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11 DESCRIPTION
Asclera
is a sterile, nonpyrogenic, and colorless to faintly greenish-yellow
solution of polidocanol for intravenous use as a sclerosing agent.
The
active ingredient, polidocanol is a non-ionic detergent, consisting of
two components, a polar hydrophillic (dodecyl alcohol) and an apolar
hydrophobic (polyethylene oxide) chain. Polidocanol has the following
structural formula:
C12H25(OCH2CH2)nOH Polyethylene glycol monododecyl ether
Mean extent of polymerization (n): Approximately 9
Mean molecular weight: Approximately 600
Each
mL contains 5 mg (0.5%) or 10 mg (1.0%) polidocanol in water for
injection with 5% (v/v) ethanol at pH 6.5-8.0; disodium hydrogen
phosphate dihydrate, potassium dihydrogen phosphate are added for pH
adjustment.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The active ingredient of Asclera is polidocanol.
Polidocanol
is a sclerosing agent that locally damages the endothelium of blood
vessels. When injected intravenously, polidocanol induces endothelial
damage. Platelets then aggregate at the site of damage and attach to
the venous wall. Eventually, a dense network of platelets, cellular
debris, and fibrin occludes the vessel. Finally, the occluded vein is
replaced with connective fibrous tissue.
12.2 Pharmacodynamics
Polidocanol has a concentration and volume dependent damaging effect on the endothelium of blood vessels.
12.3 Pharmacokinetics
During
the major effectiveness study (EASI-trial), scheduled blood samples
were taken from a sub-group of 22 patients to measure plasma levels of
polidocanol after Asclera treatment of spider and reticular veins. Low
systemic blood levels of polidocanol were seen in some patients.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term
studies to evaluate carcinogenic potential have not been conducted with
polidocanol. Poliodocanol was negative in bacterial reverse mutation
assays in Salmonella and E. Coli, and in micronucleus assay conducted
in mice. Polidocanol induced numerical chromosonal aberrations in
cultured newborn Chinese hamster lung fibroblasts in the absence of
metabolic activation.
Polidocanol did not affect reproductive
performance (fertility) of rats when administered intermittently at
dosages up to 10 mg/kg (approximately equal to the maximum human dose
on the basis of body surface area).
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14 CLINICAL STUDIES
Asclera was
evaluated in a multicenter, randomized, double-blind, placebo and
comparator controlled trial (EASI-study) in patients with spider or
reticular varicose veins. A total of 338 patients were treated with
Asclera [0.5% for spider veins (n=94), 1% for reticular veins (n=86)],
sodium tetradecyl sulfate (STS) 1% (n=105), or placebo (0.9% isotonic
saline solution) (n=53) for either spider or reticular veins. Patients
were predominantly female, ranging in age from 19 to 70 years old. All
of them received an intravenous injection in the first treatment
session; repeat injections were given three to six weeks later if the
previous injection was evaluated as unsuccessful (defined as 1, 2, or 3
on a 5-point scale, see below). Patients returned at 12 and 26 weeks
after the last injection for final assessments.
The primary
effectiveness endpoint was improvement of veins judges by a blinded
panel. Digital images of the selected treatment area were taken prior
to injection, compared with those taken at 12 weeks post-treatment, and
rated on a 5-point scale (1 = worse than before, 2 = same as before, 3
= moderate improvement, 4 = good improvement, 5 = complete treatment
success_; results are shown in Table 2.
Table 2: Improvement of veins in digital photographs after 12 weeks and 26
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Treatment Group
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Polidocanol (n=155)
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STS (n=105)
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Placebo (n=53)
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Digital Photograph Scores at 12 Weeks
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Mean + SD
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4.5* + 0.7
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4.5* + 0.7 |
2.2 + 0.7
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Digital Photograph Scores at 26 Weeks
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Mean + SD
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4.5* + 0.7 |
4.5* + 0.8 |
2.2 + 0.7 |
*p less than 0.0001 compared to placebo (Wilcoxon-Mann-Whitney test)
The
secondary efficacy criterion was the rate of treatment success,
pre-defined as a score of 4 or 5 with patients scoring 1, 2, or 3
considered treatment failures; results are shown in Table 3.
Table 3: Treatment success rates at 12 weeks and 26 weeks
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Treatment success?*
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Polidocanol (n=155)
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STS (n=105)
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Placebo (n=53)
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At 12 weeks (Visit 4)
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Yes
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95%**
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92%**
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8%
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No
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5%
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8%
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92%
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Missing
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0.6%
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0%
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0%
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At 26 weeks (Visit 5)
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Yes
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95%**
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91%**
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6%
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No
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5%
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9%
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94%
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*Treatment
success: Yes = Grade 4 to 5, no = Grade 1 to 3; derived from median of
evaluation; **p less than 0.0001 compared to placebo.
At 12 and
26 weeks, patients' judgement of the results was assessed by showing
them the digital images of their treatment area taken at baseline and
asking them to rate their satisfaction with their treatment using a
verbal rating scale (1 = very unsatisfied, 2 = somewhat satisfied, 3 =
slightly satisfied, 4 = satisfied, and 5 = very satisfied); results are
shown in Table 4.
Table 4: Patient satisfaction after 12 weeks and 26 weeks
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Polidocanol (n=155)
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STS (n=105)
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Placebo (n=53)
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Patient satisfaction with treatment after 12 weeks (Visit 4)
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Satisfied or very satisfied
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87%*
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64%
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14%
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Patient satisfaction with treatment after 26 weeks (Visit 5)
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Satisfied or very satisfied
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84%*
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63%
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16%
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*p less than 0.0001 compared to STS and placebo
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