Survanta

beractant

Dosage Form: intratracheal suspension

(beractant)

intratracheal suspension

Sterile Suspension

For Intratracheal Administration Only

Survanta Description

Survanta ® (beractant) Intratracheal Suspension is a sterile, non-pyrogenic pulmonary surfactant intended for intratracheal use only. It is a natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins to which colfosceril palmitate (dipalmitoylphosphatidylcholine), palmitic acid, and tripalmitin are added to standardize the composition and to mimic surface-tension lowering properties of natural lung surfactant. The resulting composition provides 25 mg/mL phospholipids (including 11.0-15.5 mg/mL disaturated phosphatidylcholine), 0.5-1.75 mg/mL triglycerides, 1.4-3.5 mg/mL free fatty acids, and less than 1.0 mg/mL protein. It is suspended in 0.9% sodium chloride solution, and heat-sterilized. Survanta contains no preservatives. Its protein content consists of two hydrophobic, low molecular weight, surfactant-associated proteins commonly known as SP-B and SP-C. It does not contain the hydrophilic, large molecular weight surfactant-associated protein known as SP-A.

Each mL of Survanta contains 25 mg of phospholipids. It is an off-white to light brown liquid supplied in single-use glass vials containing 4 mL (100 mg phospholipids) or 8 mL (200 mg phospholipids).

Survanta - Clinical Pharmacology

Endogenous pulmonary surfactant lowers surface tension on alveolar surfaces during respiration and stabilizes the alveoli against collapse at resting transpulmonary pressures. Deficiency of pulmonary surfactant causes Respiratory Distress Syndrome (RDS) in premature infants. Survanta replenishes surfactant and restores surface activity to the lungs of these infants.

Activity

In vitro, Survanta reproducibly lowers minimum surface tension to less than 8 dynes/cm as measured by the pulsating bubble surfactometer and Wilhelmy Surface Balance. In situ, Survanta restores pulmonary compliance to excised rat lungs artificially made surfactant-deficient. In vivo, single Survanta doses improve lung pressure-volume measurements, lung compliance, and oxygenation in premature rabbits and sheep.

Animal Metabolism

Survanta is administered directly to the target organ, the lungs, where biophysical effects occur at the alveolar surface. In surfactant-deficient premature rabbits and lambs, alveolar clearance of radio-labelled lipid components of Survanta is rapid. Most of the dose becomes lung-associated within hours of administration, and the lipids enter endogenous surfactant pathways of reutilization and recycling. In surfactant-sufficient adult animals, Survanta clearance is more rapid than in premature and young animals. There is less reutilization and recycling of surfactant in adult animals.

Limited animal experiments have not found effects of Survanta on endogenous surfactant metabolism. Precursor incorporation and subsequent secretion of saturated phosphatidylcholine in premature sheep are not changed by Survanta treatments.

No information is available about the metabolic fate of the surfactant-associated proteins in Survanta. The metabolic disposition in humans has not been studied.

Clinical Studies

Clinical effects of Survanta were demonstrated in six single-dose and four multiple-dose randomized, multi-center, controlled clinical trials involving approximately 1700 infants. Three open trials, including a Treatment IND, involved more than 8500 infants. Each dose of Survanta in all studies was 100 mg phospholipids/kg birth weight and was based on published experience with Surfactant TA, a lyophilized powder dosage form of Survanta having the same composition.

Prevention Studies

Infants of 600-1250 g birth weight and 23 to 29 weeks estimated gestational age were enrolled in two multiple-dose studies. A dose of Survanta was given within 15 minutes of birth to prevent the development of RDS. Up to three additional doses in the first 48 hours, as often as every 6 hours, were given if RDS subsequently developed and infants required mechanical ventilation with an FiO2 ≥ 0.30. Results of the studies at 28 days of age are shown in Table 1.

Table 1.

Study 1
	Survanta	Control	P-Value
Number infants studied	119	124
Incidence of RDS (%)	27.6	63.5	< 0.001
Death due to RDS (%)	2.5	19.5	< 0.001
Death or BPD due to RDS (%)	48.7	52.8	0.536
Death due to any cause (%)	7.6	22.8	0.001
Air Leaksa (%)	5.9	21.7	0.001
Pulmonary interstitial emphysema (%)	20.8	40.0	0.001

Study 2b
	Survanta	Control	P-Value
aPneumothorax or pneumopericardium bStudy discontinued when Treatment IND initiated cNo cause of death in the Survanta group was significantly increased; the higher number of deaths in this group was due to the sum of all causes.
Number infants studied	91	96
Incidence of RDS (%)	28.6	48.3	0.007
Death due to RDS (%)	1.1	10.5	0.006
Death or BPD due to RDS (%)	27.5	44.2	0.018
Death due to any cause C(%)	16.5	13.7	0.633
Air Leaks a(%)	14.5	19.6	0.374
Pulmonary interstitial emphysema (%)	26.5	33.2	0.298

Rescue Studies

Infants of 600-1750 g birth weight with RDS requiring mechanical ventilation and an FiO2 ≥ 0.40 were enrolled in two multiple-dose rescue studies. The initial dose of Survanta was given after RDS developed and before 8 hours of age. Infants could receive up to three additional doses in the first 48 hours, as often as every 6 hours, if they required mechanical ventilation and an FiO2 ≥ 0.30. Results of the studies at 28 days of age are shown in Table 2.

Table 2.

Study 3a
	Survanta	Control	P-Value
Number infants studied	198	193
Death due to RDS (%)	11.6	18.1	0.071
Death or BPD due to RDS (%)	59.1	66.8	0.102
Death due to any cause (%)	21.7	26.4	0.285
Air Leaksb (%)	11.8	29.5	<0.001
Pulmonary interstitial emphysema (%)	16.3	34.0	<0.001

Study 4
	Survanta	Control	P-Value
aStudy discontinued when Treatment IND initiated bPneumothorax or pneumopericardium
Number infants studied	204	203
Death due to RDS (%)	6.4	22.3	< 0.001
Death or BPD due to RDS (%)	43.6	63.4	< 0.001
Death due to any cause (%)	15.2	28.2	0.001
Air Leaksb (%)	11.2	22.2	0.005
Pulmonary interstitial emphysema (%)	20.8	44.4	< 0.001

Acute Clinical Effects

Marked improvements in oxygenation may occur within minutes of administration of Survanta.

All controlled clinical studies with Survanta provided information regarding the acute effects of Survanta on the arterial-alveolar oxygen ratio (a/APO2), FiO2, and mean airway pressure (MAP) during the first 48 to 72 hours of life. Significant improvements in these variables were sustained for 48-72 hours in Survanta-treated infants in four single-dose and two multiple-dose rescue studies and in two multiple-dose prevention studies. In the single-dose prevention studies, the FiO2 improved significantly.

