Limptar

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Limptar uses

Limptar consists of Aminophylline, Quinine Sulfate.

Aminophylline:



Limptar (Aminophylline)

Injection, USP

25 mg/mL Limptar (Aminophylline), Dihydrate

(Equivalent to 19.7 mg/mL of Anhydrous Theophylline)

Ampul

Fliptop Vial Rx only

DESCRIPTION

Limptar (Aminophylline) Injection, USP is a sterile, nonpyrogenic solution of Limptar (Aminophylline) in water for injection. Limptar (Aminophylline) (dihydrate) is approximately 79% of anhydrous theophylline by weight. Limptar (Aminophylline) Injection is administered by slow intravenous injection or diluted and administered by intravenous infusion.

The solution contains no bacteriostat or antimicrobial agent and is intended for use only as a single-dose injection. When smaller doses are required the unused portion should be discarded.

Limptar (Aminophylline) is a 2:1 complex of theophylline and ethylenediamine. Theophylline is structurally classified as a methylxanthine. Limptar (Aminophylline) occurs as a white or slightly yellowish granule or powder, with a slight ammoniacal odor. Limptar (Aminophylline) has the chemical name 1H-Purine-2, 6-dione, 3,7-dihydro-1,3-dimethyl-, compound with 1,2-ethanediamine (2:1). The structural formula of Limptar (Aminophylline) (dihydrate) is as follows:

The molecular formula of Limptar (Aminophylline) dihydrate is C16H24N10O4 - 2(H2O) with a molecular weight of 456.46.

Limptar (Aminophylline) Injection, USP contains Limptar (Aminophylline) (calculated as the dihydrate) 25 mg/mL (equivalent to 19.7 mg/mL anhydrous theophylline) prepared with the aid of ethylenediamine. The solution may contain an excess of ethylenediamine for pH adjustment. pH is 8.8 (8.6 to 9.0). The osmolar concentration is 0.17 mOsmol/mL (calc.).

structural formula Limptar (Aminophylline)

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CLINICAL PHARMACOLOGY

Mechanism of Action:

Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation and suppression of the response of the airways to stimuli (i.e., nonbronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV), while nonbronchodilator 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 and pulmonary function has been found in most studies to require serum theophylline concentrations >10 mcg/mL. At serum theophylline concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining the average serum theophylline concentration 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 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 receiving intravenous theophylline (e.g., at 24-hr. intervals). More frequent measurements should be made during the initiation of therapy and in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS , Effects on Laboratory Tests ).

¶ 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 nonlinear 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




Population Characteristics

Age


Total Body Clearance*

Mean (Range)††

(mL/kg/min)


Half-Life

Mean (Range)††

(hr)


Premature neonates

postnatal age 3 - 15 days

postnatal age 25 - 57 days



0.29 (0.09 - 0.49)

0.64 (0.04 - 1.2)



30 (17 - 43)

20 (9.4 - 30.6)


Term infants

postnatal age 1 - 2 days

postnatal age 3 - 30 weeks



NR

NR



25.7 (25 - 26.5)

11 (6 - 29)


Children

1 - 4 years

4 - 12 years

13 - 15 years

6 - 17 years



1.7 (0.5 - 2.9)

1.6 (0.8 - 2.4)

0.9 (0.48 - 1.3)

1.4 (0.2 - 2.6)



3.4 (1.2 - 5.6)

NR

NR

3.7 (1.5 - 5.9)


Adults (16 - 60 years)

otherwise healthy

nonsmoking asthmatics




0.65 (0.27 - 1.03)




8.7 (6.1 - 12.8)


Elderly (>60 years)

nonsmokers 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 - 8.2)


COPD- >60 years, stable

nonsmoker >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 (1.8 - 10.2)


Fever associated with acute viral respiratory


illness (children 9 - 15 years)


NR


7 (1.0 - 13)


Liver disease – cirrhosis

acute hepatitis

cholestasis


0.31** (0.1 - 0.7)

0.35 (0.25 - 0.45)

0.65 (0.25 - 1.45)


32** (10 - 56)

19.2 (16.6 - 21.8)

14.4 (5.7 - 31.8)


Pregnancy – 1st trimester

2nd trimester

3rd trimester


NR

NR

NR


8.5 (3.1 - 13.9)

8.8 (3.8 - 13.8)

13 (8.4 - 17.6)


Sepsis with multi-organ failure


0.47 (0.19 - 1.9)


18.8 (6.3 - 24.1)


Thyroid disease – hypothyroid

hyperthyroid


0.38 (0.13 - 0.57)

0.8 (0.68 - 0.97)


11.6 (8.2 - 25)

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.

