Theophylline Elixir

Dosage Form: Elixir

DESCRIPTION

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous Theophylline is C7H8N4O2 with a molecular weight of 180.17.

Theophylline Elixir is available as a liquid intended for oral administration, containing 80 mg of anhydrous Theophylline and 20% alcohol per 15 mL (one tablespoonful).

Also contains: FD&C Red #40, Artificial Mixed Fruit Flavor, Propylene Glycol, Purified Water, Saccharin Sodium. May contain Citric Acid to adjust pH.

Theophylline - Clinical Pharmacology

Mechanism Of Action:

Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship:

Bronchodilation occurs over the serum Theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theophylline concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics:

Overview Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of Theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Theophylline clearance (see PRECAUTIONS, Laboratory tests).

Table I. Mean and range of total body clearance and half-life of Theophylline related to age and altered physiological states.

Population characteristics	Total body clearance* mean (range)†† (mL/kg/min)	Half-life mean (range)†† (hr)
For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.
*Clearance represents the volume of blood completely cleared of Theophylline by the liver in one minute. Values listed were generally determined at serum Theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.
††Reported range or estimated range (mean ± 2 SD) where actual range not reported.
†NR = not reported or not reported in a comparable format.
**Median
Age
Premature neonates
postnatal age 3-15 days	0.29 (0.09-0.49)	30 (17-43)
postnatal age 25-57 days	0.64 (0.04-1.2)	20 (9.4-30.6)
Term infants
postnatal age 1-2 days	NR†	25.7 (25-26.5)
postnatal age 3-30 weeks	NR†	11 (6-29)
Children
1-4 years	1.7 (0.5-2.9)	3.4 (1.2-5.6)
4-12 years	1.6 (0.8-2.4)	NR†
13-15 years	0.9 (0.48-1.3)	NR†
16-17 years	1.4 (0.2-2.6)	3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
non-smoking asthmatics	0.65 (0.27-1.03)	8.7 (6.1-12.8)
Elderly (>60 years)
non-smokers with normal cardiac, liver, and renal function	0.41 (0.21-0.61)	9.8 (1.6-18)
Concurrent illness or altered physiological state
Acute pulmonary edema	0.33** (0.07-2.45)	19** (3.1-82)
COPD->60 years, stable non-smoker >1 year	0.54 (0.44-0.64)	11 (9.4-12.6)
COPD with cor pulmonale	0.48 (0.08-0.88)	NR†
Cystic fibrosis (14-28 years)	1.25 (0.31-2.2)	6.0 (1.8-10.2)
Fever associated with acute viral respiratory illness (children 9-15 years)	NR†	7.0 (1.0-13)
Liver disease -  cirrhosis	0.31** (0.1-0.7)	32** (10-56)
acute hepatitis	0.35 (0.25-0.45)	19.2 (16.6-21.8)
cholestasis	0.65 (0.25-1.45)	14.4 (5.7-31.8)
Pregnancy -      1st trimester	NR†	8.5 (3.1-13.9)
2nd trimester	NR†	8.8 (3.8-13.8)
3rd trimester	NR†	13.0 (8.4-17.6)
Sepsis with multi-organ failure	0.47 (0.19-1.9)	18.8 (6.3-24.1)
Thyroid disease - hypothyroid	0.38 (0.13-0.57)	11.6 (8.2-25)
hyperthyroid	0.8 (0.68-0.97)	4.5 (3.7-5.6)

Note: In addition to the factors listed above, Theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Theophylline.

Absorption  Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose. Co-administration of Theophylline with food or antacids does not cause clinically significant changes in the absorption of Theophylline from immediate-release dosage forms.

Distribution   Once Theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of Theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of Theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum Theophylline concentration. Generally, concentrations of unbound Theophylline should be maintained in the range of 6-12 mcg/mL.

Metabolism  Following oral dosing, Theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to

1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid.

1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Theophylline dose is N-methylated to caffeine. Theophylline demethylation to

3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and

P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to

1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized Theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theophylline concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theophylline metabolism, non-linearity of elimination may begin in some patients at serum Theophylline concentrations

< 10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum Theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of Theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum Theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Theophylline concentration in response to dosage changes.

Excretion In neonates, approximately 50% of the Theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as

1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Theophylline is excreted unchanged in the urine and since active metabolites of Theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the Theophylline dose excreted in the urine as unchanged Theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations in neonates with reduced renal function (See WARNINGS).

Serum Concentrations At Steady StateAfter multiple doses of Theophylline, steady state is reached in 30-65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean Theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Theophylline clearance. In patients with high Theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum Theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.

Special Populations (See Table I For Mean Clearance And Half-Life Values)

Geriatric  The clearance of Theophylline is decreased by an average of 30% in healthy elderly adults (> 60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in elderly patients (see WARNINGS).

Pediatrics  The clearance of Theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender  Gender differences in Theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race  Pharmacokinetic differences in Theophylline clearance due to race have not been studied.

Renal Insufficiency  Only a small fraction, e.g., about 10%, of the administered Theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Theophylline is excreted unchanged in the urine and since active metabolites of Theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered Theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in neonates with decreased renal function (see WARNINGS).

Hepatic Insufficiency  Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS).

Congestive Heart Failure (CHF)  Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with CHF (see WARNINGS).

Smokers  Tobacco and marijuana smoking appears to increase the clearance of Theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on Theophylline clearance.

Fever  Fever, regardless of its underlying cause, can decrease the clearance of Theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum Theophylline concentrations. Children with rapid rates of Theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with sustained fever (see WARNINGS).

Miscellaneous

Other factors associated with decreased Theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased Theophylline clearance include hyperthyroidism and cystic fibrosis.

Clinical Studies:

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that Theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

Indications and Usage for Theophylline

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Contraindications

Theophylline Elixir is contraindicated in patients with a history of hypersensitivity to Theophylline or other components in the product.

Warnings

Concurrent Illness:

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced Theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of Theophylline use and the need for more intensive monitoring of serum Theophylline concentrations in patients with the following risk factors:

Age

Neonates (term and premature)

Children <1 year

Elderly (>60 years)

Concurrent Diseases

Acute pulmonary edema

Congestive heart failure

Cor-pulmonale

Fever; >102º for 24 hours or more; or lesser temperature elevations for longer periods

Hypothyroidism

Liver disease; cirrhosis, acute hepatitis

Reduced renal function in infants <3 months of age

Sepsis with multi-organ failure

Shock

Cessation Of Smoking

Drug Interactions Adding a drug that inhibits Theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Theophylline metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II).

When Signs Or Symptoms Of Theophylline Toxicity Are Present:

Whenever a patient receiving Theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Theophylline toxicity (even if another cause may be suspected), additional doses of Theophylline should be withheld and a serum Theophylline concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI).

Dosage Increases:

Increases in the dose of Theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the Theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests).