Indications and Usage

Survanta is indicated for prevention and treatment (“rescue”) of Respiratory Distress Syndrome (RDS) (hyaline membrane disease) in premature infants. Survanta significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.

Prevention

In premature infants less than 1250 g birth weight or with evidence of surfactant deficiency, give Survanta as soon as possible, preferably within 15 minutes of birth.

Rescue

To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give Survanta as soon as possible, preferably by 8 hours of age.

Contraindications

None known.

Warnings

Survanta is intended for intratracheal use only.

Survanta can rapidly affect oxygenation and lung compliance. Therefore, its use should be restricted to a highly supervised clinical setting with immediate availability of clinicians experienced with intubation, ventilator management, and general care of premature infants. Infants receiving Survanta should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.

During the dosing procedure, transient episodes of bradycardia and decreased oxygen saturation have been reported. If these occur, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After stabilization, resume the dosing procedure.

Precautions

General

Rales and moist breath sounds can occur transiently after administration. Endotracheal suctioning or other remedial action is not necessary unless clear-cut signs of airway obstruction are present.

Increased probability of post-treatment nosocomial sepsis in Survanta-treated infants was observed in the controlled clinical trials (Table 3). The increased risk for sepsis among Survanta-treated infants was not associated with increased mortality among these infants. The causative organisms were similar in treated and control infants. There was no significant difference between groups in the rate of post-treatment infections other than sepsis.

Use of Survanta in infants less than 600 g birth weight or greater than 1750 g birth weight has not been evaluated in controlled trials. There is no controlled experience with use of Survanta in conjunction with experimental therapies for RDS (eg, high-frequency ventilation or extracorporeal membrane oxygenation).

No information is available on the effects of doses other than 100 mg phospholipids/kg, more than four doses, dosing more frequently than every 6 hours, or administration after 48 hours of age.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Survanta. Survanta was negative when tested in the Ames test for mutagenicity. Using the maximum feasible dose volume, Survanta up to 500 mg phospholipids/kg/day (approximately one-third the premature infant dose based on mg/m2/day) was administered subcutaneously to newborn rats for 5 days. The rats reproduced normally and there were no observable adverse effects in their offspring.

Adverse Reactions

The most commonly reported adverse experiences were associated with the dosing procedure. In the multiple-dose controlled clinical trials, each dose of Survanta was divided into four quarter-doses which were instilled through a catheter inserted into the endotracheal tube by briefly disconnecting the endotracheal tube from the ventilator. Transient bradycardia occurred with 11.9% of doses. Oxygen desaturation occurred with 9.8% of doses.

Other reactions during the dosing procedure occurred with fewer than 1% of doses and included endotracheal tube reflux, pallor, vasoconstriction, hypotension, endotracheal tube blockage, hypertension, hypocarbia, hypercarbia, and apnea. No deaths occurred during the dosing procedure, and all reactions resolved with symptomatic treatment.

The occurrence of concurrent illnesses common in premature infants was evaluated in the controlled trials. The rates in all controlled studies are in Table 3.

Table 3.

All Controlled Studies
Concurrent Event	Survanta (%)	Control      (%)	P-Valuea
aP-value comparing groups in controlled studies
Patent ductus arteriosus	46.9	47.1	0.814
Intracranial hemorrhage	48.1	45.2	0.241
Severe intracranial hemorrhage	24.1	23.3	0.693
Pulmonary air leaks	10.9	24.7	< 0.001
Pulmonary interstitial emphysema	20.2	38.4	< 0.001
Necrotizing enterocolitis	6.1	5.3	0.427
Apnea	65.4	59.6	0.283
Severe apnea	46.1	42.5	0.114
Post-treatment sepsis	20.7	16.1	0.019
Post-treatment infection	10.2	9.1	0.345
Pulmonary hemorrhage	7.2	5.3	0.166

When all controlled studies were pooled, there was no difference in intracranial hemorrhage. However, in one of the single-dose rescue studies and one of the multiple-dose prevention studies, the rate of intracranial hemorrhage was significantly higher in Survanta patients than control patients (63.3% v 30.8%, P = 0.001; and 48.8% v 34.2%, P = 0.047, respectively). The rate in a Treatment IND involving approximately 8100 infants was lower than in the controlled trials.

In the controlled clinical trials, there was no effect of Survanta on results of common laboratory tests: white blood cell count and serum sodium, potassium, bilirubin, and creatinine.

More than 4300 pretreatment and post-treatment serum samples from approximately 1500 patients were tested by Western Blot Immunoassay for antibodies to surfactant-associated proteins SP-B and SP-C. No IgG or IgM antibodies were detected.

Several other complications are known to occur in premature infants. The following conditions were reported in the controlled clinical studies. The rates of the complications were not different in treated and control infants, and none of the complications were attributed to Survanta.

Respiratory

lung consolidation, blood from the endotracheal tube, deterioration after weaning, respiratory decompensation, subglottic stenosis, paralyzed diaphragm, respiratory failure.

Cardiovascular

hypotension, hypertension, tachycardia, ventricular tachycardia, aortic thrombosis, cardiac failure, cardio-respiratory arrest, increased apical pulse, persistent fetal circulation, air embolism, total anomalous pulmonary venous return.

Gastrointestinal

abdominal distention, hemorrhage, intestinal perforations, volvulus, bowel infarct, feeding intolerance, hepatic failure, stress ulcer.

Renal

renal failure, hematuria.

Hematologic

coagulopathy, thrombocytopenia, disseminated intravascular coagulation.

Central Nervous System

seizures

Endocrine/Metabolic

adrenal hemorrhage, inappropriate ADH secretion, hyperphosphatemia.

Musculoskeletal

inguinal hernia.

Systemic

fever, deterioration.

Follow-Up Evaluations

To date, no long-term complications or sequelae of Survanta therapy have been found.

Single-Dose Studies

Six-month adjusted-age follow-up evaluations of 232 infants (115 treated) demonstrated no clinically important differences between treatment groups in pulmonary and neurologic sequelae, incidence or severity of retinopathy of prematurity, rehospitalizations, growth, or allergic manifestations.

Multiple-Dose Studies

Six-month adjusted age follow-up evaluations have been completed in 631 (345 treated) of 916 surviving infants. There were significantly less cerebral palsy and need for supplemental oxygen in Survanta infants than controls. Wheezing at the time of examination was significantly more frequent among Survanta infants, although there was no difference in bronchodilator therapy.

Final twelve-month follow-up data from the multiple-dose studies are available from 521 (272 treated) of 909 surviving infants. There was significantly less wheezing in Survanta infants than controls, in contrast to the six-month results. There was no difference in the incidence of cerebral palsy at twelve months.

Twenty-four month adjusted age evaluations were completed in 429 (226 treated) of 906 surviving infants. There were significantly fewer Survanta infants with rhonchi, wheezing, and tachypnea at the time of examination. No other differences were found.

Overdosage

Overdosage with Survanta has not been reported. Based on animal data, overdosage might result in acute airway obstruction. Treatment should be symptomatic and supportive.

