Doctaine

DOCTAINE CREAM

COMPOSITION:

DOCTAINE

Each gram contains:

Lidocaine USP 25 mg

Prilocaine USP 25 mg

In water-Miscible base.

CHEMICAL NAME:

Lidocaine: Acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)- Prilocaine: Propranamide, N-(2-methylphenyl)-2-(propylamino)-

CATEGORY: Local anaesthetic.

DESCRIPTION: White to off white cream filled in lami tubes.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Lidocaine and prilocaine cream, applied to intact skin under occlusive dressing, provides dermal analgesia by the release of lidocaine and prilocaine from the cream into the epidermal and dermal layers of the skin and by the accumulation of lidocaine and prilocaine in the vicinity of dermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anesthetic agents.

Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. The onset, depth and duration of dermal analgesia on intact skin provided by lidocaine and prilocaine cream depend primarily on the duration of application. To provide sufficient analgesia for clinical procedures such as intravenous catheter placement and venipuncture, lidocaine and prilocaine cream should be applied under an occlusive dressing for at least 1 hour.

To provide dermal analgesia for clinical procedures such as split skin graft harvesting, lidocaine and prilocaine cream should be applied under occlusive dressing for at least 2 hours. Satisfactory dermal analgesia is reported to be achieved 1 hour after application, reaches maximum at 2 to 3 hours, and persists for 1 to 2 hours after removal. Absorption from the genital mucosa is more rapid and onset time is shorter (5 to 10 minutes) than after application to intact skin. After a 5 to 10 minute application of lidocaine and prilocaine cream to female genital mucosa, the average duration of effective analgesia to an argon laser stimulus (which produced a sharp, pricking pain) was 15 to 20 minutes (individual variations in the range of 5 to 45 minutes). Dermal application of lidocaine and prilocaine cream may cause a transient, local blanching followed by a transient, local redness or erythema.

Pharmacokinetic Actions

Absorption:

The amount of lidocaine and prilocaine systemically absorbed from lidocaine 2.5% and prilocaine 2.5% cream is directly related to both the duration of application and to the area over which it is applied.

Distribution:

At concentrations produced by application of lidocaine and prilocaine cream, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 μg/mL of free base) the plasma protein binding of lidocaine is concentration dependent. Prilocaine is 55% bound to plasma proteins. Both lidocaine and prilocaine cross the placental and blood brain barrier, presumably by passive diffusion.

Metabolism:

It is not known if lidocaine or prilocaine are metabolized in the skin. Lidocaine 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 lidocaine. The metabolite, 2, 6-xylidine, has unknown pharmacologic activity.

Excretion:

The elimination half-life of lidocaine from the plasma following IV administration is approximately 65 to 150 minutes. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. The systemic clearance is 10 to 20 mL/min/kg. The elimination half-life of prilocaine is approximately 10 to 150 minutes. The systemic clearance is 18 to 64 mL/min/kg. During

intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). No studies are available on the intravenous pharmacokinetics of prilocaine in elderly patients. Pediatrics- Some pharmacokinetic (PK) data are available in infants (1 month to <2 years old) and children (2 to <12 years old).

INDICATIONS

Lidocaine and prilocaine cream, 2.5%/2.5% (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%) is indicated as a topical anaesthetic for use on:

– Normal intact skin for local analgesia.

– Genital mucous membranes for superficial minor surgery and as pretreatment for infiltration anaesthesia. Lidocaine and prilocaine cream, 2.5%/2.5% is not recommended in any clinical situation in which penetration or migration beyond the tympanic membrane into the middle ear is possible because of the ototoxic effects observed in animal studies.

DOSAGE AND ADMINISTRATION:

Adult Patients-Intact Skin A thick layer of lidocaine and prilocaine cream is applied to intact skin and covered with an occlusive dressing. Minor Dermal Procedures: For minor procedures such as intravenous cannulation and venipuncture, apply 2.5 grams of lidocaine and 2 prilocaine cream, over 20 to 25 cm of skin surface for at least 1 hour. Major Dermal Procedures: For more painful dermatological procedures involving a larger skin area such as split thickness skin graft harvesting, apply 2 grams of lidocaine and prilocaine cream, per 2 10 cm of skin and allow remaining in contact with the skin for at least 2 hours.

Adult Male Genital Skin: As an adjunct prior to local anesthetic infiltration, apply a thick layer of lidocaine and prilocaine cream (1 g/10 2 cm ) to the skin surface for 15 minutes. Local anaesthetic infiltration should be performed immediately after removal of lidocaine and prilocaine cream. Dermal analgesia can be expected to increase for up to 3 hours under occlusive dressing and persist for 1 to 2 hours after removal of the cream. The amount of lidocaine and prilocaine absorbed during the period of application can be estimated.

Adult Female Patients-Genital Mucous Membranes For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as well as for use as pretreatment for anaesthetic infiltration, apply a thick layer (5-10 grams) of lidocaine and prilocaine cream, for 5 to 10 minutes. Occlusion is not necessary for absorption, but may be helpful to keep the cream in place. Patients should be lying down during the lidocaine and prilocaine cream, application, especially if no occlusion is used.

