Pharmacology: Pharmacodynamics: Mechanism of Action: Wocaine when applied topically in the form of the plaster has been shown in studies to produce a local analgesic effect. The mechanism by which this occurs is due to stabilisation of neuronal membranes, which is thought to cause down regulation of sodium channels resulting in pain reduction.
Clinical Efficacy: Pain management in post-herpetic neuralgia (PHN) is difficult. There is evidence of efficacy with Wocaine in the symptomatic relief from the allodynic component of PHN in some cases.
Efficacy of Wocaine has been shown in PHN studies. Other models of neuropathic pain have not been studied.
There were 2 main controlled studies carried out to assess the efficacy of the Wocaine 5% medicated plaster.
In the 1st study, patients were recruited from a population who were already considered to respond to Wocaine. It was a crossover design of 14 days treatment with Wocaine 5% medicated plaster followed by placebo or vice versa. The primary endpoint was the time to exit, where patients withdrew because their pain relief was 2 points lower than their normal response on a 6-point scale (ranging from worse to complete relief). There were 32 patients, of whom 30 completed. The median time to exit for placebo was 4 days and for active was 14 days (p value <0.001); none of those on active discontinued during the 2-week treatment period.
In the 2nd study, 265 patients with PHN were recruited and allocated 8 weeks of open label active treatment with Wocaine 5% medicated plaster. In this uncontrolled setting, approximately 50% of patients responded to treatment as measured by 2 points lower than their normal response on a 6-point scale (ranging from worse to complete relief). A total of 71 patients were randomised to receive either placebo or Wocaine 5% medicated plaster given for 2-14 days. The primary endpoint was defined as lack of efficacy on 2 consecutive days leading to withdrawal of treatment. There were 9/36 patients on active and 16/35 patients on placebo who withdrew because of lack of treatment benefit.
Post-hoc analyses of the 2nd study showed that the initial response was independent of the duration of preexisting PHN. However, the notion that patients with longer duration of PHN (>12 months) do benefit more from active treatment is supported by the finding that this group of patients was more likely to drop out due to lack of efficacy when switched to placebo during the double-blind withdrawal part of this study.
Pharmacokinetics: Absorption: When Wocaine 5% medicated plaster is used according to the maximum recommended dose (3 plasters applied simultaneously for 12 hr) about 3±2% of the total applied Wocaine dose is systemically available and similar for single and multiple administrations.
A population kinetics analysis of the clinical efficacy studies in patients suffering from PHN revealed a mean maximum concentration for Wocaine of 45 ng/mL after application of 3 plasters simultaneously 12 hr/day after repeated application for up to 1 year. This concentration is in accordance with the observation in pharmacokinetic studies in PHN patients (52 ng/mL) and in healthy volunteers (85 and 125 ng/mL).
For Wocaine and its metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX) and 2,6-xylidine, no tendency for accumulation was found, steady state concentrations were reached within the 1st 4 days.
The population kinetic analysis indicated that when increasing the number from 1-3 plasters worn simultaneously, the systemic exposure increased less than proportionally to the number of used plasters.
Distribution: After IV administration of Wocaine to healthy volunteers, the volume of distribution was found to be 1.3±0.4 L/kg (mean ± S.D., n=15). The Wocaine distribution volume showed no age-dependency, it is decreased in patients with congestive heart failure and increased in patients with liver disease. At plasma concentrations produced by application of the plaster approximately 70% of Wocaine is bound to plasma proteins. Wocaine crosses the placenta and blood brain barriers presumably by passive diffusion.
Biotransformation: Wocaine is metabolised rapidly in the liver to a number of metabolites. The primary metabolic route for Wocaine is N-dealkylation to MEGX, GX both of which are less active than Wocaine and available in low concentrations. These are hydrolyzed to 2,6-xylidine, which is converted to conjugated 4-hydroxy-2,6-xylidine.
The metabolite, 2,6-xylidine, has unknown pharmacological activity but shows carcinogenic potential in rats. A population kinetics analysis revealed a mean maximum concentration for 2,6-xylidine of 9 ng/mL after repeated daily applications for up to 1 year This finding is confirmed by a phase I pharmacokinetic study. Data on Wocaine metabolism in the skin are not available.
Elimination: Wocaine and its metabolites are excreted by the kidneys. More than 85% of the dose is found in the urine in the form of metabolites or active substance. Less than 10% of the Wocaine dose is excreted unchanged. The main metabolite in urine is a conjugate of 4-hydroxy-2,6-xylidine, accounting for about 70-80% of the dose excreted in the urine. 2,6-xylidine is excreted in the urine in man at a concentration of <1% of the dose. The elimination t½ of Wocaine after plaster application in healthy volunteers is 7.6 hrs. The excretion of Wocaine and its metabolites may be delayed in cardiac, renal or hepatic insufficiency.
Toxicology: Preclinical Safety Data: Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In toxicological studies described in the literature using systemic administration of Wocaine, cardiovascular effects (tachycardia or bradycardia, decreases in cardiac output and blood pressure, cardiac arrest) and central nervous system effects (convulsion, coma, respiratory arrest) were observed at exposures considered sufficiently in excess of the maximum human exposure following treatment with Wocaine. This indicates that these effects have little relevance to clinical use.
Wocaine hydrochloride has shown no genotoxicity when investigated in vitro or in vivo. Its hydrolysis product and metabolite, 2,6-xylidine, showed mixed genotoxic activity in several assays particularly after metabolic activation.