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 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, nonlinearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL. Since this nonlinearity 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 State In a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg (5.7 mg/kg as Limptar (Aminophylline)), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. In non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr (0.5 mg/kg/hr as Limptar (Aminophylline)) at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline (5.7 mg/kg as Limptar (Aminophylline)) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as Limptar (Aminophylline)). (See DOSAGE AND ADMINISTRATION .)

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 children (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 nonsmoking 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. 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:

Inhaled beta-2 selective agonists and systemically administered corticosteroids are the treatments of first choice for management of acute exacerbations of asthma. The results of controlled clinical trials on the efficacy of adding intravenous theophylline to inhaled beta-2 selective agonists and systemically administered corticosteroids in the management of acute exacerbations of asthma have been conflicting. Most studies in patients treated for acute asthma exacerbations in an emergency department have shown that addition of intravenous theophylline does not produce greater bronchodilation and increases the risk of adverse effects. In contrast, other studies have shown that addition of intravenous theophylline is beneficial in the treatment of acute asthma exacerbations in patients requiring hospitalization, particularly in patients who are not responding adequately to inhaled beta-2 selective agonists.

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.

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INDICATIONS AND USAGE

Intravenous theophylline is indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

CONTRAINDICATIONS

Limptar (Aminophylline) is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product including ethylenediamine.

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

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced theophylline clearance. If the infusion rate 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; ≥102° 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), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately.

Dosage Increases

Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is <10 mcg/mL.

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 infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION , TABLE VI ).

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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 and prior to increases in theophylline dose.

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:

  • Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
  • Whenever signs or symptoms of theophylline toxicity are present.
  • Whenever there is a new illness, worsening of an existing concurrent 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).

In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is <10 mcg/mL indicating the need for an additional loading dose or >20 mcg/mL indicating the need to delay starting the constant I.V. infusion. Once the infusion is begun, a second measurement should be obtained after one expected half-life (e.g., approximately 4 hours in children 1 to 9 years and 8 hours in non-smoking adults; See Table I for the expected half-life in additional patient populations). The second measurement should be compared to the first to determine the direction in which the serum concentration has changed. The infusion rate can then be adjusted before steady state is reached in an attempt to prevent an excessive or sub-therapeutic theophylline concentration from being achieved.

If a patient has received theophylline in the previous 24 hours, the serum concentration should be measured before administering an intravenous loading dose to make sure that it is safe to do so. If a loading dose is not indicated (i.e., the serum theophylline concentration is ≥10 mcg/mL), a second measurement should be obtained as above at the appropriate time after starting the intravenous infusion. If, on the other hand, a loading dose is indicated (See DOSAGE AND ADMINISTRATION for guidance on selection of the appropriate loading dose), a second blood sample should be obtained after the loading dose and a third sample should be obtained one expected half-life after starting the constant infusion to determine the direction in which the serum concentration has changed.

Once the above procedures related to initiation of intravenous theophylline infusion have been completed, subsequent serum samples for determination of theophylline concentration should be obtained at 24-hour intervals for the duration of the infusion. The theophylline infusion rate should be increased or decreased as appropriate based on the serum theophylline levels.

When signs or symptoms of theophylline toxicity are present, the intravenous infusion should be stopped and a serum sample for theophylline concentration 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 µEq/L to 800 µEq/L), total cholesterol (from a mean of 140 vs 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.

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, 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 September 1, 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.

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 (I.V.)


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 nondepolarizing 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 Phenobarbital.


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.


90% increase


Thiabendazole


Decreases theophylline clearance.


190% increase


Ticlopidine


Decreases theophylline clearance.


60% increase


Troleandomycin


Similar to erythromycin.


33 - 100% increase depending on troleandomycin dose.


Verapamil


Similar to disulfiram.