The procedure or the local anesthetic infiltration should be performed immediately after the removal of lidocaine and prilocaine cream.

CONTRAINDICATIONS

Lidocaine and prilocaine cream, is contraindicated in patients with a known history of sensitivity to local anaesthetics of the amide type or to any other component of the product.

WARNINGS

Application of lidocaine and prilocaine cream to larger areas or for longer times than those recommended could result in sufficient absorption of lidocaine and prilocaine resulting in serious adverse effects. Patients treated with class III anti-arrhythmic drugs (eg, amiodarone, bretylium, sotalol and dofetilide) should be under close surveillance and ECG monitoring considered, because cardiac effects may be additive.

Studies in laboratory animals (guinea pigs) have shown that lidocaine and prilocaine cream, has an ototoxic effect when instilled into the middle ear.

Methemoglobinemia: Lidocaine and prilocaine cream, 2.5%/2.5% should not be used in those rare patients with congenital or idiopathic methemoglobinemia and in infants under the age of twelve months who are receiving treatment with methemoglobin inducing agents.

Very young patients or patients with glucose-6-phosphate dehydrogenase deficiencies are more susceptible to methemoglobinemia. Patients taking dr ugs associated with dr ug-induced methemoglobinemia such as sulfonamides, acetaminophen, acetanilid, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid, phenacetin,phenobarbital, phenytoin, primaquine, quinine, are also at greater risk for developing methemoglobinemia.

There have been reports of significant methemoglobinemia (20-30%) in infants and children following excessive applications of lidocaine and prilocaine cream. These cases involved the use of large doses, larger than recommended areas of application, or infants under the age of 3 months who did not have fully mature enzyme systems. In addition, a few of these cases involved the concomitant administration of methemoglobin-inducing agents. Most patients recovered spontaneously after removal of the cream. Treatment with IV methylene blue may be effective if required. Neonates and infants up to 3 months of age should be monitored for Met-Hb levels before, during, and after the application of lidocaine and prilocaine cream, provided the test results can be obtained quickly.

PRECAUTIONS

General: Repeated doses of lidocaine and prilocaine cream mayincrease blood levels of lidocaine and prilocaine. Lidocaine and prilocaine cream should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine and prilocaine including acutely ill, debilitated or elderly patients. Lidocaine and prilocaine cream should not be applied to open wounds. Care should be taken not to allow lidocaine and prilocaine cream, to come in contact with the eye because animal studies have demonstrated severe eye irritation. Also the loss of protective reflexes can permit corneal irritation and potential abrasion. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns.

Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine and benzocaine, etc.) have not shown cross sensitivity to lidocaine and/or prilocaine, however, lidocaine and prilocaine cream, should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. Patients with severe hepatic disease, because of their inability to metabolize local normally, are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine. Lidocaine and prilocaine have been shown to inhibit viral and bacterial growth. The effect of lidocaine and prilocaine cream, 2.5%/2.5% on intradermal injections of live vaccines has not been determined.

Information for Patients:

When lidocaine and prilocaine cream, is used, the patient should be aware that the production of dermal analgesia may be accompanied by the block of all sensations in the treated skin. For this reason, the patient should avoid inadvertent trauma to the treated area by scratching, rubbing, or exposure to extreme hot or cold temperatures until complete sensation has returned. Lidocaine and prilocaine cream, should not be applied near the eyes or on open wounds,

Drug Interactions:

Lidocaine and prilocaine cream, 2.5%/2.5% should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic.

Prilocaine may contribute to the formation of methemoglobin in patients treated with other drugs known to cause this condition. Should lidocaine and prilocaine cream, 2.5%/2.5% be used concomitantly with other products containing lidocaine and/or prilocaine, cumulative doses from all formulations must be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis- Metabolites of prilocaine have been shown to be carcinogenic in laboratory animals. In the animal studies reported below, doses or blood levels are compared to the Single Dermal Administration (SDA) of 60 g of lidocaine and prilocaine cream, to 400 2 cm for 3 hours to a small person (50 kg). The typical application of lidocaine and prilocaine cream, for one or two treatments for venipuncture sites (2.5 or 5 g) would be 1/24 or 1/12 of that dose in an adult or about the same mg/kg dose in an infant. Chronic oral toxicity studies of ortho-toluidine, a metabolite of 2 prilocaine, in mice (450 to 7200 mg/m ; 60 to 960 times SDA) and rats 2 (900 to 4,800 mg/m ; 60 to 320 times SDA) have shown that orthotoluidine is a carcinogen in both species. The tumors included hepatocarcinomas/adenomas in female mice, multiple occurrences of hemangiosarcomas/hemangiomas in both sexes of mice, sarcomas of multiple organs, transitional-cell carcinomas/papillomas of urinary bladder in both sexes of rats, subcutaneous fibromas/fibrosarcomas and mesotheliomas in male rats, and mammary gland fibroadenomas/adenomas in female rats. The lowest dose tested (450 2 2 mg/m in mice; 900 mg/m in rats, 60 times SDA) was carcinogenic in both species.