Rales and moist breath sounds can transiently occur after Survanta is given, and do not indicate overdosage. Endotracheal suctioning or other remedial action is not required unless clear-cut signs of airway obstruction are present.

Dosage and Administration

For intratracheal administration only.

Survanta should be administered by or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants.

Marked improvements in oxygenation may occur within minutes of administration of Survanta. Therefore, frequent and careful clinical observation and monitoring of systemic oxygenation are essential to avoid hyperoxia.

Review of audiovisual instructional materials describing dosage and administration procedures is recommended before using Survanta. Materials are available upon request from Abbott Nutrition.

Dosage

Each dose of Survanta is 100 mg of phospholipids/kg birth weight (4 mL/kg). The Survanta Dosing Chart shows the total dosage for a range of birth weights.

Survanta DOSING CHART
Weight (grams)	Total Dose (mL)	Weight (grams)	Total Dose (mL)
600-650	2.6	1301-1350	5.4
651-700	2.8	1351-1400	5.6
701-750	3.0	1401-1450	5.8
751-800	3.2	1451-1500	6.0
801-850	3.4	1501-1550	6.2
851-900	3.6	1551-1600	6.4
901-950	3.8	1601-1650	6.6
951-1000	4.0	1651-1700	6.8
1001-1050	4.2	1701-1750	7.0
1051-1100	4.4	1751-1800	7.2
1101-1150	4.6	1801-1850	7.4
1151-1200	4.8	1851-1900	7.6
1201-1250	5.0	1901-1950	7.8
1251-1300	5.2	1951-2000	8.0

Four doses of Survanta can be administered in the first 48 hours of life. Doses should be given no more frequently than every 6 hours.

Directions for Use

Survanta should be inspected visually for discoloration prior to administration. The color of Survanta is off-white to light brown. If settling occurs during storage, swirl the vial gently (DO NOT SHAKE) to redisperse. Some foaming at the surface may occur during handling and is inherent in the nature of the product.

Survanta is stored refrigerated (2-8°C). Date and time need to be recorded in the box on front of the carton or vial, whenever Survanta is removed from the refrigerator. Before administration, Survanta should be warmed by standing at room temperature for at least 20 minutes or warmed in the hand for at least 8 minutes. Artificial warming methods should not be used. If a prevention dose is to be given, preparation of Survanta should begin before the infant’s birth.

Unopened, unused vials of Survanta that have been warmed to room temperature may be returned to the refrigerator within 24 hours of warming, and stored for future use. Survanta SHOULD NOT BE REMOVED FROM THE REFRIGERATOR FOR MORE THAN 24 HOURS. Survanta SHOULD NOT BE WARMED AND RETURNED TO THE REFRIGERATOR MORE THAN ONCE. Each single-use vial of Survanta should be entered only once. Used vials with residual drug should be discarded.

Survanta does not require reconstitution or sonication before use.

Dosing Procedures

General

Survanta is administered intratracheally by instillation through a 5 French end-hole catheter. The catheter can be inserted into the infant’s endotracheal tube without interrupting ventilation by passing the catheter through a neonatal suction valve attached to the endotracheal tube. Alternatively, Survanta can be instilled through the catheter by briefly disconnecting the endotracheal tube from the ventilator.

The neonatal suction valve used for administering Survanta should be a type that allows entry of the catheter into the endotracheal tube without interrupting ventilation and also maintains a closed airway circuit system by sealing the valve around the catheter.

If the neonatal suction valve is used, the catheter should be rigid enough to pass easily into the endotracheal tube. A very soft and pliable catheter may twist or curl within the neonatal suction valve. The length of the catheter should be shortened so that the tip of the catheter protrudes just beyond the end of the endotracheal tube above the infant’s carina. Survanta should not be instilled into a mainstem bronchus.

To ensure homogenous distribution of Survanta throughout the lungs, each dose is divided into four quarter-doses.

Each quarter-dose is administered with the infant in a different position. The recommended positions are:

• Head and body inclined 5-10° down, head turned to the right


• Head and body inclined 5-10° down, head turned to the left


• Head and body inclined 5-10° up, head turned to the right


• Head and body inclined 5-10° up, head turned to the left

The dosing procedure is facilitated if one person administers the dose while another person positions and monitors the infant.

First Dose

Determine the total dose of Survanta from the Survanta dosing chart based on the infant’s birth weight. Slowly withdraw the entire contents of the vial into a plastic syringe through a large-gauge needle (eg, at least 20 gauge). Do not filter Survanta and avoid shaking.

Attach the premeasured 5 French end-hole catheter to the syringe. Fill the catheter with Survanta. Discard excess Survanta through the catheter so that only the total dose to be given remains in the syringe.

Before administering Survanta, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering Survanta. The infant should be allowed to stabilize before proceeding with dosing.

In the prevention strategy, weigh, intubate and stabilize the infant. Administer the dose as soon as possible after birth, preferably within 15 minutes. Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 seconds.

After administration of the first quarter-dose, remove the catheter from the endotracheal tube. Manually ventilate with a hand-bag with sufficient oxygen to prevent cyanosis, at a rate of 60 breaths/minute, and sufficient positive pressure to provide adequate air exchange and chest wall excursion.

In the rescue strategy, the first dose should be given as soon as possible after the infant is placed on a ventilator for management of RDS. In the clinical trials, immediately before instilling the first quarter-dose, the infant’s ventilator settings were changed to rate 60/minute, inspiratory time 0.5 second, and FiO2 1.0.

Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 seconds. After administration of the first quarter-dose, remove the catheter from the endotracheal tube and continue mechanical ventilation.

In both strategies, ventilate the infant for at least 30 seconds or until stable. Reposition the infant for instillation of the next quarter-dose.

Instill the remaining quarter-doses using the same procedures. After instillation of each quarter-dose, remove the catheter and ventilate for at least

30 seconds or until the infant is stabilized. After instillation of the final quarter-dose, remove the catheter without flushing it. Do not suction the infant for 1 hour after dosing unless signs of significant airway obstruction occur.

After completion of the dosing procedure, resume usual ventilator management and clinical care.

Repeat Doses

The dosage of Survanta for repeat doses is also 100 mg phospholipids/kg and is based on the infant’s birth weight. The infant should not be reweighed for determination of the Survanta dosage. Use the Survanta Dosing Chart to determine the total dosage.

The need for additional doses of Survanta is determined by evidence of continuing respiratory distress. Using the following criteria for redosing, significant reductions in mortality due to RDS were observed in the multiple-dose clinical trials with Survanta.

Dose no sooner than 6 hours after the preceding dose if the infant remains intubated and requires at least 30% inspired oxygen to maintain a PaO2 less than or equal to 80 torr.

Radiographic confirmation of RDS should be obtained before administering additional doses to those who received a prevention dose.