As the rate of Theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

Precautions

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Theophylline clearance and require dosage adjustment should occur prior to initiation of Theophylline therapy, prior to increases in Theophylline dose, and during follow up (see WARNINGS). The dose of Theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum Theophylline concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations:

Serum Theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Theophylline concentration should be measured as follows:

1. 
   

   When initiating therapy to guide final dosage adjustment after titration.

   
   


2. 
   

   Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.

   
   


3. 
   

   Whenever signs or symptoms of Theophylline toxicity are present.

   
   


4. 
   

   Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Theophylline clearance (e.g., fever >102°F sustained for >24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

   
   

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Theophylline concentration; 1-2 hours after a dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than two hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Theophylline cannot be used reliably to adjust dosage without special techniques.

Effects On Laboratory Tests:

As a result of its pharmacological effects, Theophylline at serum concentrations within the

10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 μЄq/l to 800 μЄq/l, total cholesterol (from a mean of 140 to 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of Theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theophylline in individual patients.

Information for Patients

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with Theophylline, even if another cause is suspected. The patient should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking Theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Drug Interactions

Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Theophylline or another drug or occurrence of adverse effects without a change in serum Theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Theophylline clearance is altered by another drug resulting in increased or decreased serum Theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with Theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Theophylline regimen. If Theophylline is being initiated in a patient who is already taking a drug that inhibits Theophylline clearance (e.g., cimetidine, erythromycin), the dose of Theophylline required to achieve a therapeutic serum Theophylline concentration will be smaller. Conversely, if Theophylline is being initiated in a patient who is already taking a drug that enhances Theophylline clearance (e.g., rifampin), the dose of Theophylline required to achieve a therapeutic serum Theophylline concentration will be larger. Discontinuation of a concomitant drug that increases Theophylline clearance will result in accumulation of Theophylline to potentially toxic levels, unless the Theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Theophylline clearance will result in decreased serum Theophylline concentrations, unless the Theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with Theophylline or do not produce a clinically significant interaction (i.e., <15% change in Theophylline clearance).

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with Theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Theophylline has been reported.

Table II. Clinically significant drug interactions with Theophylline*.

Drug		Type of Interaction	Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state Theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum Theophylline concentration than the value listed.
Adenosine		Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol		A single large dose of alcohol (3 ml/kg of whiskey) decreases Theophylline clearance for up to 24 hours.	30% increase
Allopurinol		Decreases Theophylline clearance at allopurinol doses >600 mg/day.	25% increase
Aminoglutethimide		Increases Theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine		Similar to aminoglutethimide.	30% decrease
Cimetidine		Decreases Theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin		Similar to cimetidine.	40% increase
Clarithromycin		Similar to erythromycin.	25% increase
Diazepam		Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while Theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of Theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram		Decreases Theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin		Similar to cimetidine.	300% increase
Ephedrine		Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin		Erythromycin metabolite decreases Theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen		Estrogen containing oral contraceptives decrease Theophylline clearance in a dose- dependent fashion. The effect of progesterone on Theophylline clearance is unknown.	30% increase
Flurazepam		Similar to diazepam.	Similar to diazepam.
Fluvoxamine		Similar to cimetidine	Similar to cimetidine
Halothane		Halothane sensitizes the myocardium to catecholamines, Theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A		Decreases Theophylline clearance.	100% increase
Isoproterenol (IV)	Increases Theophylline clearance.		20% decrease
Ketamine	Pharmacologic		May lower Theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.		Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.		Similar to diazepam.
Methotrexate (MTX)	Decreases Theophylline clearance.		20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.		80% increase
Midazolam	Similar to diazepam.		Similar to diazepam.
Moricizine	Increases Theophylline clearance.		25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.		Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases Theophylline clearance.		30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.		25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases Theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.		Serum Theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases Theophylline clearance and pharmacologic interaction.		40% increase. Beta-2 blocking effect may decrease efficacy of Theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.		100% increase. Beta-2 blocking effect may decrease efficacy of Theophylline.
Rifampin	Increases Theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.		20-40% decrease
Sulfinpyrazone	Increases Theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of Theophylline.		20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of Theophylline.

Sulfacleanse 8/4

Generic Name: sodium sulfacetamide and sulfur

Dosage Form: topical lotion
SULFACLEANSE TM 8/4 TOPICAL SUSPENSION REV.1.0 Sodium sulfacetamide is a sulfonamide with antibacterial activity while sulfur acts as a keratolytic agent. Chemically sodium sulfacetamide is N-[(4-aminophenyl) sulfonyl]-acetamide, monosodium salt, monohydrate.

Each mL of SulfaCleanse™ 8/4 contains 80mg of sodium sulfacetamide and 40mg of sulfur in a formulation consisting of: aloe, butylated hydroxytoluene, cetyl alcohol, disodium oleamido MEA sulfosuccinate, edetate disodium, fragrance, glyceryl stearate, green tea, magnesium aluminum silicate, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium cocoyl isethionate, sodium methyl cocoyl taurate, sodium thiosulfate, stearyl alcohol, xanthan gum.

The most widely accepted mechanism of action of sulfonamides is the Woods-Fildes theory, which is based on the fact that sulfonamides act as competitive antagonists to para- aminobenzoic acid (PABA), an essential component for bacterial growth. While absorption through intact skin has not been determined, sodium sulfacetamide is readily absorbed from the gastrointestinal tract when taken orally and excreted in the urine, largely unchanged. The biological half-life has variously been reported as 7 to 12.8 hours. The exact mode of action of sulfur in the treatment of acne is unknown, but it has been reported that it inhibits the growth of Propionibacterium acnes and the formation of free fatty acids.

SulfaCleanse™ 8/4 is indicated for the topical control of acne vulgaris, acne rosacea and seborrheic dermatitis.

SulfaCleanse™ 8/4 is contraindicated for use by patients having known hypersensitivity to sulfonamides, sulfur or any other component of this preparation. SulfaCleanse™ 8/4 is not to be used by patients with kidney disease.

Although rare, sensitivity to sodium sulfacetamide may occur. Therefore, caution and careful supervision should be observed when prescribing this drug for patients who may be prone to hypersensitivity to topical sulfonamides. Systemic toxic reactions such as agranulocytosis, acute hemolytic anemia, purpura hemorrhagica, drug fever, jaundice, and contact dermatitis indicate hypersensitivity to sulfonamides. Particular caution should be employed if areas of denuded or abraded skin are involved.

FOR EXTERNAL USE ONLY. Keep away from eyes. Keep out of reach of children. Keep container tightly closed.

General – If irritation develops, use of the product should be discontinued and appropriate therapy instituted. Patients should be carefully observed for possible local irritation or sensitization during long-term therapy. The object of this therapy is to achieve desquamation without irritation, but sodium sulfacetamide and sulfur can cause reddening and scaling of the epidermis. These side effects are not unusual in the treatment of acne vulgaris, but patients should be cautioned about the possibility.

