, the canister of 77.5mg/7.75ml (10mg/ml) varithena must be used within thirty (30) days. store activated canisters of varithena upright, with the varithena transfer unit attached, under the same temperature conditions as the varithena bi-canister or convenience box. use a new varithena transfer unit for each treatment session. discard aerosol canisters after use in accordance with state and local requirements. for more information, please refer to the ifu.

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