Amide Local Anesthetic

Pliaglis

Approved 29 Jun 2006TopicalCream

Indications

PLIAGLIS is indicated for use on intact skin in adults to provide topical local analgesia for superficial dermatological procedures such as dermal filler injection, pulsed dye laser therapy, facial laser resurfacing, and laser-assisted tattoo removal. PLIAGLIS is a combination of lidocaine, an amide local anesthetic, and tetracaine, an ester local anesthetic, indicated for use on intact skin in adults to provide topical local analgesia for superficial dermatological procedures such as dermal filler injection, pulsed dye laser therapy, facial laser resurfacing, and laser-assisted tattoo removal.

( 1 )

Contraindications

PLIAGLIS is contraindicated in patients with a known history of sensitivity to lidocaine or tetracaine, local anesthetics of the amide or ester type, or to any other component of the product [ see Warnings and Precautions (5.4) ]. PLIAGLIS is contraindicated in patients with para-aminobenzoic acid (PABA) hypersensitivity. Known history of sensitivity to lidocaine or tetracaine, or local anesthetics of the amide or ester type.

( 4 ) Para-aminobenzoic acid (PABA) hypersensitivity. ( 4 )

Warnings and precautions

Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetic use. ( 5.1 ) Overexposure : To avoid overexposure that could lead to adverse effects, do not use for longer duration or over larger surface areas than recommended. ( 5.2 ) consider total amount of local anesthetics absorbed from all formulations. ( 5.2 ) do not apply to mucous membranes or broken or inflamed skin. ( 5.2 ) use with caution in patients who may be more sensitive to systemic effects of PLIAGLIS, including acutely ill or debilitated or those with severe hepatic disease or pseudocholinesterase deficiency.

( 5.2 ) Risk of Secondary Exposure to Children and Pets : Store and dispose of PLIAGLIS out of reach of children and pets due to the risk of accidental exposure and resulting toxicity. ( 5 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs. ( 5.4 ) Eye Irritation : Avoid contact with eyes. ( 5.5 )

5.1Methemoglobinemia 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.

At a glance

Brand name: Pliaglis
Active substance: lidocaine
Pharmacologic class: Amide Local Anesthetic, Antiarrhythmic, Ester Local Anesthetic
Route: Topical
Dosage form: Cream
Applicant: Crescita Therap
Status: Prescription
FDA approval: 29 Jun 2006
Application: NDA021717-001

Indications

( 1 )

Contraindications

( 4 ) Para-aminobenzoic acid (PABA) hypersensitivity. ( 4 )

Warnings and precautions

5.1Methemoglobinemia Cases

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

There are no available data on PLIAGLIS use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from an epidemiologic study and case series with parenteral lidocaine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Published data on tetracaine use in pregnant women are not sufficient to determine any drug-associated risks.

The amount of lidocaine and tetracaine systemically absorbed from PLIAGLIS is low compared to the parenteral route of administration and is not expected to result in significant fetal exposure. Systemic exposure of PLIAGLIS is directly related to both the duration of application and the surface area over which it is applied [ see Clinical Pharmacology (12.3) ] . In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at doses approximately 1.3 times the maximum recommended human dose (MRHD) of 53 grams of PLIAGLIS during the period of organogenesis resulted in lower fetal body weights.

In a published animal reproduction study, pregnant rats administered lidocaine, containing 1:100,000 epinephrine, injected into the masseter muscle of the jaw or into the gum of the lower jaw on Gestation Day 11 at 0.02 times the MRHD of PLIAGLIS resulted in developmental delays in neonates. Subcutaneous administration of tetracaine to pregnant rats and rabbits during organogenesis did not produce adverse embryofetal effects at 0.03 times the MRHD of PLIAGLIS (see Data ) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background 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 Lidocaine administered by subcutaneous injection to pregnant rats during organogenesis was not teratogenic at doses up to 60 mg/kg (0.16 times the level of lidocaine contained in the MRHD of 53 grams of PLIAGLIS based on a mg/m 2 body surface area (BSA) comparison).

Lidocaine administered by subcutaneous injection to pregnant rabbits during organogenesis was not teratogenic at doses up to 15 mg/kg (0.08 times the level of lidocaine in the MRHD of PLIAGLIS on a mg/m 2 basis). In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 1.3 times the level of lidocaine in the MRHD of PLIAGLIS on a mg/m 2 basis) in the absence of maternal toxicity.

Tetracaine administered by subcutaneous injection to pregnant rats during organogenesis was not teratogenic at doses up to 10 mg/kg or in rabbits at doses up to 5 mg/kg (equivalent to 0.03 times of tetracaine in the MRHD of PLIAGLIS on a mg/m 2 basis). Lidocaine and tetracaine administered by subcutaneous injection to pregnant rats during organogenesis as a 1:1 eutectic mixture of 10 mg/kg each (equivalent to 0.03 times the active components in the MRHD of PLIAGLIS on a mg/m 2 basis) was not teratogenic.