Information for Patients – Avoid contact with eyes, eyelids, lips and mucous membranes. If accidental contact occurs, rinse with water. If excessive irritation develops, discontinue use and consult your physician.

Carcinogenesis, Mutagenesis and Impairment

of Fertility – Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Category C – Animal reproduction studies have not been conducted with SulfaCleanse™ 8/4. It is also not known whether SulfaCleanse™ 8/4 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SulfaCleanse™ 8/4 should be given to a pregnant woman only if clearly needed.

It is not known whether sodium sulfacetamide is excreted in the human milk following topical use of SulfaCleanse™ 8/4. However, small amounts of orally administered sulfonamides have been reported to be eliminated in human milk. In view of this and because many drugs are excreted in human milk, caution should be exercised when SulfaCleanse™ 8/4 is administered to a nursing woman.

Safety and effectiveness in children under the age of 12 has not been established.

Although rare, sodium sulfacetamide may cause local irritation.

Apply SulfaCleanse™ 8/4 once or twice daily to affected areas, or as directed by your physician. Wet skin and liberally apply to areas to be cleansed. Massage gently into skin for 10-20 seconds, working into a full lather, rinse thoroughly and pat dry. If drying occurs, it may be controlled by rinsing off SulfaCleanse™ 8/4 sooner or using less often.

SulfaCleanse™ 8/4 is available in a 16 fl. oz. (473 mL) bottle, NDC 42546-175-16.

Store at controlled room temperature 20°-25° C (68°-77° F); excursions permitted to 15°-30°C (59°-86°F).

Protect from freezing.


KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

NDC 42546-175-16

SulfaCleanseTM 8/4 (sodium sulfacetamide 8% and sulfur 4%)

Topical Suspension in a vehicle containing Green Tea and Aloe

Rx only

16 fl oz (473 ml)

PruGen, Inc. Pharmaceuticals

Sulfacleanse 8/4  sodium sulfacetamide and sulfur  lotion

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 42546-175 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SULFACETAMIDE SODIUM (SULFACETAMIDE) SULFACETAMIDE SODIUM 80 mg  in 1 mL SULFUR (SULFUR) SULFUR 40 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Aloe   BUTYLATED HYDROXYTOLUENE   Cetyl alcohol   Disodium oleamido MEA-sulfosuccinate   EDETATE DISODIUM   GLYCERYL MONOSTEARATE   Green tea leaf   MAGNESIUM ALUMINUM SILICATE   METHYLPARABEN   PEG-100 STEARATE   PROPYLPARABEN   WATER   SODIUM COCOYL ISETHIONATE   TAURINE   SODIUM THIOSULFATE   STEARYL ALCOHOL   XANTHAN GUM

Product Characteristics Color yellow Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 42546-175-16 1 BOTTLE In 1 BOX contains a BOTTLE, PUMP 1 473 mL In 1 BOTTLE, PUMP This package is contained within the BOX (42546-175-16)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		05/01/2011

Labeler - PruGen, Inc. (929922750)

Revised: 05/2011PruGen, Inc.

More Sulfacleanse 8/4 resources

• Sulfacleanse 8/4 Side Effects (in more detail)
• Sulfacleanse 8/4 Use in Pregnancy & Breastfeeding
• Sulfacleanse 8/4 Drug Interactions
• Sulfacleanse 8/4 Support Group
• 18 Reviews for Sulfacleanse 8/4 - Add your own review/rating

Compare Sulfacleanse 8/4 with other medications

• Acne
• Rosacea
• Seborrheic Dermatitis

Phazyme-95

Generic Name: simethicone (sye METH i cone)

Brand Names: Alka-Seltzer Anti-Gas, Equalize Gas Relief Drops, Gas Aide, Gas Free Extra Strength, Gas-X, Gas-X Extra Strength, Gas-X Infant Drops, Gas-X Maximum Strength, Gas-X Thin Strips Cinnamon, Gas-X Thin Strips Peppermint, Gas-X Tongue Twisters Thin Strips Children's, Gas-X Ultra Softgels, Genasyme, Infantaire Gas Relief, Little Tummys, Maalox Anti-Gas, Maalox Anti-Gas Extra Strength, Mi-Acid Gas Relief, Mylanta Gas, Mylanta Gas Maximum Strength, Mylicon, Mytab Gas, Phazyme, Phazyme Maximum Strength, Phazyme Ultra, Phazyme-125, Phazyme-95

What is Phazyme-95 (simethicone)?

Simethicone allows gas bubbles in the stomach and intestines to come together more easily, which allows for easier passage of gas.

Simethicone is used to relieve painful pressure caused by excess gas in the stomach and intestines. Simethicone is for use in babies, children, and adults.

Simethicone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Phazyme-95 (simethicone)?

Never use more than the recommended dose of simethicone.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you are allergic to any drugs, or if you have any type of serious illness (especially one that affects your stomach or intestines).

Simethicone works best if you take it after meals and at bedtime.

Simethicone may be only part of a complete program of treatment that may also include a special diet or increased exercise. It is very important to follow the diet and exercise plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you must avoid to help control your condition.

There may be other drugs that can interact with simethicone. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

What should I discuss with my healthcare provider before taking Phazyme-95 (simethicone)?

You should not use this medication if you are allergic to simethicone.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you are allergic to any drugs, or if you have any type of serious illness (especially one that affects your stomach or intestines).

Simethicone is not expected to harm an unborn baby. It is not known whether simethicone passes into breast milk or if it could harm a nursing baby. Do not use this medication without medical advice if you are breast-feeding a baby.

The liquid form may contain phenylalanine. Talk to your doctor before using this form of simethicone if you have phenylketonuria (PKU).

How should I take Phazyme-95 (simethicone)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Do not take more of this medication than is directed.

Simethicone works best if you take it after meals and at bedtime.

The simethicone chewable tablet must be chewed before swallowing.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one. Clean the medicine dropper after each use. Allow it to air dry.

Simethicone liquid drops can be mixed with water, baby formula, or other liquids to make swallowing easier for an infant or child.

Children should never be given more than the recommended dose of simethicone. Call your doctor if the child's gas symptoms do not improve after treatment with simethicone.

Simethicone may be only part of a complete program of treatment that may also include a special diet or increased exercise. It is very important to follow the diet and exercise plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you must avoid to help control your condition.

Store at room temperature away from moisture, heat, and light. Do not allow the liquid form of this medicine to freeze.

What happens if I miss a dose?

Since simethicone is used on an as needed basis, you are not likely to miss a dose. Do not use more of this medication than is directed.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Phazyme-95 (simethicone)?

Ask a doctor or pharmacist before using any other stomach medicine or antacid. Simethicone is contained in many combination medicines. Taking certain products together can cause you to get too much simethicone.