Prepare Survanta and position the infant for administration of each quarter-dose as previously described. After instillation of each quarter-dose, remove the dosing catheter from the endotracheal tube and ventilate the infant for at least 30 seconds or until stable.

In the clinical studies, ventilator settings used to administer repeat doses were different than those used for the first dose. For repeat doses, the FiO2 was increased by 0.20 or an amount sufficient to prevent cyanosis. The ventilator delivered a rate of 30/minute with an inspiratory time less than

1.0 second. If the infant’s pretreatment rate was 30 or greater, it was left unchanged during Survanta instillation.

Manual hand-bag ventilation should not be used to administer repeat doses. During the dosing procedure, ventilator settings may be adjusted at the discretion of the clinician to maintain appropriate oxygenation and ventilation.

After completion of the dosing procedure, resume usual ventilator management and clinical care.

Dosing Precautions

If an infant experiences bradycardia or oxygen desaturation during the dosing procedure, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After the infant has stabilized, resume the dosing procedure.

Rales and moist breath sounds can occur transiently after administration of Survanta. Endotracheal suctioning or other remedial action is unnecessary unless clear-cut signs of airway obstruction are present.

How Supplied

Survanta (beractant) Intratracheal Suspension is supplied in single-use glass vials containing 4 mL (NDC 0074-1040-04) or 8 mL of Survanta (NDC 0074-1040-08). Each milliliter contains 25 mg of phospholipids suspended in 0.9% sodium chloride solution. The color is off-white to light brown.

Store unopened vials at refrigeration temperature (2-8°C). Protect from light. Store vials in carton until ready for use. Vials are for single use only. Upon opening, discard unused drug.

May, 2008

LITHO IN USA

Manufactured by:

Hospira, Inc.

Lake Forest , Illinois 60045 USA

For:

Abbott Nutrition

Abbott Laboratories

Columbus, Ohio 43215-1724 USA

Survanta  beractant  suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0074-1040 Route of Administration ENDOTRACHEAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength beractant (beractant) Active 100 MILLIGRAM  In 4 MILLILITER sodium chloride Inactive   water Inactive

Product Characteristics Color white (off-white to light brown) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0074-1040-04 4 mL (MILLILITER) In 1 VIAL, SINGLE-USE None

Survanta  beractant  suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0074-1040 Route of Administration ENDOTRACHEAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength beractant (beractant) Active 200 MILLIGRAM  In 8 MILLILITER sodium chloride Inactive   water Inactive

Product Characteristics Color white (off-white to light brown) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0074-1040-08 8 mL (MILLILITER) In 1 VIAL, SINGLE-USE None

Revised: 08/2008Abbott Laboratories, Inc.

More Survanta resources

• Survanta Side Effects (in more detail)
• Survanta Use in Pregnancy & Breastfeeding
• Survanta Support Group
• 0 Reviews for Survanta - Add your own review/rating

Compare Survanta with other medications

• Respiratory Distress Syndrome

Thalitone

Generic Name: chlorthalidone (Oral route)

klor-THAL-i-done

Commonly used brand name(s)

In the U.S.

• Thalitone

Available Dosage Forms:

• Tablet

Therapeutic Class: Cardiovascular Agent

Pharmacologic Class: Diuretic

Chemical Class: Thiazide Related

Uses For Thalitone

Chlorthalidone is used alone or together with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.

Chlorthalidone is also used to treat fluid retention (edema) that is caused by congestive heart failure, severe liver disease (cirrhosis), kidney disease, or treatment with a hormone or steroid medicine.

Chlorthalidone is a diuretic (water pill). It reduces the amount of water in the body by increasing the flow of urine, which helps to lower blood pressure.

Chlorthalidone is available only with your doctor's prescription.

Before Using Thalitone

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of chlorthalidone in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of chlorthalidone in geriatric patients. However, elderly patients are more likely to have age-related kidney disease, which may require an adjustment in the dose for patients receiving chlorthalidone.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetyldigoxin


• Arsenic Trioxide


• Bepridil


• Deslanoside


• Digitalis


• Digitoxin


• Digoxin


• Dofetilide


• Droperidol


• Flecainide


• Ketanserin


• Levomethadyl


• Lithium


• Metildigoxin


• Sotalol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alacepril


• Apazone


• Aspirin


• Benazepril


• Bromfenac


• Captopril


• Celecoxib


• Chlorpropamide


• Cilazapril


• Delapril


• Diclofenac


• Diflunisal


• Enalaprilat


• Enalapril Maleate


• Etodolac


• Fenoprofen


• Flurbiprofen


• Fosinopril


• Gossypol


• Ibuprofen


• Ibuprofen Lysine


• Imidapril


• Indomethacin


• Ketoprofen


• Ketorolac


• Licorice


• Lisinopril


• Magnesium Salicylate


• Meclofenamate


• Mefenamic Acid


• Meloxicam


• Moexipril


• Nabumetone


• Naproxen


• Nepafenac


• Oxaprozin


• Pentopril


• Perindopril


• Piroxicam


• Quinapril


• Ramipril


• Salicylic Acid


• Salsalate


• Spirapril


• Sulindac


• Temocapril


• Tolmetin


• Trandolapril


• Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Anuria (not able to form urine)—Should not be used in patients with this condition.

• Asthma or


• Diabetes or


• Gout or


• Hypercalcemia (high calcium in the blood) or


• Hyperuricemia (high uric acid in the blood) or


• Hypochloremia (low chloride in the blood) or


• Hypokalemia (low potassium in the blood) or


• Hypomagnesemia (low magnesium in the blood) or


• Hyponatremia (low sodium in the blood) or


• Hypophosphatemia (low phosphorus in the blood) or


• Systemic lupus erythematosus—Use with caution. This medicine may make these conditions worse.

• Kidney disease or


• Liver disease—Use with caution. The effects of the medicine may be increased because of slower removal of the medicine from the body.

Proper Use of Thalitone

In addition to the use of this medicine, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium or potassium. Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that this medicine will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.

Chlorthalidone is usually taken in the morning with food.

Dosing

The dose of this medicine 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 this medicine. 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.

• For oral dosage forms (tablets):
  
  • For fluid retention (edema):
    
    • Adults—At first, 50 to 100 milligrams (mg) once a day, or 100 mg once every other day. Your doctor may adjust your dose if needed.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For high blood pressure:
    
    • Adults—At first, 25 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take 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. Do not double doses.

Storage

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.

Precautions While Using Thalitone

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Check with your doctor right away if you have any of the following symptoms while taking this medicine: convulsions or seizures; decreased urine; drowsiness; dry mouth; excessive thirst; muscle pains or cramps; nausea or vomiting; increased heart rate or pulse; or unusual tiredness or weakness. These may be symptoms of a condition called hypokalemia or potassium loss.

This medicine may cause some people to become dizzy. Do not drive, use machines, or do anything else that could be dangerous if you are dizzy.

