Overview of Cold Sore Ointment
Dosage Strength of Cold Sore Ointment
Acyclovir / Lidocaine / Lysine HCl 5/1/5% 10 mL Pump
Acyclovir is a synthetic purine deoxynucleoside analogue (specifically acyclic guanosine analogue) with potent activity against herpes simplex viruses type 1 and 2 (HSV-1, HSV-2) and much less activity against varicella-zoster virus (VZV). Clinically, the drug is indicated to treat the following infections: herpes labialis, herpes genitalis, herpes simplex encephalitis, herpes simplex keratitis, neonatal herpes infection, chickenpox (varicella), and shingles (zoster). In order to be active, the drug must be phosphorylated by viral thymidine kinase to acyclovir monophosphate, and then further converted to acyclovir triphosphate. After phosphorylation, the drug binds to viral DNA polymerase, is incorporated into viral DNA, and ultimately inhibits viral DNA synthesis. The greater antiviral activity of acyclovir against HSV as compared to VZV is due to its more efficient phosphorylation by HSV thymidine kinase. Acyclovir is commercially available as a topical cream and ointment, ophthalmic ointment, oral capsule, tablet and suspension, solution for injection, and buccal tablets.123456
Lidocaine is a widely used antiarrhythmic and amide-type local anesthetic. As an anesthetic agent, it is available as an ointment, jelly, patch, or aerosol for topical use, as an oral solution, and as an injection. Lidocaine is classified as a class Ib antiarrhythmic. It may be considered for ventricular fibrillation (VF) and pulseless ventricular tachycardia (pVT) that is unresponsive to cardiopulmonary resuscitation (CPR), defibrillation, and vasopressor therapy. Evidence is inadequate regarding the routine use of lidocaine after cardiac arrest or early (within the first hour) after return of spontaneous circulation (ROSC). However, prophylactic use of lidocaine may be considered in certain circumstances (e.g., during emergency medical services transport) when treatment of recurrent VF/pVT may be challenging.7 Due to the potential for serious adverse reactions, including cardiovascular depression, continuous electrocardiogram monitoring is recommended during intravenous lidocaine treatment.8 There is limited evidence suggesting that nebulized lidocaine exhibits steroid-sparing effects when used in corticosteroid-dependent asthmatics.91011 However, extreme caution is recommended until long-term safety and efficacy can be established.
Lysine, or L-lysine, is an essential amino acid, meaning it is necessary for human health, but the body cannot make it. You have to get lysine from food or supplements. Amino acids like lysine are the building blocks of protein. Lysine is important for proper growth, and it plays an essential role in the production of carnitine, a nutrient responsible for converting fatty acids into energy and helping lower cholesterol. Lysine has antiviral effects by blocking the activity of arginine, which promotes HSV replication.
Mechanism of Action
Acyclovir is a synthetic purine deoxynucleoside analogue with inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). Acyclovir inhibits viral DNA synthesis and must be phosphorylated intracellularly to be active. Acyclovir is converted to the monophosphate by viral thymidine kinase (TK), then to diphosphate by cellular guanylate kinase, and finally to the triphosphate by various cellular enzymes. Acyclovir triphosphate stops replication of herpes viral DNA by the following 3 mechanisms: competitive inhibition of viral DNA polymerase, incorporation into and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.123 4
Herpes virus DNA polymerases differ in sensitivity to acyclovir. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral thymidine kinase. Acyclovir is effective only against actively replicating viruses; therefore, it does not eliminate the latent herpes virus genome. Uninfected cells show only minimal phosphorylation of acyclovir, and there is only a small amount of acyclovir taken up into these cells. The concentration of acyclovir triphosphate is 40- to 100- times higher in HSV-infected cells than non-infected cells.6
Resistance to acyclovir by herpes virus results from mutations in viral thymidine kinase and DNA polymerase that cause a loss of thymidine kinase activity, alterations in thymidine kinase substrate specificity, or decreased DNA polymerase sensitivity. The most common mechanism of resistance is loss of thymidine kinase activity. These viral variants are also cross resistant to other antiviral agents (e.g., foscarnet, famciclovir, and penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in infants and immunocompromised patients. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.123412
Lidocaine's antiarrhythmic effects result from its ability to inhibit the influx of sodium through the "fast" channels of the myocardial cell membrane, thereby increasing the recovery period after repolarization. Lidocaine suppresses automaticity and decreases the effective refractory period and the action potential duration in the His-Purkinje system at concentrations that do not suppress automaticity at the SA node. The drug suppresses spontaneous depolarizations in the ventricles by inhibiting reentry mechanisms, and it appears to act preferentially on ischemic tissue. Lidocaine shortens the refractory period, unlike procainamide, which lengthens it. Also, lidocaine does not possess vagolytic properties.