Phazyme-95 (simethicone) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Phazyme-95 (simethicone)?

There may be other drugs that can interact with simethicone. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Phazyme-95 resources

• Phazyme-95 Side Effects (in more detail)
• Phazyme-95 Use in Pregnancy & Breastfeeding
• Phazyme-95 Support Group
• 0 Reviews for Phazyme-95 - Add your own review/rating

• Simethicone Professional Patient Advice (Wolters Kluwer)


• Simethicone Monograph (AHFS DI)


• Alka-Seltzer Anti-Gas Advanced Consumer (Micromedex) - Includes Dosage Information


• Bicarsim MedFacts Consumer Leaflet (Wolters Kluwer)


• Gas-X Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Gas-X Extra Strength MedFacts Consumer Leaflet (Wolters Kluwer)


• Gas-X Infant Drops Liquid Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Genasyme Suspension MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Phazyme-95 with other medications

• Endoscopy or Radiology Premedication
• Functional Gastric Disorder
• Gas
• Postoperative Gas Pains

Where can I get more information?

• Your pharmacist can provide more information about simethicone.

See also: Phazyme-95 side effects (in more detail)

Ivy Soothe

Generic Name: hydrocortisone (Topical application route)

hye-droe-KOR-ti-sone

Commonly used brand name(s)

In the U.S.

• Ala-Cort


• Ala-Scalp HP


• Anusol HC


• Aquanil HC


• Beta HC


• Caldecort


• Cetacort


• Corta-Cap


• Cortagel Extra Strength


• Cortaid


• CortAlo With Aloe


• Corticaine


• Corticool Maximum Strength


• Cortizone-10


• Cortizone-5


• Cotacort


• Delacort


• Dermarest


• Dermtex-HC


• Foille Cort


• Gly-Cort


• Hydrozone Plus


• Hytone


• Instacort-10


• Ivy Soothe


• IvyStat


• Keratol HC


• Kericort 10


• Lacticare-HC


• Locoid


• Locoid Lipocream


• Medi-Cortisone Maximum Strength


• Microcort


• Mycin Scalp


• Neutrogena T/Scalp


• NuCort


• Nupercainal HC


• Nutracort


• Pandel


• Pediaderm HC Kit


• Preparation H Hydrocortisone


• Proctocream-HC


• Recort Plus


• Sarnol-HC Maximum Strength


• Scalacort


• Scalpcort


• Summer's Eve Specialcare


• Texacort


• Therasoft Anti-Itch & Dermatitis


• U-Cort


• Westcort

In Canada

• Barriere-Hc


• Cortate


• Cort-Eze


• Cortoderm Mild Ointment


• Cortoderm Regular Ointment


• Emo-Cort


• Emo-Cort Scalp Solution


• Hydrocortisone Cream


• Novo-Hydrocort


• Novo-Hydrocort Cream


• Prevex Hc


• Sarna Hc

Available Dosage Forms:

• Solution


• Cream


• Spray


• Lotion


• Ointment


• Pad


• Liquid


• Gel/Jelly


• Kit


• Foam


• Stick


• Paste

Therapeutic Class: Corticosteroid, Weak

Pharmacologic Class: Adrenal Glucocorticoid

Uses For Ivy Soothe

Hydrocortisone topical is used to help relieve redness, itching, swelling, or other discomfort caused by skin conditions. This medicine is a corticosteroid (cortisone-like medicine or steroid).

This medicine is available both over-the-counter (OTC) and with your doctor's prescription.

Before Using Ivy Soothe

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 performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of hydrocortisone topical in the pediatric population. However, because of this medicine's toxicity, it should be used with caution. Children may absorb large amounts through the skin, which can cause serious side effects. If your child is using this medicine, follow your doctor's instructions very carefully.

Geriatric

No information is available on the relationship of age to the effects of hydrocortisone topical in geriatric patients.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

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:

• Cushing's syndrome (adrenal gland disorder) or


• Diabetes or


• Hyperglycemia (high blood sugar) or


• Intracranial hypertension (increased pressure in the head)—Use with caution. May make these conditions worse.

• Infection of the skin at or near the place of application or


• Large sores, broken skin, or severe skin injury at the place of application—The chance of side effects may be increased.

Proper Use of hydrocortisone

This section provides information on the proper use of a number of products that contain hydrocortisone. It may not be specific to Ivy Soothe. Please read with care.

It is very important that you use this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects or skin irritation.

This medicine is for use on the skin only. Do not get it in your eyes. Do not use it on skin areas that have cuts, scrapes, or burns. If it does get on these areas, rinse it off right away with water.

This medicine should only be used for skin conditions that your doctor is treating. Check with your doctor before using it for other conditions, especially if you think that a skin infection may be present. This medicine should not be used to treat certain kinds of skin infections or conditions, such as severe burns.

To use:

• Wash your hands with soap and water before and after using this medicine.


• Apply a thin layer of this medicine to the affected area of the skin. Rub it in gently.


• With the lotion, shake it well before using.


• Do not bandage or otherwise wrap the skin being treated unless directed to do so by your doctor.


• If the medicine is applied to the diaper area of an infant, do not use tight-fitting diapers or plastic pants unless directed to do so by your doctor.


• If your doctor ordered an occlusive dressing or airtight covering to be applied over the medicine, make sure you know how to apply it. Occlusive dressings increase the amount of medicine absorbed through your skin, so use them only as directed. If you have any questions about this, check with your doctor.

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 redness, itching, and swelling of the skin:
  
  • For topical dosage form (cream):
    
    • Adults—Apply to the affected area of the skin two or three times per day.
    
    
    • Children—Apply to the affected area of the skin two or three times per day.
    
    
  
  
  • For topical dosage form (lotion):
    
    • Adults—Apply to the affected area of the skin two to four times per day.
    
    
    • Children—Apply to the affected area of the skin two to four times per day.
    
    
  
  
  • For topical dosage form (ointment):
    
    • Adults—Apply to the affected area of the skin three or four times per day.
    
    
    • Children—Apply to the affected area of the skin three or four times per day.
    
    
  
  
  • For topical dosage form (solution):
    
    • Adults—Apply to the affected area of the skin three or four times per day.
    
    
    • Children—Apply to the affected area of the skin three or four times per day.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply 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.

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 Ivy Soothe

It is very important that your doctor check your or your child's progress at regular visits for any unwanted effects that may be caused by this medicine.

If your or your child's symptoms do not improve within a few days, or if they become worse, check with your doctor.

Using too much of this medicine or using it for a long time may increase your risk of having adrenal gland problems. The risk is greater for children and patients who use large amounts for a long time. Talk to your doctor right away if you or your child have more than one of these symptoms while you are using this medicine: blurred vision; dizziness or fainting; a fast, irregular, or pounding heartbeat; increased thirst or urination; irritability; or unusual tiredness or weakness.

