ZINGO Powder intradermal injection Ref.[49663] Active ingredients: Lidocaine

Do not use around the eyes.

Do not use ZINGO on body orifices, mucous membranes, or on areas with a compromised skin barrier. Only use ZINGO on skin locations where an adequate seal can be maintained.

Patients with severe hepatic disease or pseudocholinesterase deficiency, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations of lidocaine.

Patients with bleeding tendencies or platelet disorders could have a higher risk of superficial dermal bleeding.

5.1 Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue ZINGO and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ZINGO has been evaluated in 10 clinical trials, five in adults and five in pediatric patients.

The five adult clinical trials consisted of a randomized, double-blind, parallel-arm, sham-placebo controlled Phase 3 trial that enrolled 693 patients, two randomized, double-blind, crossover design, sham-placebo controlled Phase 1 trials that enrolled 455 patients, and two open-label studies that enrolled 44 patients. A total of 742 adults received an active treatment with an active treatment that delivered a 0.5 mg dose of lidocaine, while 775 received placebo.

The five pediatric clinical trials consisted of five randomized, double-blind, parallel-arm, sham-placebo controlled trials in which 1761 patients, ages 3 to 18, received either ZINGO or a sham placebo device. A total of 906 pediatric patients received active treatment, while 855 received placebo.

Application Site Reaction

The application site was specifically assessed for four categories of skin site reaction (erythema, edema, pruritus, and petechiae).

In adults, erythema occurred in 67.3% of ZINGO-treated patients, and in 25.0% of placebo-treated patients. Petechiae occurred in 46.4% of ZINGO-treated patients, and in 7.0% of placebo-treated patients. Edema occurred in 4.3% of ZINGO-treated patients, and in 0.8% of placebo-treated patients. Pruritus occurred in 9.4% of ZINGO-treated patients and in 6.2% of placebo-treated patients.

In pediatric patients, erythema occurred in 53% of ZINGO-treated patients, and in 27% of placebo-treated patients. Petechiae occurred in 44% of ZINGO-treated patients, and in 5% of placebo-treated patients. Edema occurred in 8% of ZINGO-treated patients, and in 3% of placebo-treated patients. Pruritus occurred in 1% of patients in both treatment groups.

Adverse Reactions

Amongst the 742 adult patients receiving active treatment and 775 adult patients receiving sham placebo treatment in the 5 adult studies, the percentage of adult patients with any adverse reactions was 3.9% in the active-treated patients and 4.9% in the sham placebo treated patients.

Most adverse reactions were application-site related (i.e., hypoaesthesia (0% active, 0.5% sham placebo), burning (0.54% active, 0.4% sham placebo), and venipuncture site hemorrhage (0.4% active, 1.7% sham placebo)).

The most common systemic adverse reaction was dizziness, which occurred in 0.9% of active-treated adult patients and in 0.7% of sham placebo treated adult patients. No other systemic adverse events occurred in more than two patients in either treatment group.

Amongst the 906 pediatric patients receiving active treatment and 855 pediatric patients receiving sham placebo treatment, the percentage of pediatric patients with any adverse reactions was approximately 9% in each treatment group.

Most adverse reactions were application-site related (i.e., bruising, burning, pain, contusion, hemorrhage), occurring in 4% of pediatric patients in each treatment group.

The most common systemic adverse reactions were nausea (2%) and vomiting (1%).

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

Examples of Drugs Associated with Methemoglobinemia:

ZINGO was not formally evaluated for effects on reproduction. Significant systemic exposure to lidocaine is not expected under recommended conditions of use of ZINGO as lidocaine levels were below the limit of detection in human studies. Lidocaine has been previously tested for reproductive toxicity in animal studies, however. The following ratios are based on the assumption that the applied dose is completely absorbed through the skin.

Teratogenic Effects

Pregnancy Category B. Lidocaine was not teratogenic in rats given subcutaneous doses up to 60 mg/kg [360 mg/m² or 1200-fold the single dermal administration (SDA) of 0.5 mg lidocaine in a 60 kg individual (0.3 mg/m²)] or in rabbits up to 15 mg/kg (180 mg/m² or 600-fold the SDA).

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ZINGO should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Lidocaine, containing 1:100,000 epinephrine, at a dose of 6 mg/kg (36 mg/m² or 120-fold the SDA) injected into the masseter muscle of the jaw or into the gum of the lower jaw of Long-Evans hooded pregnant rats on gestation day 11 led to developmental delays in neonatal behavior among offspring. Developmental delays were observed for negative geotaxis, static righting reflex, visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient with responses becoming comparable to untreated animals later in life. The clinical relevance of the animal data is uncertain. No adequate and well–controlled studies have been conducted in pregnant women. Because animal studies are not always predictive of human response, ZINGO should be used during pregnancy only if the potential benefit justifies risk to the fetus.

Lidocaine is excreted into human milk; therefore, caution should be exercised when ZINGO is administered to a nursing mother. Because no plasma concentrations of lidocaine are detected after topical administration of ZINGO in recommended doses, the small amount of lidocaine that would be ingested orally by a suckling infant is unlikely to cause adverse effects.

Lidocaine is not contraindicated in labor and delivery. In humans, the use of lidocaine for labor conduction analgesia has not been associated with an increased incidence of adverse fetal effects either during delivery or during the neonatal period. Should ZINGO be used concomitantly with other products containing lidocaine, total doses contributed by all formulations must be considered.

Safety and effectiveness in pediatric patients below the age of 3 years have not been established.

Of the 693 patients evaluated in a Phase 3 randomized, double blind, sham-placebo-controlled trial in adults, 17% were of 65 and over. The safety and effectiveness of ZINGO in geriatric patients were similar to that of ZINGO in adults under 65 years of age.