Lidocaine stabilizes neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action.13 Lidocaine produces its analgesics effects through a reversible nerve conduction blockade by diminishing nerve membrane permeability to sodium, just as it affects sodium permeability in myocardial cells. This action decreases the rate of membrane depolarization, thereby increasing the threshold for electrical excitability. The blockade affects all nerve fibers in the following sequence: autonomic, sensory and motor, with effects diminishing in reverse order. Loss of nerve function clinically is as follows: pain, temperature, touch, proprioception, skeletal muscle tone. Direct nerve membrane penetration is necessary for effective anesthesia, which is achieved by applying the anesthetic topically or injecting it subcutaneously, intradermally, or submucosally around the nerve trunks or ganglia supplying the area to be anesthetized.
Lysine, an indispensable amino acid (IAA), is involved in receptor affinity, protease-cleavage points, retention of endoplasmic reticulum, nuclear structure and function, and muscle elasticity. It is required for biosynthesis of such substances as carnitine, collagen, and elastin. Essential functions of the lysine residue in cell and body proteins often involve its epsilon-amino group. In the latter part of the 20th century, a major nonlysosomal pathway for degradation of intracellular proteins, especially those with short half-lives, via ubiquitation of the epsilon-amino group of lysine, was elucidated. Ubiquitin is a polypeptide found in all eukaryotic cells and its conjugation to cell proteins as a side chain attached to a lysine residue marks those proteins for proteolysis. Although it is unclear how the degradation rates of different proteins are controlled in this pathway, the most rapid degradation occurs with the N-terminal arginine, phenylalanine, tyrosine, tryptophan, or lysine. Lysine is thus involved in both synthesis of short half-life proteins and their rapid disposal. Improving the biological value of protein with lysine may improve utilization of dietary calcium, perhaps by enhancing production of one of the calcium-binding proteins by enterocytes. Its interaction with calcium may make lysine important to bone health. Because weekly weight gain has improved in poorly thriving infants but not in normal infants, when formula is supplemented by L-lysine monochloride (LMH), it is posited that lysine supplementation may increase a subnormal rate of enzyme or protein production involved in protein digestion or amino-acid transport in poorly thriving infants.14 Evidence has been accrued for a saturable transport system for lysine that is shared by dibasic amino acids.15 Excess amino acids, including lysine, can stimulate biosynthesis of orotic acid and inhibit the urea cycle16; high lysine levels damage the kidneys. As do other amino acids, lysine chelates certain metals. Since the 1970s when it was found that the arginine requirement of the herpes simplex virus is high and that L-lysine inhibits replication of the virus, oral LMH has been used, with varying results, to treat recurrent herpes simplex.14 Some of the variation in results may be attributable to the isomer employed, the L-isomer of lysine hydrochloride inhibits herpes allosterically in vitro while the D- isomer is biologically inactive.17 Limited human and animal studies suggest that a high-lysine diet or LMH supplements may have a moderating effect on blood pressure and the incidence of stroke. Three case histories provide limited evidence that oral LMH supplements relieve exercise-induced angina. With high blood- glucose levels, as is seen in diabetes, nonenzymatic glycosylation can contribute to diabetic complications.14 When given in high doses to rats, lysine produces an acute and sustained decrease in the glomerular filtration rate.18
Acyclovir is administered topically, ophthalmically, orally, buccally, and intravenously. Acyclovir distributes extensively into all tissues, with the highest concentrations in the kidneys, liver, and intestines; acyclovir crosses the placenta. Cerebrospinal fluid (CSF) concentrations are approximately 50% of plasma concentrations.19 Acyclovir is poorly protein bound at 9% to 33%; protein binding is independent of plasma acyclovir concentrations.20 Excretion is via glomerular filtration and tubular secretion, with approximately 62% to 91% of the drug excreted unchanged.2 The only known urinary metabolite is 9-[(carboxy-methoxy)methyl]guanine, which accounts for 8.5% to 14% of the dose in patients with normal renal function. Probenecid decreases acyclovir renal clearance by approximately 32%, presumably by inhibiting tubular secretion of acyclovir.19 The elimination half-life of acyclovir in patients with normal renal function is 2.5 to 3.3 hours.12