Drinking alcoholic beverages may also make the dizziness worse. While you are taking this medicine, be careful to limit the amount of alcohol you drink.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Thalitone Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Incidence not known

• Abdominal or stomach pain


• black, tarry stools


• bleeding gums


• blistering, peeling, or loosening of skin


• bloating


• blood in urine or stools


• blurred vision


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• chest pain


• chills


• clay-colored stools


• cold sweats


• confusion


• constipation


• cough or hoarseness


• coughing up blood


• darkened urine


• diarrhea


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly


• dry mouth


• fast heartbeat


• fatigue


• fever


• flushed, dry skin


• fruit-like breath odor


• general feeling of tiredness or weakness


• headache


• increased hunger


• increased thirst


• increased urination


• indigestion


• itching


• joint pain, stiffness, or swelling


• loss of appetite


• lower back or side pain


• nausea


• pain in joints or muscles


• painful or difficult urination


• pains in stomach, side, or abdomen, possibly radiating to the back


• pinpoint red spots on skin


• red irritated eyes


• red skin lesions, often with a purple center


• redness, soreness or itching skin


• shortness of breath


• skin rash


• sore throat


• sores, ulcers, or white spots on lips or in mouth


• sores, welting, or blisters


• sugar in the urine


• sweating


• swelling of feet or lower legs


• swollen glands


• tightness in chest


• troubled breathing


• unpleasant breath odor


• unusual bleeding or bruising


• unusual tiredness or weakness


• unusual weight loss


• vomiting


• vomiting of blood


• weight loss


• wheezing


• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Cramping


• decreased interest in sexual intercourse


• difficulty having a bowel movement (stool)


• feeling of constant movement of self or surroundings


• hives


• inability to have or keep an erection


• increased sensitivity of skin to sunlight


• loss in sexual ability, desire, drive, or performance


• muscle spasm


• redness or other discoloration of skin


• restlessness


• sensation of spinning


• severe sunburn


• weakness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Thalitone side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Thalitone resources

• Thalitone Side Effects (in more detail)
• Thalitone Dosage
• Thalitone Use in Pregnancy & Breastfeeding
• Drug Images
• Thalitone Drug Interactions
• Thalitone Support Group
• 0 Reviews for Thalitone - Add your own review/rating

• Thalitone Prescribing Information (FDA)


• Thalitone MedFacts Consumer Leaflet (Wolters Kluwer)


• Thalitone Concise Consumer Information (Cerner Multum)


• Thalitone Monograph (AHFS DI)


• Chlorthalidone Prescribing Information (FDA)


• Chlorthalidone Professional Patient Advice (Wolters Kluwer)

Compare Thalitone with other medications

• Edema
• High Blood Pressure

Brolene Eye Ointment

1. Name Of The Medicinal Product

Brolene Eye Ointment.

2. Qualitative And Quantitative Composition

Dibrompropamidine isetionate 0.15% w/w.

3. Pharmaceutical Form

Ointment.

4. Clinical Particulars

4.1 Therapeutic Indications

Dibrompropamidine isetionate is an aromatic diamidine which is active against Gram-positive non-spore forming organisms, but less active against Gram-negative bacteria and spore forming organisms. It also has antifungal properties. It may be used topically for the treatment of minor eye infections such as conjunctivitis and blepharitis.

4.2 Posology And Method Of Administration

Adults, elderly persons and children: for the treatment of minor eye infections.

Apply topically once or twice daily. Medical advice should be obtained if there has been no significant improvement after two days.

4.3 Contraindications

Hypersensitivity to dibrompropamidine or any component of the preparation.

4.4 Special Warnings And Precautions For Use

If vision is disturbed or symptoms become worse during therapy, discontinue use and consult a physician.

If there is no significant improvement after two days' therapy, discontinue use and consult a physician.

The eye ointment is unsuitable for use with hard or soft contact lenses.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Safety of use in pregnancy and lactation has not been established. Use during pregnancy and lactation only if considered essential by a physician.

4.7 Effects On Ability To Drive And Use Machines

Eye ointment will cause blurring of vision on instillation. Warn patients not to drive or operate hazardous machinery unless vision is clear.

4.8 Undesirable Effects

Hypersensitivity may occur, in which case treatment should be discontinued immediately.

4.9 Overdose

Topical overdose not applicable. Oral ingestion of a full 5g tube is unlikely to cause any toxic effects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Dibrompropamidine is a member of the aromatic diamidine group of compounds which possess bacteriostatic properties against a wide range of fungi and bacteria. These diamidines exert antibacterial action against pyrogenic cocci, antibiotic resistant staphylococci and some Gram-negative bacilli. The activity of the diamidines is retained in the presence of organic matter such as pus and blood.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

No relevant data.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Paraffin soft yellow, Paraffin liquid, Lanolin anhydrous, Phenylethanol,Water for injections.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months. Use within 4 weeks of first opening

6.4 Special Precautions For Storage

Store below 25^oC.

6.5 Nature And Contents Of Container

Printed, internally lacquered aluminium collapsible tubes with screw capped nozzle fitted with a polythene cap containing 5g ointment.

6.6 Special Precautions For Disposal And Other Handling

No relevant instructions.

7. Marketing Authorisation Holder

sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

8. Marketing Authorisation Number(S)

PL 04425/0198

9. Date Of First Authorisation/Renewal Of The Authorisation

22 July 2002

10. Date Of Revision Of The Text

November 2006

11 LEGAL CLASSIFICATION

P

Sentry AV Ornacyn

Dosage Form: FOR ANIMAL USE ONLY
Broad-spectrum, antibiotic for use in drinking water as an aid in the treatment of respiratory diseases of pet birds.

INDICATIONS & USAGE

Treatment of respiratory diseases of pet birds.

• Treats most common bird respiratory ailments


• Useful as a prophylaxis
  


• Readily soluble and easily administered in drinking water.
  


• Field tested extensively


• Used by bird fanciers, commercial breeders, aviaries
  

Obvious changes in a bird's appearance or posture indicate signs of stress.  Ruffled feathers, eyes closing as in sleeping fashion, sitting low on the perch, unusual breathing, sneezing or rasping indicate illness.

DOSAGE & ADMINISTRATION

Ailing birds - For small birds (i.e. canary) use one packet per eight ounces of water.  For larger birds (i.e. mynah), use two packets per eight ounces of water.  Use as the bird's only drinking water for five days.  Make a fresh solution every day.  For best results, use distilled water.  If no water is consumed for 48-72 hours or bird's condition gets worse, consult your veterinarian.

PRECAUTIONS

Read instructions before using.  This product is intended for exclusive use with pet birds and is not intended for use with poultry for human consumption.  Not for human consumption.