Mutagenesis- The mutagenic potential of lidocaine HCl has been studied in the Ames Salmonella/mammalian microsome test and by analysis of structural chromosome aberrations in human lymphocytes in vitro, and by the mouse micronucleus test in vivo. There was no indication in these three tests of any mutagenic effects. Ortho-toluidine, a metabolite of prilocaine, (0.5 mcg/mL) showed positive results in Escherichia coli DNA repair and phage-induction assays. Urine concentrates from rats treated with ortho-toluidine (300 mg/kg orally; 300 times SDA) were mutagenic for Salmonella typhimurium with metabolic activation.

Several other tests on ortho-toluidine, including reverse mutations in five different Salmonella typhimurium strains with or without metabolic activation and with single strand breaks in DNA of V79 Chinese hamster cells, were negative. Impairment of Fertility was reported.

PREGNANCY AND LACTATION:

Teratogenic Effects: Pregnancy Category B. Reproduction studies with lidocaine have been reported in rats and have revealed no evidence of harm to the fetus (30 mg/kg subcutaneously; 22 times SDA). Reproduction studies with prilocaine have been performed in rats and have revealed no evidence of impaired fertility or harm to the fetus (300 mg/kg intramuscularly; 188 times SDA). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, lidocaine and prilocaine cream, 2.5%/2.5% should be used during pregnancy only if clearly needed.

Labor and Delivery:

Neither lidocaine nor prilocaine are contraindicated in labor and delivery. Should lidocaine and prilocaine cream, 2.5%/2.5% be used concomitantly with other products containing lidocaine and/or prilocaine, cumulative doses from all formulations must be considered.

Nursing Mothers:

Lidocaine, and probably prilocaine, are excreted in human milk. Therefore, caution should be exercised when lidocaine and prilocaine cream, 2.5%/2.5% is administered to a nursing mother since the milk:plasma ratio of lidocaine is 0.4 and is not determined for prilocaine. Pediatric Use: Controlled studies of lidocaine and prilocaine cream, 2.5%/2.5% in children under the age of seven years have shown less overall benefit than in older children or adults. These results illustrate the importance of emotional and psychological support of younger children undergoing medical or surgical procedures. Lidocaine and prilocaine cream, 2.5%/2.5% should be used with care in patients with conditions or therapy associated with methemoglobinemia. When using lidocaine and prilocaine cream, in young children, especially infants under the age of 3 months, care must be taken to insure that the caregiver understands the need to limit the dose and area of application, and to prevent accidental ingestion. In neonates (minimum gestation age: 37 weeks) and children weighing less than 20 kg, the area and duration of application should be limited.

Studies have not demonstrated the efficacy of lidocaine and prilocaine cream, for heel lancing in neonates.

Geriatric Use:

No overall differences in safety or efficacy were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Effect to Drive & Use the Machine: None

ADVERSE REACTIONS

Localized Reactions: During or immediately after treatment with lidocaine and prilocaine cream, 2.5%/2.5% on intact skin, the skin at the site of treatment may develop erythema or edema or may be the locus of abnormal sensation. Rare cases of discrete purpuric or petechial reactions at the application site have been reported. Rare cases of hyperpigmentation following the use of lidocaine and prilocaine cream have been reported. The relationship to lidocaine and prilocaine cream or the underlying procedure has not been established. In reported clinical studies on genital mucous membranes lidocaine and prilocaine cream, treated patients, one or more application site reactions, usually mild and transient, were noted in patients. The most common application site reactions were redness (21%), burning sensation (17%) and edema (10%).

Allergic Reactions: Allergic and anaphylactoid reactions associated with lidocaine or prilocaine can occur. They are characterized by urticaria, angioedema, bronchospasm and shock. If they occur they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.

Systemic (Dose Related) Reactions: Systemic adverse reactions following appropriate use of lidocaine and prilocaine cream, Systemic adverse effects of lidocaine and/or prilocaine are similar in nature to those observed with other amide local anesthetic agents including CNS excitation and/or depression (light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations 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.

Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest.

OVERDOSAGE:

2 Peak blood levels following a 60 g application to 400 cm of intact skin for 3 hours are 0.05 to 0.16 mcg/mL for lidocaine and 0.02 to 0.10 mcg/mL for prilocaine. Toxic levels of lidocaine (>5 mcg/mL) and/or prilocaine (>6 mcg/mL) cause decreases in cardiac output, total peripheral resistance and mean arterial pressure. These changes may be attributable to direct depressant effects of these local anesthetic agents on the cardiovascular system. In the absence of massive topical overdose or oral ingestion, evaluation should include evaluation of other etiologies for the clinical effects or overdosage from other sources of lidocaine, prilocaine or other local Anesthetics.

Packing: Lami tube of 30gm.

Storage: Store in dry place, below 30ºC.

Keep out of Reach of Children.