Affected cytochrome P450 isoenzymes: CYP1A2
Acyclovir is a weak inhibitor of the CYP1A2 isoenzyme. Data on clinical interactions resulting from CYP1A2 inhibition by acyclovir are limited.2122
After administration of the topical ointment, 30% to 50% of the drug reaches the basal epidermis in cutaneous infections.20 Data suggests systemic absorption of acyclovir after topical application is minimal. Percutaneous absorption of acyclovir 5% ointment was evaluated in 2 clinical pharmacology studies. In the first study, patients were administered a 1-cm strip (25 mg acyclovir) dose 4-times daily for 7 days to an intact skin surface area of 4.5 square inches. After 7 days, a radioimmunoassay (sensitivity, 0.01 mcg/mL) failed to detect any drug in the blood or urine of these patients. In the second study, absorption of acyclovir ointment was evaluated in 11 patients with localized varicella-zoster infections. In this study, acyclovir was identified in the urine of all 11 patients, and in the blood of 9 patients. More specifically, in 8 patients with normal renal function the drug plasma concentrations ranged from less than 0.01 to 0.28 mcg/mL; in 1 patient with impaired renal function, drug concentrations ranged from less than 0.01 to 0.78 mcg/mL. Acyclovir excretion in the urine ranged from less than 0.02% to 9.4% of the daily dose.23
Lidocaine is administered dermally, topically, ophthalmically, and parenterally. It is extensively metabolized in the liver into 2 active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), which possess 100% and 25% of the potency of lidocaine, respectively. The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. After intravenous administration, MEGX and GX concentrations in serum range from 11% to 36% and from 5% to 11%, respectively, of lidocaine concentrations. Serum concentrations of MEGX were about one-third the serum lidocaine concentrations. It is not known if lidocaine is metabolized in the skin. The initial half-life in an otherwise healthy individual is 7 to 30 minutes, followed by a terminal half-life of 1.5 to 2 hours. The half-life of MEGX is 0.5 to 3.3 hours.242526 Lidocaine and its metabolites are excreted by the kidneys. More than 98% of an absorbed dose can be recovered in the urine as metabolites or parent drug. Less than 10% is excreted unchanged in adults.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4
Lidocaine is extensively metabolized in the liver into 2 active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4.272829
The acute toxicity level of L-lysine monohydrochloride (LMH) given intravenously to young adult rats was determined to be 22 millimoles (mmol) per kilogram (kg). Effects of high-dose, long-term oral supplementation of L-lysine were addressed in an ad-lib feeding study with rats over a 2-year period. A diet containing 25% protein with 5.6% lysine was supplemented with 1% LMH, increasing already sufficient lysine levels by approximately 50%. After 15 weeks, supplemental LMH was increased to 3%, providing 170% of required lysine. Lethal dosage was not obtained and no adverse clinical or hematological effects were noted in this 2-year study. Pregnant female rats in gestational days 0 to 20 were fed a 20% casein diet supplemented with 50%, 100%, or 500% of required lysine. Although no fetal abnormalities were noted in any of the supplemented groups, the rats receiving 500% of required lysine demonstrated a lower maternal weight gain, smaller fetuses, and had a higher fetal mortality rate. In regard to human consumption, individuals on a balanced American diet appear to be able to safely ingest up to 3 grams daily of L-lysine as a long-term supplement. Until more data is available, dosages exceeding 3 grams/day should be monitored by a physician (Flodin, 1997).14
Safe and effective use of acyclovir ointment in neonates, infants, children, and adolescents has not been established. Safety and efficacy of acyclovir cream have not been established in neonates, infants, and children less than 12 years of age. Use of the buccal tablet should be avoided in pediatric populations because of its complex administration procedure and the potential risk of choking. Oral and ophthalmic formulations are not recommended by the manufacturer for use in children younger than 2 years of age, infants, and neonates. The intravenous formulations are approved for all pediatric populations, including neonates.1303136