20% increase


albuterol,

systemic and inhaled

amoxicillin

ampicillin,

with or without sulbactam

atenolol

azithromycin

caffeine,

dietary ingestion

cefaclor

co-trimoxazole

(trimethoprim and sulfamethoxazole)

diltiazem

dirithromycin

enflurane

famotidine

felodipine

finasteride

hydrocortisone

isoflurane

isoniazid

isradipine

influenza vaccine

ketoconazole


lomefloxacin

mebendazole

medroxyprogesterone

methylprednisolone

metronidazole

metoprolol

nadolol

nifedipine

nizatidine

norfloxacin

ofloxacin

omeprazole

prednisone, prednisolone

ranitidine

rifabutin

roxithromycin

sorbitol

(purgative doses do not inhibit

theophylline absorption)

sucralfate

terbutaline, systemic

terfenadine

tetracycline

tocainide


The Effect of Other Drugs on Theophylline Serum Concentration Measurements:

Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Long term carcinogenicity studies have been carried out in mice (oral doses 30 - 150 mg/kg) and rats (oral doses 5 - 75 mg/kg). Results are pending.

Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0 - 3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40 - 300 mg/kg (approximately 2 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy:

Category C: There are no adequate and well controlled studies in pregnant women. Additionally, there are no teratogenicity studies in nonrodents. Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m2 basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

Nursing Mothers:

Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10 - 20 mcg/mL of theophylline per day is likely to receive 10 - 20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

Pediatric Use:

Theophylline is safe and effective for the approved indications in pediatric patients. The constant infusion rate of intravenous theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY , Table I , WARNINGS , and DOSAGE AND ADMINISTRATION , Table V ). Due to the immaturity of theophylline metabolic pathways in pediatric patients under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group.

Geriatric Use:

Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline infusion rate. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum infusion rate of theophylline in patients greater than 60 years of age ordinarily should not exceed 17 mg/hr (21 mg/hr as Limptar (Aminophylline)) unless the patient continues to be symptomatic and the peak steady state serum theophylline concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theophylline infusion rates greater than 17 mg/hr (21 mg/hr as Limptar (Aminophylline)) should be prescribed with caution in elderly patients.

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ADVERSE REACTIONS

Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ).

Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

Products containing Limptar (Aminophylline) may rarely produce severe allergic reactions of the skin, including exfoliative dermatitis, after systemic administration in a patient who has been previously sensitized by topical application of a substance containing ethylenediamine. In such patients skin patch tests are positive for ethylenediamine, a component of Limptar (Aminophylline), and negative for theophylline. Pharmacists and other individuals who experience repeated skin exposure while physically handling Limptar (Aminophylline) may develop a contact dermatitis due to the ethylenediamine component.

* These data are derived from two studies in patients with serum theophylline concentrations

>30 mcg/mL. In the first study (Study #1 – Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 – Sessler, Am J Med 1990; 88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results.

** NR = Not reported in a comparable manner.


Acute Overdose

(Large Single Ingestion)


Chronic Overdosage

(Multiple Excessive Doses)


Sign/Symptom


Study 1

(n=157)


Study 2

(n=14)


Study 1

(n=92)


Study 2

(n=102)


Asymptomatic


NR**


0


NR**


6


Gastrointestinal


Vomiting


73


93


30


61


Abdominal pain


NR**


21


NR**


12


Diarrhea


NR**


0


NR**


14


Hematemesis


NR**


0


NR**


2


Metabolic/Other


Hypokalemia


85


79


44


43


Hyperglycemia


98


NR**


18


NR**


Acid/base disturbance


34


21


9


5


Rhabdomyolysis


NR**


7


NR**


0


Cardiovascular


Sinus tachycardia


100


86


100


62


Other supraventricular


2


21


12


14


tachycardias


Ventricular premature beats


3


21


10


19


Atrial fibrillation or flutter


1


NR**


12


NR**


Multifocal atrial tachycardia


0


NR**


2


NR**


Ventricular arrhythmias with


7


14


40


0


hemodynamic instability


Hypotension/shock


NR**


21


NR**


8


Neurologic


Nervousness


NR**


64


NR**


21


Tremors


38


29


16


14


Disorientation


NR**


7


NR**


11


Seizures


5


14


14


5


Death


3


21


10


4

OVERDOSAGE

General:

The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: 1) acute overdose, i.e., infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and 2) chronic overdosage, i.e., excessive maintenance infusion rate for greater than 24 hours. The most common causes of chronic theophylline overdosage include clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe.