KEEP OUT OF REACH OF CHILDREN

HOW SUPPLIED

8 Powder Packets

Each Packet Contains:  0.021 oz. (0.6 g)


Contents:  Each packet contains 29 mg of erythromycin.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Distributed by:


Sergeant's Pet Care Products, Inc., Omaha NE 68130


Made in USA


www.sentrypetcare.com

Sentry AV Ornacyn  erythromycin  powder

Product Information Product Type OTC ANIMAL DRUG NDC Product Code (Source) 21091-721 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ERYTHROMYCIN PHOSPHATE (ERYTHROMYCIN) ERYTHROMYCIN PHOSPHATE 29 mg  in 0.6 g

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 21091-721-08 8 PACKET In 1 CARTON contains a PACKET 1 0.6 g In 1 PACKET This package is contained within the CARTON (21091-721-08)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		02/06/2009

Labeler - Sergeant's Pet Care Products, Inc. (876995171)

Revised: 07/2010Sergeant's Pet Care Products, Inc.

Xylocaine Dental

Dosage Form: injection
2% Xylocaine® DENTAL with epinephrine 1:50,000 (Lidocaine HCl 2% and Epinephrine 1:50,000 Injection)

2% Xylocaine® DENTAL with epinephrine 1:100,000 (Lidocaine HCl 2% and Epinephrine 1:100,000 Injection)

(Lidocaine HCl and epinephrine injection, USP)

Rx only

Solutions for local anesthesia in Dentistry

Xylocaine Dental Description

Sterile isotonic solutions containing a local anesthetic agent, Lidocaine Hydrochloride, and a vasoconstrictor, Epinephrine (as bitartrate) and are administered parenterally by injection. Both solutions are available in single dose cartridges of 1.7 mL (See INDICATIONS AND USAGE for specific uses).

Solutions contain lidocaine hydrochloride which is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-monohydrochloride, and has the following structural formula :

C14H22N20•HCl•H20 M.W. 288.8

Epinephrine is ( - )-3,4-Dihydroxy-

C9H13NO3•C4H606 M.W. 333.3

COMPOSITION OF LIDOCAINE HYDROCHLORIDE AND EPINEPHRINE INJECTIN, USP

BRAND NAME	PRODUCT IDENTIFICATION		FORMULA
			SINGLE DOSE CARTRIDGE
	Lidocaine hydrochloride	Epinephrine (as the bitartrate)	Sodium Chloride	Potassium metabisulfite	Edetate Disodium
	Concentration %	Dilution	(mg/mL)	(mg/mL)	(mg/mL)
The pH of the solutions are adjusted to USP limits with sodium hydroxide.
2% XYLOCAINE® DENTAL with epinephrine 1:50,000	2	1:50,000	6.5	1.2	0.25
2% XYLOCAINE® DENTAL with epinephrine 1:100,000	2	1:100,000	6.5	1.2	0.25

Xylocaine Dental - Clinical Pharmacology

Mechanism of action

Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of nerve impulses, thereby effecting local anesthetic action.

Onset and duration of anesthesia

When used for infiltration anesthesia in dental patients, the time of onset averages less than two minutes for each of the two forms of lidocaine hydrochloride epinephrine injection, USP. 2% Xylocaine® DENTAL with epinephrine 1:50,000 or 2% Xylocaine® DENTAL with epinephrine 1:100,000 provide an average pulp anesthesia of at least 60 minutes with an average duration of soft tissue anesthesia of approximately 2½ hours.

When used for nerve blocks in dental patients, the time of onset for both forms of lidocaine hydrochloride epinephrine injection, USP averages 2-4 minutes. 2% Xylocaine® DENTAL with epinephrine 1:50,000 or 2% Xylocaine® DENTAL with epinephrine 1:100,000 provide pulp anesthesia averaging at least 90 minutes with an average duration of soft tissue anesthesia of 3 to 3¼ hours.

Hemodynamics

Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. These changes may be attributable to a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system and/or the beta-adrenergic receptor stimulating action of epinephrine when present.

Pharmacokinetics and metabolism

Information derived from diverse formulations, concentrations and usages reveals that lidocaine is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration.

The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentratlon. At concentration of 1 to 4 µg of free base per mL, 60 to 80 percent of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-l-acid glycoprotein.

Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion.

Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than those of lidocaine. Approximately 90% of lidocaine administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2, 6-dimethylaniline.

Studies of lidocaine metabolism following intravenous bolus injections have shown that the elimination half-life of this agent is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites.

Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 µg free base per mL. In the rhesus monkey, arterial blood levels of 18-21 µg/mL have been shown to be the threshold for convulsive activity.

Indications and Usage for Xylocaine Dental

Lidocaine hydrochloride epinephrine injection, USP solutions are indicated for the production of local anesthesia for dental procedures by nerve block or infiltration techniques.

Only accepted procedures for these techniques as described in standard textbooks are recommended.

Contraindications

Lidocaine hydrochloride epinephrine injection, USP is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any components of the injectable formulations.

Warnings

DENTAL PRACTITIONERS WHO EMPLOY LOCAL ANESTHETIC AGENTS SHOULD BE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF EMERGENCIES WHICH MAY ARISE FROM THEIR USE. RESUSCITATIVE EQUIPMENT, OXYGEN AND OTHER RESUSCITATIVE DRUGS SHOULD BE AVAILABLE FOR IMMEDIATE USE.

To minimize the likelihood of intravascular injection, aspiration should be performed before the local anesthetic solution is injected. If blood is aspirated, the needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not assure that intravascular injection will be avoided.

Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection.

Lidocaine hydrochloride epinephrine injection, USP solutions contain potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Lidocaine hydrochloride epinephrine injection, USP,along with other local anesthetics, is capable of producing methemoglobinemia. The clinical signs of methemoglobinemia are cyanosis of the nail beds and lips, fatigue and weakness. If methemoglobinemia does not respond to administration of oxygen, administration of methylene blue intravenously 1-2 mg/kg body weight over a 5 minute period is recommended.

The American Heart Association has made the following recommendations regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: "Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used." (Kaplan, EL, editor: Cardiovascular disease in dental practice, Dallas 1986, American Heart Association.)

Precautions

General

The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate precautions and readiness for emergencies. Consult standard textbooks for specific techniques and precautions for various regional anesthetic procedures. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use (See WARNINGS AND ADVERSE REACTIONS).

The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Repeated doses of lidocaine may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical condition.

If sedatives are employed to reduce patient apprehension, reduced doses should be used since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. Young children should be given minimal doses of each agent.

Lidocaine should be used with caution in patients with severe shock or heart block. Lidocaine should also be used with caution in patients with impaired cardiovascular function. Local anesthetic solutions containing a vasoconstrictor should be used with caution in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Preparations containing a vasoconstrictor should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions.

Cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be monitored after each local anesthetic injection. Restlessness, anxiety tinnitus, dizziness, blurred vision, tremors, depression or drowsiness should alert the practitioner to the possibility of central nervous system toxicity. Signs and symptoms of depressed cardiovascular function may commonly result from a vasovagal reaction, particularly if the patient is in an upright position : placing the patient in the recumbent position is recommended when an adverse response is noted after injection of a local anesthetic (See ADVERSE REACTIONS - Cardiovascular System.).