Acyclovir topical cream and ointment products are approved for external use only; avoid ophthalmic administration or use inside the mouth or nose. To treat acute herpetic keratitis, use the 3% ophthalmic ointment.30316
Systemic acyclovir has been associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, in immunocompromised patients. Monitor patients receiving immunosuppression carefully while on acyclovir therapy.12 Acyclovir cream is indicated for immunocompetent patients only; efficacy has not been established for immunocompromised patients.30
Lidocaine is contraindicated in patients with amide local anesthetic hypersensitivity. Parenteral preparations containing preservatives should not be used for spinal or epidural anesthesia. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. There have been no reports of cross-sensitivity between lidocaine and either procainamide or quinidine.8
Lidocaine does not provide adequate anesthesia in patients with collagen-vascular disease, such as Ehlers Danlos Type III. Lidocaine is relatively contraindicated in these conditions.32
Methemoglobinemia has been reported with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), preexisting (congenital or idiopathic) methemoglobinemia, cardiac or pulmonary compromise (cardiac disease or pulmonary disease), those younger than 6 months, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing methemoglobinemia. Monitor such patients closely for signs and symptoms of methemoglobinemia if a local anesthetic must be used. Signs of methemoglobinemia may occur immediately or may be delayed hours after exposure. Immediately discontinue the local anesthetic to avoid serious central nervous system and cardiovascular adverse events, as methemoglobin concentrations may continue to rise. Patients may require supportive care such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.333435
Use lidocaine with caution in patients at increased risk of adverse events. Conditions that reduce hepatic blood flow such as hepatic disease and congestive heart failure may reduce hepatic metabolism and lead to drug accumulation, increasing the risk of developing systemic toxicity, particularly with parenteral, prescription topical jelly, or transdermal patch use.836373538 Resuscitative equipment and facilities should be readily available in case of an emergency when using parenteral products. Repeated doses of parenteral lidocaine may cause a significant increase in blood concentrations with each successive dose; these increases may be poorly tolerated, particularly by those who are debilitated, pediatric patients, geriatric patients, or the acutely ill.836373538 Excessive dosing by applying lidocaine transdermal patches to larger areas or for longer than the recommended wearing time could result in increased absorption of lidocaine and high blood concentrations, leading to serious systemic adverse effects. Lidocaine toxicity could be expected at lidocaine blood concentrations above 5 mcg/mL. The blood concentration of lidocaine is determined by the rate of systemic absorption and elimination. Longer duration of transdermal application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of lidocaine.39 40 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. The OBRA guidelines caution that antiarrhythmics can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals.41
Applying dermal, transdermal, or oromucosal lidocaine preparations to severely traumatized skin (e.g.,mucosal or skin abrasion, eczema, burns), to large surface areas, or to warm skin (i.e., exercise, or application of thermal heat wraps or a heating pad immediately before or during topical lidocaine use) can increase its absorption, possibly increasing the risk of systemic toxicity. Also, applying large amounts of lidocaine or using an occlusive dressing (skin wraps) can increase absorption. Patches and administration via Zingo injection system should only be used on intact skin, and transoral delivery systems should only be applied to intact mucosa. Excessive dosing by applying patches to larger areas or for longer than the recommended wearing time could result in increased absorption of lidocaine. Application of one additional Zingo at a new location is acceptable after a failed attempt at venous access. However, multiple administrations of Zingo at the same location are not recommended. Multiple Zingo applications could result in plasma concentrations