Several studies have described the clinical manifestations of theophylline overdose following oral administration and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of oral theophylline overdose according to the mode of overdose are listed in Table IV .

Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.

Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management:

General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL While Receiving Intravenous Theophylline.

  • Stop the theophylline infusion.
  • While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
  • Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
  • Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1 - 0.2 mg/kg every 1 - 3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital. Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
  • Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin , has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
  • Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
  • Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2 - 4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to nontoxic levels.
  • General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a nontoxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
  • Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see OVERDOSAGE , Extracorporeal Removal ).

Specific Recommendations:

Acute Overdose (e.g., excessive loading dose or excessive infusion rate <24 hours)

  • Serum Concentration >20 <30 mcg/mL
    • Stop the theophylline infusion.
    • Monitor the patient and obtain a serum theophylline concentration in 2 - 4 hours to insure that the concentration is decreasing.
  • Serum Concentration >30 <100 mcg/mL
    • Stop the theophylline infusion.
    • Administer multiple dose oral activated charcoal and measures to control emesis.
    • Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
    • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE , Extracorporeal Removal ).
  • Serum Concentration >100 mcg/mL
    • Stop the theophylline infusion.
    • Consider prophylactic anticonvulsant therapy.
    • Administer multiple-dose oral activated charcoal and measures to control emesis.
    • Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE , Extracorporeal Removal ).
    • Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage (e.g., excessive infusion rate for greater than 24 hours)

  • Serum Concentration >20 <30 mcg/mL (with manifestations of theophylline toxicity)
    • Stop the theophylline infusion.
    • Monitor the patient and obtain a serum theophylline concentration in 2 - 4 hours to insure that the concentration is decreasing.
  • Serum Concentration >30 mcg/mL in patients <60 years of age
    • Stop the theophylline infusion.
    • Administer multiple-dose oral activated charcoal and measures to control emesis.
    • Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
    • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE , Extracorporeal Removal ).
  • Serum Concentration >30 mcg/mL in patients ≥60 years of age
    • Stop the theophylline infusion.
    • Consider prophylactic anticonvulsant therapy.
    • Administer multiple-dose oral activated charcoal and measures to control emesis.
    • Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE , Extracorporeal Removal ).
    • Monitor the patient and obtain serial theophylline concentrations every 2 - 4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal:

Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5 - 10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

General Considerations:

The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:

C = LD/V

If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg (5.7 mg/kg as Limptar (Aminophylline)), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:

D = (Desired C - Measured C) (V)

where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours.

A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V ). For example, in non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr (0.5 mg/kg/hr as Limptar (Aminophylline)) at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline (5.7 mg/kg as Limptar (Aminophylline)) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as Limptar (Aminophylline)). Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient's clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half-life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; See Table I for the expected half-life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient's course.

In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr (21 mg/hr as Limptar (Aminophylline)) unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.

Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

* To achieve a target concentration of 10 mcg/mL Aminophylline=theophylline/0.8. Use ideal body weight for obese patients.

† Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine).

‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea.

§ Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose.

ı Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose.


Patient population


Age


Theophylline infusion rate (mg/kg/hr)*†


Neonates


Postnatal age up to 24 days

Postnatal age beyond 24 days


1 mg/kg q12h/‡

1.5 mg/kg q12h/‡


Infants


6-52 weeks old


mg/kg/hr= (0.008)(age in weeks) + 0.21


Young children


1-9 years


0.8


Older children


9-12 years


0.7


Adolescents

(cigarette or marijuana

smokers)


12-16 years


0.7


Adolescents (nonsmokers)


12-16 years


0.5 §


Adults

(otherwise healthy

nonsmokers)


16-60 years


0.4 §


Elderly


>60 years


0.3 ı


Cardiac decompensation,

cor pulmonale, liver

dysfunction, sepsis with

multiorgan failure,

or shock


0.2 ı

¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS ).

Peak Serum Concentration


Dosage Adjustment


<9.9 mcg/mL


If symptoms are not controlled and current dosage is tolerated, increase infusion rate about 25%. Recheck serum concentration after 12 hours in children and 24 hours in adults for further dosage adjustment.


10 to 14.9 mcg/mL


If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24 hour intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.