Lidocaine should be used with caution in patients with hepatic disease, since amide-type local anesthetics are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations.

Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction, and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspected triggering agent (s) and prompt treatment, including oxygen therapy, dantrolene (consult dantrolene sodium intravenous package insert before using) and other supportive measures.

Lidocaine should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine.

Use in the Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratony depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (See DOSAGE AND ADMINISTRATION).

Information for Patients

The patient should be informed of the possibility of temporary loss of sensation and muscle function following infiltration or nerve block injections.

The patient should be advised to to exert caution to avoid inadvertent trauma to the lips, tongue, cheek mucosae or soft palate when these structures are anesthetized. The ingestion of food should therefore be postponed until normal function returns. The patient should be advised to consult the dentist if anesthesia persists or if a rash develops.

Clinically Significant Drug Interactions

The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or phenothiazines may produce severe prolonged hypotension or hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

Concurrent administration of vasopressor drugs and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

As the 2% Xylocaine® DENTAL with epinephrine 1:50,000 and the 2% Xylocaine® DENTAL with epinephrine 1:100,000 solutions both contain a vasoconstrictor (epinephrine), concurrent use of either with a Beta-adrenergic blocking agent (propranolol, timolol, etc.) may result in dose-dependent hypertension and bradycardia with possible heart block.

Drug/Laboratory test interactions

The intramuscular injection of lidocaine may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine.

Carcinogenesis, mutagenesis, impairment of fertility

Studies of lidocaine in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted.

PREGNANCY

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place.

Nursing mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman.

Pediatric use

Dosages in pediatric population should be reduced, commensurate with age, body weight and physical condition (See DOSAGE AND ADMINISTRATION).

Adverse Reactions

Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide-type local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels (which may be caused by excessive dosage, rapid absorption, unintended intravascular injection or slow metabolic degradation), injection technique, volume of injection, hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported :

Central Nervous System

CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, 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. 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 following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.

Cardiovascular system

Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.

Signs and symptoms of depressed cardiovascular function may commonly result from a vasovagal reaction, particularly if the patient is in an upright position. Less commonly, they may result from a direct effect of the drug. Failure to recognize the premonitory signs such as sweating, a feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Management consists of placing the patient in the recumbent position and ventilation with oxygen. Supportive treatment of circulatory depression may require the administration of intravenous fluids and, when appropriate, a vasopressor (e.g, ephedrine) as directed by the clinical situation.

Allergic reactions

Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.

Neurologic reactions

The incidences of adverse reactions (e.g., persistent neurologic deficit) associated with the use of local anesthetics may be related to the technique employed, the total dose of local anesthetic administered, the particular drug used, the route of administration, and the physical condition of the patient.

Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of lidocaine, with slow, incomplete, or no recovery. These post-marketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches.

Overdosage

Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (See ADVERSE REACTIONS, WARNINGS AND PRECAUTIONS).

Management of local anesthetic emergencies

The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.

The first step in the management of convulsions consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask.

Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of clrculatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. If cardiac arrest should occur, standard cardio-pulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

Dialysis is of negligible value in the treatment of acute overdosage with lidocaine.

The intravenous LD50 of lidocaine HCl in female mice is 26 (21-31) mg/kg and the subcutaneous LD50 is 264 (203-304) mg /kg.

Xylocaine Dental Dosage and Administration

The dosage of lidocaine hydrochloride epinephrine injection depends on the physical status of the patient, the area of the oral cavity to be anesthetized, the vascularity of the oral tissues, and the technique of anesthesia used. The least volume of solution that results in effective local anesthesia should be administered; time should be allowed between injections to observe the patient for manifestations of an adverse reaction. For specific techniques and procedures of a local anesthesia in the oral cavity, refer to standard textbooks.

For most routine dental procedures, 2% Xylocaine® DENTAL with epinephrine 1:100,000 is preferred. However, when greater depth and a more pronounced hemostasis are required, 2% Xylocaine® DENTAL with epinephrine 1:50,000 should be used.

Dosage requirements should be determined on an individual basis. In oral infiltration and / or mandibular block, initial dosages of 1.0 - 5.0 mL (½ to 2½ cartridges) of 2 % Xylocaine® DENTAL with epinephrine 1:50,000 or 2% Xylocaine® DENTAL with epinephrine 1:100,000 are usually effective.

In children under 10 years of age, it is rarely necessary to administer more than one-half cartridge (0.9-1.0 mL or 18-20 mg of lidocaine) per procedure to achieve local anesthesia for a procedure involving a single tooth. In maxillary infiltration, this amount will often suffice to the treatment of two or even three teeth. In the mandibular block, however, satisfactory anesthesia achieved with this amount of drug, will allow treatment of the teeth of an entire quadrant. Aspiration is recommended since it reduces the possibility of intravascular injection, thereby keeping the incidence of side effects and anesthetic failures to a minimum. Moreover, injection should always be made slowly.

Maximum recommended dosages for lidocaine HCl 2% and epinephrine 1:50,000 or lidocaine HCl 2% and epinephrine 1:100,000.

Adult

For normal healthy adults, the amount of lidocaine HCl administered should be kept below 500 mg, and in any case, should not exceed 7 mg/kg (3.2 mg/lb) of body weight.

Pediatric

Pediatric patients : It is difficult to recommend a maximum dose of any drug for pediatric patients since this varies as a function of age and weight. For pediatric patients of less than ten years who have a normal lean body mass and normal body development, the maximum dose may be determined by the application of one of the standard pediatric drug formulas (e.g., Clark's rule). For example, in pediatric patients of five years weighing 50 Ibs, the dose of lidocaine hydrochloride should not exceed 75-100mg when calculated according to Clark's rule. In any case, the maximum dose of lidocaine hydrochloride should not exceed 7 mg/kg (3.2 mg/lb) of body weight.

NOTE : Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored and / or contain particulate matter should not be used and any unused portion of a cartridge of lidocaine hydrochloride epinephrine injection, U.S.P. should be discarded.

How is Xylocaine Dental Supplied

-

2% Xylocaine® DENTAL with epinephrine 1:50,000 is available in cardboard boxes containing 5 blisters of 10 × 1.7 mL cartridges (NDC 66312-181-16).

-

2% Xylocaine® DENTAL with epinephrine 1:100,000 is available in cardboard boxes containing 5 blisters of 10 × 1.7 mL cartridges (NDC 66312-176-16).

Store at controlled room temperature, below 25°C (77°F). Protect from light. Do not permit to freeze.

BOXES : For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the end flap.

Do not use if color is pinkish or darker than slightly yellow or if it contains a precipitate.

STERILIZATION : STORAGE AND TECHNICAL PROCEDURES

1. Cartridges should not be autoclaved, because the closures employed cannot withstand autoclaving temperatures and pressures.