that could produce systemic toxicity.37 At least 2 reports of deaths exist after application of topical anesthetics prior to cosmetic procedures. In both instances, women, aged 22 and 25 years, applied topical anesthetics to their legs and wrapped the treated area, as directed, in plastic wrap to enhance the numbing effect of the cream. Both women died from toxic effects of the topical anesthetic. The preparations used in both cases were compounded in pharmacies and contained high amounts of lidocaine and tetracaine. In order to reduce the risk of toxicity due to increased absorption of topical anesthetic, the FDA recommends patients use a topical anesthetic containing the lowest amount of medication needed to relieve pain, apply the medication sparingly, and only treat known or anticipated areas of pain. Further, do not apply the anesthetic to broken or irritated skin, be aware of potential adverse reactions, and do not cover or apply heat to the treated area.
Avoid unintended ocular exposure of lidocaine dermal, oromucosal, and transdermal products. Severe eye irritation has been reported in animals treated with similar products. If eye contact occurs, immediately wash the eye with water or saline and protect the eye until sensation returns. Lidocaine ophthalmic gel is intended for application to the eye surface; however, prolonged use may produce permanent corneal opacification and ulceration with accompanying visual loss.42 Use with caution in patients with pre-existing cataracts or ocular trauma or ulceration.
To avoid accidental exposure and/or ingestion, advise patients and/or their caregivers to store and dispose of all lidocaine products out of the reach of any pediatric-age person and pets. It is important to note that whether new or used, lidocaine patches contain a large amount of lidocaine (at least 665 mg post-use). The potential exists for small kids or pets to suffer serious adverse reactions from unintended lidocaine exposure including chewing or ingesting a new or used lidocaine patch.39
Avoid use in patients with hypersensitivity or allergies to lysine hydrochloride or with liver or kidney disease.
No adequate or well-controlled studies have been conducted to evaluate use of acyclovir during human pregnancies; however, published observational studies over decades of acyclovir use have not identified a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. Further, a prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for specific defects or to permit definitive conclusions regarding the safety of acyclovir in pregnant women. Acyclovir was not found to be teratogenic in standard animal studies. Avoided use of systemic acyclovir during pregnancy unless the potential benefits outweigh the possible risks to the fetus.13036
Lidocaine is classified as FDA pregnancy category B. Reproductive studies conducted in rats have not demonstrated lidocaine-induced fetal harm; however, animal studies are not always predictive of human response. There are no adequate or well controlled studies of lidocaine in pregnant women.8 Local anesthetics are known to cross the placenta rapidly and, when administered for epidural, paracervical, pudendal, or caudal block anesthesia, and to cause fetal toxicity. The frequency and extent of toxicity are dependent on the procedure performed. Maternal hypotension can result from regional anesthesia, and elevating the feet and positioning the patient on her left side may alleviate this effect. Topical ocular application of lidocaine is not expected to result in systemic exposure.43 When lidocaine is used for dental anesthesia, no fetal harm has been observed; lidocaine is generally the dental anesthetic of choice during pregnancy and guidelines suggest the second trimester is the best time for dental procedures if they are necessary.44 A study by the American Dental Association provides some evidence that, when needed, the use of dental local or topical anesthetics at 13 weeks to 21 weeks of pregnancy or later is likely safe and does not raise incidences of adverse pregnancy outcomes or other adverse events; the study analyzed data from the Obstetrics and Periodontal Therapy (OPT) trial, a multicenter study of over 800 pregnant patients in the early to mid second trimester who received required dental procedures.45
Safe and effective use of Lysine Hydrochloride during pregnancy has not been established. It is also not known whether it can cause fetal harm when used topically on a pregnant woman or affect reproductive capacity. Use during pregnancy may not be recommended.