Carcinogenicity studies have not been performed with Wocaine. Studies performed with the metabolite 2,6-xylidine mixed in the diet of male and female rats resulted in treatment-related cytotoxicity and hyperplasia of the nasal olfactory epithelium and carcinomas and adenomas in the nasal cavity were observed. Tumorigenic changes were also found in the liver and subcutis. Because the risk to humans is unclear, long-term treatment with high doses of Wocaine should be avoided.
Wocaine had no effect on general reproductive performance or female fertility in rats at plasma concentrations up to 130-fold those observed in patients. No adverse effects were seen in an embryofoetal/teratogenicity study in rats at plasma concentrations >200-fold that observed in humans.
Animal studies are incomplete with respect to effects on pregnancy, embryofoetal development, parturition or postnatal development.
Use Wocaine exactly as directed by your doctor. Do not use it for any other condition without first checking with your doctor. Wocaine may cause unwanted effects if it is used too much, because more of it is absorbed into the body through the skin.
Wocaine should only be used for problems being treated by your doctor. Check with your doctor before using it for other problems, especially if you think that an infection may be present. Wocaine should not be used to treat certain kinds of skin infections or serious problems, such as severe burns.
If you are using the topical jelly or ointment:
If you are using the viscous topical solution:
If you are using the skin patch:
The dose of Wocaine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Wocaine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Wocaine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
After removing a used patch, fold the patch in half with the sticky sides together. Make sure to dispose of it out of the reach of children and pets.
Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Wocaine comes in many different forms for different uses. Wocaine cream, lotion, spray, solution, film, and transdermal patch are generally for use on the skin only.
If your medication comes with patient instructions for safe and effective use, follow these directions carefully. Ask your doctor or pharmacist if you have any questions.
Your body may absorb more of this medication if you use too much, if you apply it over large skin areas, or if you apply heat, bandages, or plastic wrap to treated skin areas. Skin that is cut or irritated may also absorb more topical medication than healthy skin.
Use the smallest amount of this medication needed to numb the skin or relieve pain. Do not use large amounts of Wocaine, or cover treated skin areas with a bandage or plastic wrap without medical advice. Be aware that many cosmetic procedures are performed without a medical doctor present.
Wocaine may be applied with your finger tips or a cotton swab. Follow your doctor's instructions.
Do not apply this medication to swollen skin areas or deep puncture wounds. Avoid using the medicine on skin that is raw or blistered, such as a severe burn or abrasion.
Store at room temperature away from moisture and heat.
Keep both used and unused Wocaine patches out of the reach of children or pets. The amount of Wocaine in the skin patches could be harmful to a child or pet who accidentally sucks on or swallows the patch. Seek emergency medical attention if this happens.
Wocaine is an amide-type local anesthetic agent and is suggested to stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses.
The penetration of Wocaine into intact skin after application of Wocaine Patch is sufficient to produce an analgesic effect, but less than the amount necessary to produce a complete sensory block.
Absorption: The amount of Wocaine systemically absorbed from Wocaine Patch is directly related to both the duration of application and the surface area over which it is applied. In a pharmacokinetic study, three Wocaine Patches were applied over an area of 420 cm2 of intact skin on the back of normal volunteers for 12 hours. Blood samples were withdrawn for determination of Wocaine concentration during the application and for 12 hours after removal of patches. The results are summarized in Table 1.
|Area (cm2)||Dose Absorbed (mg)||Cmax |
|3 patches |
|Back||420||64 ± 32||0.13 ± 0.06||11 hr|
When Wocaine Patch is used according to the recommended dosing instructions, only 3 ± 2% of the dose applied is expected to be absorbed. At least 95% (665 mg) of Wocaine will remain in a used patch. Mean peak blood concentration of Wocaine is about 0.13 mcg/mL (about 1/10 of the therapeutic concentration required to treat cardiac arrhythmias). Repeated application of three patches simultaneously for 12 hours (recommended maximum daily dose), once per day for three days, indicated that the Wocaine concentration does not increase with daily use. The mean plasma pharmacokinetic profile for the 15 healthy volunteers is shown in Figure 1.
Figure 1: Mean Wocaine blood concentrations after three consecutive daily applications of three Wocaine Patches simultaneously for 12 hours per day in healthy volunteers (n = 15).
Distribution: When Wocaine is administered intravenously to healthy volunteers, the volume of distribution is 0.7 to 2.7 L/kg (mean 1.5 ± 0.6 SD, n = 15). At concentrations produced by application of Wocaine Patch, Wocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mcg/mL of free base), the plasma protein binding of Wocaine is concentration dependent. Wocaine crosses the placental and blood brain barriers, presumably by passive diffusion.
Metabolism: It is not known if Wocaine is metabolized in the skin. Wocaine is metabolized rapidly by the liver to a number of metabolites, including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that of Wocaine. A minor metabolite, 2, 6-xylidine, has unknown pharmacologic activity but is carcinogenic in rats. The blood concentration of this metabolite is negligible following application of Wocaine Patch 5%. Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of Wocaine concentrations, respectively.
Excretion: Wocaine and its metabolites are excreted by the kidneys. Less than 10% of Wocaine is excreted unchanged. The half-life of Wocaine elimination from the plasma following IV administration is 81 to 149 minutes (mean 107 ± 22 SD, n = 15). The systemic clearance is 0.33 to 0.90 L/min (mean 0.64 ± 0.18 SD, n = 15).
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Information checked by Dr. Sachin Kumar, MD Pharmacology