2. If chemical disinfection of anesthetic cartridges is desired, either isopropyl alcohol (91%) or 70% ethyl alcohol is recommended. Many commercially available brands of rubbing alcohol, as well as solutions of ethyl alcohol not of U.S.P grade, contain denaturants that are injurious to rubber and, therefore, are not to be used. It is recommended that chemical disinfection be accomplished just prior to use by wiping the cartridge cap thoroughly with a pledge of cotton that has been moistened with recommended alcohol.


3. Certain metallic ions (mercury, zinc, copper, etc.) have been related to swelling and edema after local anesthesia in dentistry. Therefore, chemical disinfectants containing or releasing these ions are not recommended. Antirust tablets usually contain sodium nitrite or some similar agents that may be capable of releasing metal ions. Because of this, aluminium sealed cartridges should not be kept in such solutions.


4. Quaternary ammonium salts, such as benzalkonium chloride, are electrolytically incompatible with aluminium. Cartridges of 2 % Xylocaine® DENTAL with epinephrine 1:50,000 and 2% Xylocaine® DENTAL with epinephrine 1:100,000 are sealed with aluminium caps and therefore should not be immersed in any solution containing these salts.


5. To avoid leakage of solutions during injection, be sure to penetrate the center of the rubber diaphragm when loading the syringe. An off-center penetration produces an oval shaped puncture that allows leakage around the needle.
   
   Other causes of leakage and breakage include badly worn syringes, aspirating syringes with bent harpoons, the use of syringes not designed to take 1.7 mL cartridges, and inadvertent freezing.


6. Cracking of glass cartridges is most often the result of an attempt to use a cartridge with an extruded plunger. An extruded plunger loses its lubrication and can be forced back into the cartridge only with difficulty. Cartridges with extruded plungers should be discarded.


7. Store at controlled room temperature, below 25°C (77°F).

Manufactured for

DENTSPLY Pharmaceutical by

Novocol Pharmaceutical of Canada, Inc.

Cambridge, Ontario, Canada N1R 6X3

Rev. 03/09 (2616-0)

PRINCIPAL DISPLAY PANEL - 1.7 mL Cartridge

2% Xylocaine® DENTAL

1.7 mL

with epinephrine 1:50,000

(lidocaine HCl and epinephrine Injection, USP)

Distributed by DENTSPLY Pharmaceutical

York, PA 17404

Manufactured by Novocol Pharmaceutical of Canada, Inc.

Cambridge, Ontario N1R 6X3

LOT

EXP.

2619-0

PRINCIPAL DISPLAY PANEL - 1.7 Cartridge Carton

NDC 66312-181-16

DENTSPLY

PHARMACEUTICAL

2% Xylocaine® DENTAL

with epinephrine 1:50,000

(lidocaine HCl and epinephrine Injection, USP)

20 mg/mL

Store at room temperature

below 25°C (77°F).

DO NOT PERMIT TO FREEZE.

Rx only

50 Cartridges, 1.7 mL each

COLOR

CODED

STERILE AQUEOUS

SOLUTION FOR INJECTION

DENTSPLY Reorder #: 22216

PRINCIPAL DISPLAY PANEL 1.7 mL Cartridge Shipper

NDC 66312-181-16

20 Boxes

DENTSPLY

PHARMACEUTICAL

2% Xylocaine® DENTAL

with epinephrine 1:50,000

(lidocaine HCl and epinephrine Injection, USP)

1000 Cartridges containing minimum content of 1.7mL

Distributed by DENTSPLY Pharmaceutical

York, PA 17404

Manufactured by Novocol Pharmaceutical of Canada, Inc.

Cambridge, Ontario N1R 6X3

Lot No.

Exp.

2621-0

PRINCIPAL DISPLAY PANEL 1.7 mL Cartridge

2% Xylocaine® DENTAL

1.7 mL

with epinephrine 1:100,000

(lidocaine HCl and epinephrine Injection, USP)

Distributed by DENTSPLY Pharmaceutical

York, PA 17404

Manufactured by Novocol Pharmaceutical of Canada, Inc.

Cambridge, Ontario N1R 6X3

LOT

EXP.

2615-0

PRINCIPAL DISPLAY PANEL 1.7 mL Cartridge Carton

NDC 66312-176-16

DENTSPLY

PHARMACEUTICAL

2% Xylocaine® DENTAL

with epinephrine 1:100,000

(lidocaine HCl and epinephrine Injection, USP)

20 mg/mL

Store at room temperature

below 25°C (77°F).

DO NOT PERMIT TO FREEZE.

Rx only

50 Cartridges, 1.7 mL each

COLOR

CODED

STERILE AQUEOUS

SOLUTION FOR INJECTION

DENTSPLY Reorder #: 20016

PRINCIPAL DISPLAY PANEL 1.7 mL Cartridge Shipper

NDC 66312-176-16

20 Boxes

DENTSPLY

PHARMACEUTICAL

2% Xylocaine® DENTAL

with epinephrine 1:100,000

(lidocaine HCl and epinephrine Injection, USP)

1000 Cartridges containing minimum content of 1.7mL

Distributed by DENTSPLY Pharmaceutical

York, PA 17404

Manufactured by Novocol Pharmaceutical of Canada, Inc.

Cambridge, Ontario N1R 6X3

Lot No.

Exp.

2617-0

XYLOCAINE  lidocaine hydrochloride and epinephrine bitartrate  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 66312-181 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Lidocaine Hydrochloride (Lidocaine) Lidocaine 20 mg  in 1 mL Epinephrine Bitartrate (Epinephrine) Epinephrine 20 ug  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride 6.5 mg  in 1 mL Potassium Bisulfite 1.2 mg  in 1 mL Edetate Disodium 0.25 mg  in 1 mL Sodium hydroxide   Hydrochloric acid   Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 66312-181-16 50 CARTRIDGE In 1 CARTON contains a CARTRIDGE 1 1.7 mL In 1 CARTRIDGE This package is contained within the CARTON (66312-181-16)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA088389	01/22/1985

XYLOCAINE  lidocaine hydrochloride and epinephrine bitartrate  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 66312-176 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Lidocaine Hydrochloride (Lidocaine) Lidocaine 20 mg  in 1 mL Epinephrine Bitartrate (Epinephrine) Epinephrine 10 ug  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride 6.5 mg  in 1 mL Potassium Bisulfite 1.2 mg  in 1 mL Edetate Disodium 0.25 mg  in 1 mL Sodium hydroxide   Hydrochloric acid   Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 66312-176-16 50 CARTRIDGE In 1 CARTON contains a CARTRIDGE 1 1.7 mL In 1 CARTRIDGE This package is contained within the CARTON (66312-176-16)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA088390	01/22/1985

Labeler - Dentsply Pharmaceutical (102221942)

Revised: 08/2009Dentsply Pharmaceutical

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