Stop using this medicine and check with your doctor right away if you or your child have a skin rash, burning, stinging, swelling, or irritation on the skin.

Do not use cosmetics or other skin care products on the treated areas.

Ivy Soothe 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

• Blistering, burning, crusting, dryness, or flaking of the skin


• irritation


• itching, scaling, severe redness, soreness, or swelling of the skin


• redness and scaling around the mouth


• thinning of the skin with easy bruising, especially when used on the face or where the skin folds together (e.g. between the fingers)


• thinning, weakness, or wasting away of the 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

• Acne or pimples


• burning and itching of the skin with pinhead-sized red blisters


• burning, itching, and pain in hairy areas, or pus at the root of the hair


• increased hair growth on the forehead, back, arms, and legs


• lightening of normal skin color


• lightening of treated areas of dark skin


• reddish purple lines on the arms, face, legs, trunk, or groin


• softening of the skin

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.

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 Ivy Soothe resources

• Ivy Soothe Use in Pregnancy & Breastfeeding
• Ivy Soothe Drug Interactions
• Ivy Soothe Support Group
• 15 Reviews for Ivy Soothe - Add your own review/rating

Compare Ivy Soothe with other medications

• Anal Itching
• Aphthous Stomatitis, Recurrent
• Atopic Dermatitis
• Dermatitis
• Eczema
• Gingivitis
• Hemorrhoids
• Proctitis
• Pruritus
• Psoriasis
• Seborrheic Dermatitis
• Skin Rash
• Ulcerative Colitis, Active

Gentamicin Sodium Chloride

Generic Name: gentamicin sulfate in sodium chloride

Dosage Form: injection, solution
Gentamicin Sulfate in 0.9% Sodium Chloride Injection

in Plastic Container

VIAFLEX Plus Container

For Intravenous Administration

Further Dilution Not Required

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Gentamicin Sulfate in 0.9% Sodium Chloride Injection and other antibacterial drugs, Gentamicin Sulfate in 0.9% Sodium Chloride Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Warnings

Patients treated with aminoglycosides should be under close clinical observation because of the potential toxicity associated with their use.

As with other aminoglycosides, gentamicin sulfate is potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high dosage or prolonged therapy.

Neurotoxicity manifested by ototoxicity, both vestibular and auditory, can occur in patients treated with gentamicin sulfate, primarily those with pre-existing renal damage and in patients with normal renal function treated with higher doses and/or for longer periods than recommended. Aminoglycoside-induced ototoxicity is usually irreversible. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

Renal and eighth cranial nerve function should be closely monitored, especially in patients with known or suspected reduced renal function at onset of therapy and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Urine should be examined for decreased specific gravity, increased excretion of protein, and the presence of cells or casts. Blood urea nitrogen (BUN), serum creatinine, or creatinine clearance should be determined periodically. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears or hearing loss) or nephrotoxicity requires dosage adjustment or discontinuance of the drug. As with the other aminoglycosides, on rare occasions changes in renal and eighth cranial nerve function may not become manifest until soon after completion of therapy.

Serum concentrations of aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels. When monitoring gentamicin peak concentrations, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided. When monitoring gentamicin trough concentrations, dosage should be adjusted so that levels above 2 mcg/mL are avoided. Excessive peak and/or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity. In the event of overdose or toxic reactions, hemodialysis may aid in the removal of gentamicin from the blood, especially if renal function is, or becomes compromised. The rate of removal of gentamicin is considerably lower by peritoneal dialysis than it is by hemodialysis.

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as cisplatin, cephaloridine, kanamycin, amikacin, neomycin, polymyxin B, colistin, paromomycin, streptomycin, tobramycin, vancomycin, and viomycin, should be avoided (see PRECAUTIONS, Drug Interactions section).

Other factors which may increase patient risk of toxicity are advanced age and dehydration (see PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION sections).

The concurrent use of gentamicin with potent diuretics, such as ethacrynic acid or furosemide, should be avoided, since certain diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering the antibiotic concentration in serum and tissue (see PRECAUTIONS, Drug Interactions section).

Aminoglycosides can cause fetal harm when administered to a pregnant woman (see WARNINGS and PRECAUTIONS, Pregnancy sections).

Gentamicin Sodium Chloride Description

Gentamicin Sulfate, USP, a water soluble antibiotic of the aminoglycoside group, is derived from Micromonospora purpurea, and actinomycete.

Gentamicin Sulfate in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic solution of Gentamicin Sulfate, USP in water for injection with 9 mg/mL sodium chloride (NaCl) to provide isotonicity. The solution is intended for intravenous use and requires no further dilution. pH may be adjusted with sulfuric acid or sodium hydroxide and is approximately 4.5.

This VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the presence of a drug additive in a drug vehicle. The VIAFLEX Plus plastic container system utilizes the same container as the VIAFLEX plastic container system. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Gentamicin Sodium Chloride - Clinical Pharmacology

After intramuscular (IM) administration of gentamicin sulfate, peak serum concentrations usually occur between 30 to 60 minutes and serum levels are measurable for 6 to 8 hours. When gentamicin is administered by intravenous (IV) infusion over a two-hour period, the serum concentrations are similar to those obtained by intramuscular administration.

In patients with normal renal function, peak serum concentrations of gentamicin (mcg/mL) are usually up to four times the single intramuscular dose (mg/kg); for example, a 1 mg/kg injection in adults may be expected to result in a peak serum concentration up to 4 mcg/mL; a 1.5 mg/kg dose may produce levels up to 6 mcg/mL. While some variation is to be expected due to a number of variables such as age, body temperature, surface area and physiologic differences, the individual patient given the same dose tends to have similar levels in repeated determinations. Gentamicin administered at 1 mg/kg every eight hours for the usual 7- to 10- day treatment period to patients with normal renal function does not accumulate in the serum.

Gentamicin, like all aminoglycosides, may accumulate in the serum and tissue of patients treated with higher doses and/or for prolonged periods, particularly in the presence of impaired renal function. In adult patients, treatment with gentamicin dosages of 4 mg/kg/day or higher for seven to ten days may result in a slight, progressive rise in both peak and trough concentrations. In patients with impaired renal function, gentamicin is cleared from the body more slowly than in patients with normal renal function. The more severe the impairment, the slower the clearance. Dosage must be adjusted.

Since gentamicin is distributed in extracellular fluid, peak serum concentrations may be lower than usual in adult patients who have a large volume of this fluid. Serum concentrations of gentamicin in febrile patients may be lower than those in afebrile patients given the same dose. When body temperature returns to normal, serum concentrations of the drug may rise. Febrile and anemic states may be associated with a shorter than usual serum half-life. (Dosage adjustment is usually not necessary.) In severely burned patients, the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg/kg dose.