15-19.9 mcg/mL


Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶


20-24.9 mcg/mL


Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.


25-30 mcg/mL


Stop infusion for 12 hours in children and 24 hours in adults and decrease subsequent infusion rate at least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated.


>30 mcg/mL


Stop the infusion and treat overdose as indicated. If theophylline is subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.


Intravenous Admixture Incompatibility:

Although there have been reports of Limptar (Aminophylline) precipitating in acidic media, these reports do not apply to the dilute solutions found in intravenous infusions. Limptar (Aminophylline) injection should not be mixed in a syringe with other drugs but should be added separately to the intravenous solution.

When an intravenous solution containing Limptar (Aminophylline) is given "piggyback", the intravenous system already in place should be turned off while the Limptar (Aminophylline) is infused if there is a potential problem with admixture incompatibility.

Because of the alkalinity of Limptar (Aminophylline) containing solutions, drugs known to be alkali labile should be avoided in admixtures. These include epinephrine HCl, norepinephrine bitartrate, isoproterenol HCl and penicillin G potassium. It is suggested that specialized literature be consulted before preparing admixtures with Limptar (Aminophylline) and other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Do not use if crystals have separated from solution.

HOW SUPPLIED

Limptar (Aminophylline) Injection, USP 25 mg/mL is supplied in single-dose containers as follows:


NDC No.


Container


Volume


Total Content


0409-7385-01


Ampul


10 mL


250 mg


0409-7386-01


Ampul


20 mL


500 mg


0409-5921-01


Partial-fill Fliptop Vial


10 mL


250 mg


0409-5922-01


Partial-fill Fliptop Vial


20 mL


500 mg


Store at 20 to 25°C (68 to 77°F).

PROTECT FROM LIGHT. Store in carton until time of use.

SINGLE-DOSE CONTAINER. Discard unused portion.


Revised: November, 2009




Printed in USA EN-2301

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira logo

10 mL Single-dose

Limptar (Aminophylline)

Inj., USP

250 mg (25 mg/mL)

Protect from light.

Do not use if crystals have

separated from solution.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Rx only

10 mL Single-dose Ampul

25/NDC 0409-7385-01

Limptar (Aminophylline)

Injection, USP

250 mg (25 mg/mL)

Protect from light.

Each mL contains Limptar (Aminophylline) (calculated as the dihydrate) 25 mg

(equivalent to 19.7 mg/mL of anhydrous theophylline). May contain an

excess of ethylenediamine for pH adjustment. pH 8.8 (8.6 to 9.0).

Sterile, nonpyrogenic. Protect from light by retaining in carton until ready

for use. Do not use if crystals have separated from solution.

For I.V. use. Usual dose: See insert. Store at controlled room temperature

15° to 30°C (59° to 86°F).

©Hospira 2004

RL-0277 (6/04)

Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Rx only

Hospira

20 mL

Single-dose

Ampul

Limptar (Aminophylline)

Inj., USP

500 mg (25 mg/mL)

Protect from light.

DO NOT USE IF CRYSTALS HAVE

SEPARATED FROM SOLUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Rx only

20 mL Single-dose Ampul

25/NDC 0409-7386-01

Rx only

Limptar (Aminophylline)

Injection, USP

500 mg (25 mg/mL)

Protect from light.

Each mL contains Limptar (Aminophylline) (calculated as the dihydrate) 25 mg

(equivalent to 19.7 mg/mL of anhydrous theophylline). May contain an

excess of ethylenediamine for pH adjustment. pH 8.8 (8.6 to 9.0).

Headspace nitrogen gassed. Sterile, nonpyrogenic. Protect from light

by retaining in carton until ready for use. Do not use if crystals have

separated from solution. For I.V. use. Usual dose: See insert. Store at

20 to 25°C (68 to 77°F).

Printed in USA

RL-3070

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

10 mL Single-dose

Limptar (Aminophylline)

Injection, USP

250 mg (25 mg/mL)

Protect from light.