Following oral administration of acyclovir, breast milk concentrations 1- to 4-times that of those found in maternal plasma have been observed.46 These concentrations would potentially expose the nursing infant to a dose of acyclovir as high as 0.3 mg/kg/day. Intravenous acyclovir doses of 60 mg/kg/day are used for the treatment of neonatal herpes, and the American Academy of Pediatrics considers maternal use of systemic acyclovir to be compatible with breast-feeding.47 Although there are no data on the presence of acyclovir in human milk following buccal administration, this route produces low systemic drug exposures.3 Exposure of the infant after maternal use of topical administration of acyclovir is also minimal, provided the treatment area does not involve the breast. Women who have active herpetic lesions on or near the breast should avoid nursing until the lesions have completely resolved. There are no data regarding the presence of acyclovir in human milk following ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
According to the manufacturers, caution should be exercised when lidocaine is administered to breast-feeding women (regardless of dosage formulation). Lidocaine is excreted in breast milk with a milk:plasma ratio of 0.4. Many specific dosage forms, including Lidoderm brand lidocaine transdermal patches, have not been studied in breast-feeding women.39 The American Academy of Pediatrics lists lidocaine as usually compatible with breast-feeding.47 When lidocaine is used for dental or short-term, limited local anesthesia, the healthy term infant can generally safely nurse as soon as the mother is awake and alert.4844 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternal drug exposure, healthcare providers are encouraged to report the adverse effect to the FDA.
It is unknown whether topical Lysine Hydrochloride is absorbed or excreted in human milk and caution is advised when it is used in breast-feeding mothers.
Adverse Reactions/Side Effects
Dermatologic adverse reactions have occurred in patients receiving systemic and topical acyclovir formulations. Pruritus was reported in 2% of patients during clinical trials of the IV formulation and with postmarketing reports of the oral formulations; local pruritus was reported with the cream (1%) and ointment (4%). Rash was reported in 2% of patients during clinical trials of the IV formulation, 1% of patients in the buccal tablet clinical trial, and with the oral and topical ointment formulations in postmarketing reports. During clinical trials, 2% of IV acyclovir recipients developed hives and 1% of buccal tablet recipients developed erythema. With systemic formulations (both oral and IV) there have been postmarketing reports of alopecia, photosensitivity rash, urticaria, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In topical acyclovir clinical trials, skin irritation (manifested as stinging, burning, pain) was experienced by 1% to 2% of patients after application of the topical cream and 30% of patients receiving acyclovir ointment. Other dermatologic adverse reactions experienced by topical product recipients during clinical trials included contact sensitization (2%, cream), peeling skin or desquamation (1%, cream), dry and cracked lips (1%, cream), and xerosis (1%, cream). Postmarketing dermatologic adverse reactions associated with topical formulations include application site inflammation (cream and ointment), contact dermatitis (cream), eczema (cream), edema (ointment), pruritus (ointment). Patients receiving treatment with the ophthalmic ointment during the postmarketing period have developed urticaria.12303136
Postmarketing adverse reactions associated with systemic acyclovir (both oral and IV) include anaphylactoid reactions, angioedema, peripheral edema, hypotension (IV only), fever, myalgia, generalized pain, and visual impairment. Cases of anaphylactoid reactions and angioedema have also been noted after use of the topical cream and ophthalmic ointment.12306