Protein binding studies have indicated that the degree of gentamicin binding is low. Depending upon the methods used for testing, this may be between 0 and 30%.

After initial administration to patients with normal renal function, generally 70% or more of the gentamicin dose is recoverable in the urine in 24 hours; concentrations in urine above 100 mcg/mL may be achieved. Little, if any, metabolic transformation occurs; the drug is excreted principally by glomerular filtration. After several days of treatment, the amount of gentamicin excreted in the urine approaches the daily dose administered. As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys. Minute quantities of aminoglycosides have been detected in the urine weeks after the drug administration was discontinued. Renal clearance of gentamicin is similar to that of endogenous creatinine.

In patients with marked impairment of renal function, there is a decrease in the concentration of aminoglycosides in urine and in their penetration into defective renal parenchyma. This decreased drug excretion, together with the potential nephrotoxicity of aminoglycosides, should be considered when treating such patients who have urinary tract infections.

Probenecid does not affect renal tubular transport of gentamicin.

The endogenous creatinine clearance rate and serum creatinine level have a high correlation with the half-life of gentamicin in serum. Results of these tests may serve as guides for adjusting dosage in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Following parenteral administration, gentamicin can be detected in serum, lymph, tissues, sputum, and in pleural, synovial, and peritoneal fluids. Concentrations in renal cortex sometimes may be eight times higher than the usual serum levels. Concentrations in bile, in general, have been low and have suggested minimal biliary excretion. Gentamicin crosses the peritoneal as well as the placental membranes (see PRECAUTIONS, Pregnancy section). Since aminoglycosides diffuse poorly into the subarachnoid space after parenteral administration, concentrations of gentamicin in cerebrospinal fluid are often low and dependent upon dose, rate of penetration, and degree of meningeal inflammation. There is minimal penetration of gentamicin into ocular tissues following intramuscular or intravenous administration.

Microbiology

In vitro tests have demonstrated that gentamicin is a bactericidal antibiotic which acts by inhibiting normal protein synthesis in susceptible microorganisms. It is active against a wide variety of pathogenic bacteria including Escherichia coli, Proteus species (indole-positive and indole-negative), Pseudomonas aeruginosa, species of the Klebsiella- Enterobacter-Serratia group, Citrobacter species and Staphylococcus species (including penicillin- and methicillin-resistant strains). Gentamicin is also active in vitro against species of Salmonella and Shigella. The following bacteria are usually resistant to aminoglycosides: Streptococcus pneumoniae, most species of streptococci, particularly group D and anaerobic organisms, such as Bacteriodes species or Clostridium species.

In vitro studies have shown that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some group D streptococcal strains. The combination of gentamicin and penicillin G has a synergistic bactericidal effect against virtually all strains of Streptococcus faecalis and its varieties (S. faecalis var. liquifaciens, S. faecalis var. zymogenes), S. faecium and S. durans. An enhanced killing effect against many of these strains has also been shown in vitro with combinations of gentamicin and ampicillin, carbenicillin, nafcillin, or oxacillin.

The combined effect of gentamicin and carbenicillin is synergistic for many strains of Pseudomonas aeruginosa. In vitro synergism against other gram-negative organisms has been shown with combinations of gentamicin and cephalosporins.

Gentamicin may be active against clinical isolates of bacteria resistant to other aminoglycosides. Bacteria resistant to one aminoglycoside may be resistant to one or more other aminoglycosides. Bacterial resistance to gentamicin is generally developed slowly.

Susceptibility Testing

If the disc method of susceptibility testing used is that described by Bauer et al (Am J Clin Path 45:493, 1966; Federal Register 37:20525-20529, 1972), a disc containing 10 mcg of gentamicin should give a zone of inhibition of 15 mm or more to indicate susceptibility of the infecting organism. A zone of 12 mm or less indicates that the infecting organism is likely to be resistant. Zones greater than 12 mm and less than 15 mm indicate intermediate susceptibility. In certain conditions it may be desirable to do additional susceptibility testing by the tube or agar dilution method; gentamicin is available for this purpose.

Indications and Usage for Gentamicin Sodium Chloride

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Gentamicin Sulfate in 0.9% Sodium Chloride Injection and other antibacterial drugs, Gentamicin Sulfate in 0.9% Sodium Chloride Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Gentamicin Sulfate in 0.9% Sodium Chloride Injection is indicated in the treatment of serious infections caused by susceptible strains of the following microorganisms: Pseudomonas aeruginosa, Proteus species (indole-positive and indole-negative), Escherichia coli, Klebsiella-Enterobacter- Serratia species, Citrobacter species, and Staphylococcus species (coagulase-positive and coagulase-negative).

Clinical studies have shown gentamicin sulfate to be effective in bacterial neonatal sepsis; bacterial septicemia; and serious bacterial infections of the central nervous system (meningitis), urinary tract, respiratory tract, gastrointestinal tract (including peritonitis), skin, bone and soft tissue (including burns). Aminoglycosides, including gentamicin, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are susceptible to these antibiotics and are not susceptible to antibiotics having less potential for toxicity.

Specimens for bacterial culture should be obtained to isolate and identify causative organisms and to determine their susceptibility to gentamicin.

Gentamicin Sulfate in 0.9% Sodium Chloride Injection may be considered as initial therapy in suspected or confirmed gram-negative infections, and therapy may be instituted before obtaining results of susceptibility testing. The decision to continue therapy with this drug should be based on the results of susceptibility tests, the severity of the infection, and the important additional concepts contained in the boxed WARNINGS. If the causative organisms are resistant to gentamicin, other appropriate therapy should be instituted.

In serious infections when the causative organisms are unknown, Gentamicin Sulfate in 0.9% Sodium Chloride Injection may be administered as initial therapy in conjunction with a penicillin-type or cephalosporin-type drug before obtaining results of susceptibility testing. If anaerobic organisms are suspected as etiologic agents, consideration should be given to using other suitable antimicrobial therapy in conjunction with gentamicin. Following identification of the organism and its susceptibility, appropriate antibiotic therapy should then be continued.

Gentamicin injection has been used effectively in combination with carbenicillin for the treatment of life-threatening infections caused by Pseudomonas aeruginosa. It has also been found effective when used in conjunction with a penicillin-type drug for the treatment of endocarditis caused by group D streptococci.

Gentamicin injection has also been shown to be effective in the treatment of serious staphylococcal infections. While not the antibiotic of first choice, gentamicin may be considered when penicillins or other less potentially toxic drugs are contraindicated and bacterial susceptibility tests and clinical judgement indicate its use. It may also be considered in mixed infections caused by susceptible strains of staphylococci and gram-negative organisms.

In the neonate with suspected bacterial sepsis or staphylococcal pneumonia, a penicillin-type drug is also usually indicated as concomitant therapy with gentamicin (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION sections).