DO NOT USE IF CRYSTALS HAVE

SEPARATED FROM SOLUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Rx only

Quinine Sulfate:


WARNING:

Limptar (Quinine Sulfate)® use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with Limptar (Quinine Sulfate) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

WARNING:

Limptar (Quinine Sulfate)® use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with Limptar (Quinine Sulfate) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

Dose and Administration
Hepatic Impairment (2.3) 4/2013
Warnings and Precautions
QT Prolongation and Ventricular Arrhythmias (5.3) 9/2012

1 INDICATIONS AND USAGE

Limptar (Quinine Sulfate) (quinine sulfate) is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Limptar (Quinine Sulfate) has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see Clinical Studies (14) ].

Limptar (Quinine Sulfate) oral capsules are not approved for:

  • Treatment of severe or complicated P. falciparum malaria.
  • Prevention of malaria.
  • Treatment or prevention of nocturnal leg cramps [see Warnings and Precautions (5.1) ].

Limptar (Quinine Sulfate)® (quinine sulfate) is a cinchona alkaloid indicated for treatment of uncomplicated Plasmodium falciparum malaria (1).

2 DOSAGE AND ADMINISTRATION

  • Adults : 648 mg (two capsules) every 8 hours for 7 days (2.1).
  • Patients with severe chronic renal impairment: one loading dose of 648 mg (two capsules) followed 12 hours later by 324 mg (one capsule) every 12 hours for 7 days (2.2).

2.1 Treatment of Uncomplicated P. falciparum Malaria

For treatment of uncomplicated P. falciparum malaria in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days [see Clinical Studies (14) ].

Limptar (Quinine Sulfate) should be taken with food to minimize gastric upset [see Clinical Pharmacology (12.3) ].

2.2 Renal Impairment

In patients with acute uncomplicated malaria and severe chronic renal impairment, the following dosage regimen is recommended: one loading dose of 648 mg Limptar followed 12 hours later by maintenance doses of 324 mg every 12 hours.

The effects of mild and moderate renal impairment on the safety and pharmacokinetics of Limptar (Quinine Sulfate) are not known [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].

2.3 Hepatic Impairment

Adjustment of the recommended dose is not required in mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, but patients should be monitored closely for adverse effects of quinine. Quinine should not be administered in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

324 mg capsules - hard gelatin, clear cap/clear body, imprinted with 'AR 102'

  • 324 mg hard gelatin, clear cap/clear body capsules, imprinted with 'AR 102' (3).

4 CONTRAINDICATIONS

Limptar (Quinine Sulfate) is contraindicated in patients with the following:

  • Prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received Limptar (Quinine Sulfate) intravenously for P. falciparum malaria [see Warnings and Precautions (5.3) ].
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Hemolysis can occur in patients with G6PD deficiency receiving quinine.
  • Known hypersensitivity reactions to quinine.
    • These include, but are not limited to, the following [see Warnings and Precautions (5.6) ]:
      • Thrombocytopenia
      • Idiopathic thrombocytopenia purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP)
      • Hemolytic uremic syndrome (HUS)
      • Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia)
  • Known hypersensitivity to mefloquine or quinidine: cross-sensitivity to quinine has been documented [see Warnings and Precautions (5.6) ].
    • Myasthenia gravis. Quinine has neuromuscular blocking activity, and may exacerbate muscle weakness.
    • Optic neuritis. Quinine may exacerbate active optic neuritis [see Adverse Reactions (6) ].

Limptar (Quinine Sulfate) is contraindicated in patients with the following:

  • Prolongation of QT interval (4)
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency (4)
  • Myasthenia gravis (4)
  • Known hypersensitivity to quinine, mefloquine, or quinidine (4)
  • Optic neuritis (4)

5 WARNINGS AND PRECAUTIONS

  • Not indicated for the prevention or treatment of nocturnal leg cramps. Risk of serious and life-threatening adverse reactions.
  • Thrombocytopenia, including ITP and HUS/TTP, has been reported. Discontinue drug (5.2).
  • QT prolongation and ventricular arrhythmias. Avoid concomitant use with drugs known to prolong QT interval (5.3).
  • Avoid concomitant use with rifampin. Limptar (Quinine Sulfate) treatment failures have been reported (5.4).
  • Avoid concomitant use with neuromuscular blocking agents. Limptar (Quinine Sulfate) may potentiate neuromuscular blockade and cause respiratory depression (5.5).
  • Serious and life threatening hypersensitivity reactions. Discontinue drug (4, 5.6).
  • Atrial fibrillation and flutter. Paradoxical increase in ventricular rate may occur. Closely monitor digoxin levels if used concomitantly (5.7).
  • Hypoglycemia. Monitor for signs and symptoms (5.8).