Lidocaine crosses the blood brain barrier and can produce significant central nervous system (CNS) toxicity, particularly when high plasma concentrations (more than 6 mcg/mL free base) are achieved. CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness (dizziness), anxiety (i.e., nervousness or apprehension), restlessness, euphoria, confusion, drowsiness, tinnitus, blurred vision or double vision, vomiting, metallic taste, dysgeusia, sensations of heat (hot flashes), cold or numbness, hyperesthesia, hypoesthesia, asthenia, twitching, tremor, convulsions (seizures), unconsciousness, respiratory depression, and respiratory arrest. Agitation, dysarthria, oral hypoesthesia, and disorientation have also been reported with systemic use. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness after the administration of lidocaine is usually an early sign of a high blood concentration of the drug and may occur as a consequence of rapid absorption. In some patients, the symptoms of CNS toxicity are minor and transient.839354950 51 38 5253 Dizziness and vomiting occurred in 0.9% and 1% of patients, respectively, who were treated with the lidocaine intradermal injection system during clinical trials.37
Systemic adverse reactions after appropriate application of topical or transdermal lidocaine are unlikely because of the small amount of lidocaine absorbed. The skin at the site of treatment may develop erythema, swelling, or dysesthesia (abnormal sensation).39 Application site reactions may occur during or immediately after treatment with the lidocaine transdermal patch. Blisters, ecchymosis, depigmentation (skin discoloration), skin erosion, exfoliation, flushing, skin irritation (including burning sensation and dermatitis), papules, petechiae, pruritus, or vesicles may develop on the skin at the site of application. These reactions are usually mild and transient resolving within a few minutes to hours.39 53 Preexisting inflammation or infection increases the risk of developing serious skin side effects. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration of lidocaine.35 Additionally, small doses of local anesthetics injected into the head and neck area may produce an adverse reaction similar to systemic toxicity after unintentional intravascular injection.54 During adult and pediatric clinical trials of lidocaine injectable powder (Zingo), erythema (an injection site reaction) occurred in 53% to 67.3% of patients who received active drug, petechiae in 44% to 46.4% of patients, edema in 4.3% to 8% of patients, and pruritus in 1% to 9.4% of patients. Burning and venipuncture site hemorrhage occurred in 0.54% and 0.4% of adults, respectively. A total of 4% of pediatric patients experienced application site reactions that included ecchymosis, burning, pain, contusion, and hemorrhage.37
Allergic and anaphylactoid reactions have been infrequently associated with lidocaine administration. Allergic reactions may manifest as cutaneous lesions, urticaria, edema, angioedema, bronchospasm, dermatitis, dyspnea, laryngospasm, pruritus, or anaphylactic shock. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to other components in the formulation. The detection of sensitivity by skin testing is of questionable value. There have been no reports of cross-sensitivity between lidocaine and para-amino-benzoic acid derivatives (procaine, tetracaine, benzocaine, etc.).39544950 51555653
Methemoglobinemia has been reported with local anesthetic use. Signs and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after local anesthetic exposure and are characterized by cyanotic skin discoloration and abnormal coloration of the blood. Other symptoms may include headache, rapid heart rate, shortness of breath, dizziness, and drowsiness. Since methemoglobin concentrations may continue to rise, immediately discontinue lidocaine to avoid serious central nervous system and cardiovascular adverse events including seizures, coma, arrhythmias, and death. Depending on the severity of symptoms, patients may require supportive care, such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.575835
A 44-year-old woman developed FANCONI'S SYNDROME in association with prolonged oral intake of L-lysine. The patient's medical history included a kidney infection at age 14 treated with a prolonged course of antibiotics, and recovery from substance abuse. She had been taking lysine 3 grams daily for 5 years as oral herpes prophylaxis. Renal biopsy revealed chronic vascular injury with marked interstitial fibrosis, tubular atrophy, and prominent lysosomes in the proximal tubules. There was also evidence of immune complex-mediated glomerular injury. Despite termination of lysine intake and improvement in proximal tubule function, renal failure progressed to end-stage by 5 months from the time of biopsy, requiring initiation of peritoneal dialysis. Although previously quiescent, glomerular injury was thought a possible explanation for the continued deterioration in renal function.59
Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
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