Contraindications

Hypersensitivity to gentamicin is a contraindication to its use. A history of hypersensitivity or serious toxic reactions to other aminoglycosides may contraindicate use of gentamicin because of known cross-sensitivity of patients to drugs in this class.

Warnings

(See boxed WARNINGS.)

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycoside antibiotics cross the placenta, and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Serious side effects to mother, fetus or newborn have not been reported in the treatment of pregnant women with other aminoglycosides. Animal reproduction studies conducted on rats and rabbits did not reveal evidence of impaired fertility or harm to the fetus due to gentamicin sulfate. It is not known whether gentamicin sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. If gentamicin is used during pregnancy or if the patient becomes pregnant while taking gentamicin, she should be apprised of the potential hazard to the fetus.

Solutions containing sodium ions should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention.

Precautions

General

Prescribing Gentamicin Sulfate in 0.9% Sodium Chloride Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Do not use additives or premix with other drugs. See DOSAGE AND ADMINISTRATION.

Neurotoxic and nephrotoxic antibiotics may be almost completely absorbed from body surfaces (except the urinary bladder) after local irrigation and after topical application during surgical procedures. The potential toxic effects of antibiotics administered in this fashion (neuromuscular blockade, respiratory paralysis, oto- and nephrotoxicity) should be considered (see boxed WARNINGS).

Aminoglycosides should be used with caution in patients with neuromuscular disorders such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effects on the neuromuscular junction. During or following gentamicin therapy, paresthesias, tetany, positive Chvostek and Trousseau signs and mental confusion have been described in patients with hypomagnesemia, hypocalcemia and hypokalemia. When this has occurred in infants, tetany and muscle weakness has been described. Both adults and infants required appropriate corrective electrolyte therapy (see PRECAUTIONS, Pediatric Use section).

A Fanconi-like syndrome, with aminoaciduria and metabolic acidosis has been reported in some adults and infants being given gentamicin injections.

Cross allergenicity among aminoglycosides has been demonstrated.

Patients should be well hydrated during treatment.

Treatment with gentamicin may result in overgrowth of nonsusceptible organisms. If this occurs, appropriate therapy is indicated.

See boxed WARNINGS regarding concurrent use of potent diuretics and regarding concurrent and/or sequential use of other neurotoxic and/or nephrotoxic antibiotics, and for other essential information (see also PRECAUTIONS, Drug Interactions section).

Information for Patients

Patients should be counseled that antibacterial drugs including Gentamicin Sulfate in 0.9% Sodium Chloride Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Gentamicin Sulfate in 0.9% Sodium Chloride Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Gentamicin Sulfate in 0.9% Sodium Chloride Injection or other antibacterial drugs in the future.

Laboratory Tests

Laboratory abnormalities possibly related to gentamicin include: increased levels of serum transaminase (SGOT, SGPT), serum LDH and billirubin; decreased serum calcium, magnesium, sodium and potassium; anemia, leukopenia, granulocytopenia, transient agranulocytosis, eosinophilia, increased and decreased reticulocyte counts and thrombocytopenia. While clinical laboratory test abnormalities may be isolated findings, they may also be associated with clinically related signs and symptoms. For example, tetany and muscle weakness may be associated with hypomagnesemia, hypocalcemia, and hypokalemia.

Drug Interactions

The concurrent use of gentamicin with potent diuretics, such as ethacrynic acid or furosemide, should be avoided, since certain diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering the antibiotic concentration in serum and tissue.

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs such as cisplatin, cephaloridine, kanamycin, amikacin, neomycin, polymyxin B, colistin, paromomycin, streptomycin, tobramycin, vancomycin, and viomycin, should be avoided.

Increased nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

Neuromuscular blockade and respiratory paralysis have been reported in the cat receiving high doses (40 mg/kg) of gentamicin. The possibility of these phenomena occurring in man should be considered if aminoglycosides are administered by any route to patients receiving anesthetics, or to patients receiving neuro-muscular blocking agents, such as succinylcholine, tubocurarine, or decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood. If neuromuscular blockade occurs, calcium salts may reverse it.

Although the in vitro mixing of gentamicin and carbenicillin results in a rapid and significant inactivation of gentamicin, this interaction has not been demonstrated in patients with normal renal function who received both drugs by different routes of administration. A reduction in gentamicin serum half-life has been reported in patients with severe renal impairment receiving carbenicillin concomitantly with gentamicin.

Probenecid does not affect renal tubular transport of gentamicin.

Pregnancy

Pregnancy Category D.

See WARNINGS section.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycoside antibiotics cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Serious side effects to mother, fetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides. Animal reproduction studies conducted on rats and rabbits did not reveal evidence of impaired fertility or harm to the fetus due to gentamicin sulfate. It is not known whether gentamicin sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. If gentamicin is used during pregnancy or if the patient becomes pregnant while taking gentamicin, she should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from gentamicin, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

In the neonate with suspected bacterial sepsis or staphylococcal pneumonia, a penicillin-type drug is also usually indicated as concomitant therapy with gentamicin.

During or following gentamicin therapy, paresthesias, tetany, positive Chvostek and Trousseau signs and mental confusion have been described in patients with hypomagnesemia, hypocalcemia and hypokalemia. When this has occurred in infants, tetany and muscle weakness have been described. Both adults and infants required appropriate corrective electrolyte therapy.

A Fanconi-like syndrome, with aminoaciduria and metabolic acidosis has been reported in some adults and infants being given gentamicin injections.

Geriatric Use

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients may have reduced renal function which may not be evident in the results of routine screening tests such as BUN or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with gentamicin, as with other aminoglycosides, is particularly important in such patients.

Adverse Reactions

Nephrotoxicity - Adverse renal effects, as demonstrated by the presence of casts, cells, or protein in the urine or by rising BUN, NPN, serum creatinine and oliguria, have been reported. They occur more frequently in patients with a history of renal impairment and in patients treated for longer periods or with larger dosages than recommended.

Neurotoxicity - Serious adverse effects on both vestibular and auditory branches of the eighth cranial nerve have been reported, primarily in patients with renal impairment (especially if hemodialysis is required) and in patients on high doses and/or prolonged therapy. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears and also hearing loss, which, as with the other aminoglycosides, may be irreversible. Hearing loss is usually manifested initially by diminishing high-tone acuity. Other factors which may increase the risk of toxicity include excessive dosage, dehydration and previous exposure to other ototoxic drugs.

Peripheral neuropathy or encephalopathy, including numbness, skin tingling, muscle twitching, convulsions, and a myasthenia gravis-like syndrome, have been reported.

Note: This risk of toxic reactions is low in patients with normal renal function who do not receive gentamicin sulfate at higher doses or for longer periods of time than recommended.