Lidocaine and tetracaine by subcutaneous injection to pregnant rabbits during organogenesis as a 1:1 eutectic mixture of 5 mg/kg each was not teratogenic in rabbits (equivalent to 0.03 times the active components in the MRHD of PLIAGLIS on a mg/m 2 basis). Lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (approximately 0.02 times the level of lidocaine in the MRHD of PLIAGLIS on a mg/m 2 basis) injected into the masseter muscle of the jaw or into the gum of the lower jaw of pregnant Long-Evans hooded rats on Gestation Day 11, lead 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. Pre- and post-natal maturational, behavioral, or reproductive development was not affected by maternal subcutaneous administration of tetracaine during gestation (Gestation Day 6 to Post-Partum Day 20) and lactation up to doses of 7.5 mg/kg (equivalent to 0.02 times the level of tetracaine in the MRHD of PLIAGLIS on a mg/m 2 basis).

Adverse reactions

The following adverse reactions are described elsewhere in the labeling: Methemoglobinemia [see Warnings and Precautions (5.1) ] Overexposure [see Warnings and Precautions (5.2) ] Risks of Secondary Exposure in Children and Pets [see Warnings and Precautions (5.3) ] Anaphylactic Reactions [see Warnings and Precautions (5.4) ] Eye Irritation [see Warnings and Precautions (5.5) ] Most common local reactions were erythema (47%), skin discoloration (16%), and edema (14%).

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact IPG Pharmaceuticals, Inc. at 1-888-711-7116 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice. However, the adverse reaction information from clinical trials does provide a basis for identifying the adverse events that appear to be related to drug use and for approximating their incidence in clinical practice.

PLIAGLIS has been evaluated for safety in 2159 persons undergoing a superficial dermal procedure. PLIAGLIS was studied in 11 placebo-controlled and 1 active-controlled trials, and in open-label safety trials. All 2159 persons were exposed to only a single application of PLIAGLIS. Adverse reactions were assessed by collecting spontaneously reported adverse reactions, and observations made on formal evaluation of the skin for specific reactions.

Most common adverse reactions in clinical trials Localized Reactions: In clinical studies, the most common local reactions were erythema (47%), skin discoloration (e.g., blanching, ecchymosis, and purpura) (16%), and edema (14%). There were no serious adverse reactions. However, one patient withdrew due to burning pain at the treatment site. Other Localized Reactions: The following dermal adverse reactions occurred in 1% or less of PLIAGLIS-treated patients: ecchymosis, petechial rash, vesiculobullous rash, perifollicular erythema, perifollicular edema, pruritus, rash, maculopapular rash, dry skin, contact dermatitis, and acne.

Systemic (Dose-Related) Reactions: Across all trials, 19 subjects experienced a systemic adverse reaction, 15 of whom were treated with PLIAGLIS and 4 with placebo. The frequency of systemic adverse reactions was greater for the PLIAGLIS group (1%) than the placebo group (0.3%). The most common systemic adverse events were headache, vomiting, dizziness, and fever, all of which occurred with a frequency of <1%. Other systemic reactions were syncope, nausea, confusion, dehydration, hyperventilation, hypotension, nervousness, paresthesia, pharyngitis, stupor, pallor, and sweating.

Systemic adverse reactions of lidocaine and tetracaine are similar in nature to those observed with other amide and ester local anesthetic agents, including CNS excitation and/or depression (lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensation of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest).

Excitatory CNS reactions may be brief or not occur at all, in which case the first manifestation may be drowsiness merging into unconsciousness. Signs of CNS toxicity may start at plasma concentrations of lidocaine at 1000 ng/mL. The plasma concentrations at which tetracaine toxicity may occur are less well characterized; however, systemic toxicity with tetracaine is thought to occur with much lower plasma concentrations compared with lidocaine.

The toxicity of co-administered local anesthetics is thought to be at least additive. Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest.

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PLIAGLIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye disorders: Eyelid swelling Skin: Pruritus, Rash, Skin Burning Sensation, Erythema, Urticaria Other: Drug ineffective

Pliaglis

Indications

Contraindications

Warnings and precautions

5.1Methemoglobinemia Cases

At a glance

Two medicines in one question?

Pliaglis

Indications

Contraindications

Warnings and precautions

5.1Methemoglobinemia Cases

At a glance

Two medicines in one question?

5.2Overexposure Application of

5.3Risks of Secondary Exposure to Children and Pets Used

5.4Anaphylactic Reactions Allergic

5.5Eye Irritation

5.6Vaccinations

Interactions

7.1Antiarrhythmic Drugs

7.2Local Anesthetics When

7.3Drugs That May Cause Methemoglobinemia When Used with

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Official product information