Other reported adverse reactions possibly related to gentamicin include: respiratory depression, lethargy, confusion, depression, visual disturbances, decreased appetite, weight loss, hypotension and hypertension; rash, itching, urticaria, generalized burning, laryngeal edema, anaphylactoid reactions, fever, and headache; nausea, vomiting, increased salivation, and stomatitis; purpura, pseudotumor cerebri, acute organic brain syndrome, pulmonary fibrosis, alopecia, joint pain, transient hepatomegaly, and splenomegaly.

Laboratory abnormalities possibly related to gentamicin include: increased levels of serum transaminase (SGOT, SGPT), serum LDH and bilirubin; decreased serum calcium, magnesium, sodium and potassium; anemia, leukopenia, granulocytopenia, transient agranulocytosis, eosinophilia, increased and decreased reticulocyte counts and thrombocytopenia. While clinical laboratory test abnormalities may be isolated findings, they may also be associated with clinically related signs and symptoms. For example, tetany and muscle weakness may be associated with hypomagnesemia, hypocalcemia, and hypokalemia.

While local tolerance of gentamicin sulfate is generally excellent, there has been an occasional report of pain at the injection site. Subcutaneous atrophy or fat necrosis suggesting local irritation has been reported rarely.

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.

Overdosage

In the event of overdosage or toxic reactions, hemodialysis may aid in the removal of gentamicin from the blood, and is especially important if renal function is, or becomes compromised. The rate of removal of gentamicin is considerably lower by peritoneal dialysis than it is by hemodialysis.

Gentamicin Sodium Chloride Dosage and Administration

Gentamicin Sulfate in 0.9% Sodium Chloride Injection is for intravenous use only.

The patient’s pretreatment body weight should be obtained for calculation of correct dosage. The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass. It is desirable to limit the duration of treatment with aminoglycosides to short term.

Patients with Normal Renal Function

Adults: The recommended dosage of Gentamicin Sulfate in 0.9% Sodium Chloride Injection for patients with serious infections and normal renal function is 3 mg/kg/day administered in three equal doses every eight hours (Table 1).

For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses. The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table 1).

It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage. When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels. For example, the peak concentration (at 30 to 60 minutes following cessation of infusion) is expected to be in the range of 4 to 6 mcg/mL. When monitoring peak concentrations, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided. When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided. Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection, and the status of the patient’s host-defense mechanisms.

In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

Table 1.

* The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass. † For q6h schedules, dosage should be recalculated.
Dosage Schedule Guide for Adults With Normal Renal Function (Dosage at Eight-Hour Intervals)
Patient’s Weight*		Usual Dose for Serious Infections 1 mg/kg q8h (3 mg/kg/day)	Dose for Life-Threatening Infections (Reduce as Soon as Clinically Indicated) 1.7 mg/kg q8h† (5 mg/kg/day)
kg	(lb)
		mg/dose q8h	mg/dose q8h
40	( 88)	40	66
45	( 99)	45	75
50	(110)	50	83
55	(121)	55	91
60	(132)	60	100
65	(143)	65	108
70	(154)	70	116
75	(165)	75	125
80	(176)	80	133
85	(187)	85	141
90	(198)	90	150
95	(209)	95	158
100	(220)	100	166

Children: 6 to 7.5 mg/kg/day (2 to 2.5 mg/kg administered every eight hours).

Infants and Neonates: 7.5 mg/kg/day (2.5 mg/kg administered every eight hours).

Premature or Full-Term Neonates One Week of Age or Less: 5 mg/kg/day (2.5 mg/kg administered every 12 hours).

NOTE: For further information concerning the use of gentamicin in infants and children, see Pediatric Gentamicin Sulfate Injection product information.

The usual duration of treatment for all patients is seven to ten days. In difficult and complicated infections, a longer course of therapy may be necessary. In such cases monitoring of renal, auditory, and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than ten days. Dosage should be reduced if clinically indicated.

For Intravenous Administration

The intravenous administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock. It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns, or those with reduced muscle mass. For intermittent intravenous administration in adults, a single dose of Gentamicin Sulfate in 0.9% Sodium Chloride Injection may be administered according to individual patient requirements from the appropriate premixed container. The solution may be infused over a period of one-half to two hours.

Gentamicin Sulfate Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

Patients with Impaired Renal Function

Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate, but not excessive blood levels. Whenever possible, serum concentrations of gentamicin should be monitored. One method of dosage adjustment is to increase the interval between administration of the usual doses. Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses. The interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8. For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).

In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage. In such patients, serum concentrations of gentamicin should be measured so that adequate, but not excessive levels result. A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage. After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 2). For example, after an initial dose of 60 mg (1 mg/kg), a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 30 mg every eight hours (60 ÷ 2). It should be noted that the status of renal function may be changing over the course of the infectious process.

It is important to recognize that deteriorating renal function may require a greater reduction of dosage than that specified in the above guidelines for patients with stable renal impairment.

This container system may be inappropriate for the dosage requirements of children, infants, and neonates. Other dosage forms may be more appropriate.

Table 2

Dosage Adjustment Guide For Patients With Renal Impairment (Dosage at Eight-Hour Intervals After the Usual Initial Dose)
Serum Creatinine (mg %)	Approximate Creatinine Clearance (mL/min/1.73m²)	Percent of Usual Doses Shown in Table 1
≤1	>100	100
1.1 - 1.3	70 - 100	80
1.4 - 1.6	55 - 70	65
1.7 - 1.9	45 - 55	55
2 - 2.2	40 - 45	50
2.3 - 2.5	35 - 40	40
2.6 - 3	30 - 35	35
3.1 - 3.5	25 - 30	30
3.6 - 4	20 - 25	25
4.1 - 5.1	15 - 20	20
5.2 - 6.6	10 - 15	15
6.7 - 8	<10	10

In adults with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used. An eight hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%. The recommended dosage at the end of each dialysis period is 1 to 1.7 mg/kg depending upon the severity of infection.

In children, a dose of 2 mg/kg may be administered.

The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of gentamicin serum levels is not feasible.

A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

Gentamicin Sulfate in 0.9% Sodium Chloride Injection is a ready-to-use isotonic solution. No dilution or buffering is required.

If the prescribed dose is exactly 60, 80, or 100 mg use the appropriate container. If the prescribed dose is higher or lower than that of the supplied container adjustments can be made. If the dose is higher than the contents of a 100 mg container the additional amount should be removed from a container of gentamicin sulfate (60 mg/mL) and added to the 100 mg container. If the prescribed dose is less than that contained in a supplied container, use the container with the dose closest to (but above) the prescribed dose, removing and discarding an appropriate amount from it.

Do not use plastic containers in series connection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and container and seals are intact.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

These solutions are intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours.

Instructions for the Administration of Gentamicin Sulfate in 0.9% Sodium Chloride Injection.