5.1 Use of Limptar (Quinine Sulfate) for Treatment or Prevention of Nocturnal Leg Cramps

Limptar (Quinine Sulfate) may cause unpredictable serious and life-threatening hematologic reactions including thrombocytopenia and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in addition to hypersensitivity reactions, QT prolongation, serious cardiac arrhythmias including torsades de pointes, and other serious adverse events requiring medical intervention and hospitalization. Chronic renal impairment associated with the development of TTP, and fatalities have also been reported. The risk associated with the use of Limptar (Quinine Sulfate) in the absence of evidence of its effectiveness for treatment or prevention of nocturnal leg cramps, outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition [see Boxed Warning and Contraindications (4) ].

5.2 Thrombocytopenia

Quinine-induced thrombocytopenia is an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported, including cases of HUS/TTP. Chronic renal impairment associated with the development of TTP has also been reported. Thrombocytopenia usually resolves within a week upon discontinuation of quinine. If quinine is not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to quinine from any source, a patient with quinine-dependent antibodies could develop thrombocytopenia that is more rapid in onset and more severe than the original episode.

5.3 QT Prolongation and Ventricular Arrhythmias

QT interval prolongation has been a consistent finding in studies which evaluated electrocardiographic changes with oral or parenteral quinine administration, regardless of age, clinical status, or severity of disease. The maximum increase in QT interval has been shown to correspond with peak quinine plasma concentration [see Clinical Pharmacology ]. Limptar (Quinine Sulfate) has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation.

Limptar (Quinine Sulfate) has been shown to cause concentration-dependent prolongation of the PR and QRS interval. At particular risk are patients with underlying structural heart disease and preexisting conduction system abnormalities, elderly patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia or patients receiving drugs known to prolong the PR interval (e.g. verapamil) or QRS interval (e.g. flecainide or quinidine) [see Clinical Pharmacology (12.2) ].

Limptar (Quinine Sulfate) is not recommended for use with other drugs known to cause QT prolongation, including Class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), and Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide).

The use of macrolide antibiotics such as erythromycin should be avoided in patients receiving Limptar (Quinine Sulfate). Fatal torsades de pointes was reported in an elderly patient who received concomitant quinine, erythromycin, and dopamine. Although a causal relationship between a specific drug and the arrhythmia was not established in this case, erythromycin is a CYP3A4 inhibitor and has been shown to increase quinine plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has also been shown to increase quinine exposure in a pharmacokinetic study [see Drug Interactions (7.1) ].

Quinine may inhibit the metabolism of certain drugs that are CYP3A4 substrates and are known to cause QT prolongation, e.g., astemizole, cisapride, terfenadine, pimozide, halofantrine and quinidine. Torsades de pointes has been reported in patients who received concomitant quinine and astemizole. Therefore, concurrent use of Limptar (Quinine Sulfate) with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7.2) ].

Concomitant administration of Limptar (Quinine Sulfate) with the antimalarial drugs, mefloquine or halofantrine, may result in electrocardiographic abnormalities, including QT prolongation, and increase the risk for torsades de pointes or other serious ventricular arrhythmias. Concurrent use of Limptar (Quinine Sulfate) and mefloquine may also increase the risk of seizures [see Drug Interactions (7.2) ].

Limptar (Quinine Sulfate) should also be avoided in patients with known prolongation of QT interval and in patients with clinical conditions known to prolong the QT interval, such as uncorrected hypokalemia, bradycardia, and certain cardiac conditions [see Contraindications (4) ].

5.4 Concomitant Use of Rifampin

Treatment failures may result from the concurrent use of rifampin with Limptar (Quinine Sulfate), due to decreased plasma concentrations of quinine, and concomitant use of these medications should be avoided [see Drug Interactions (7.1) ].

5.5 Concomitant Use of Neuromuscular Blocking Agents

The use of neuromuscular blocking agents should be avoided in patients receiving Limptar. In one patient who received pancuronium during an operative procedure, subsequent administration of quinine resulted in respiratory depression and apnea. Although there are no clinical reports with succinylcholine or tubocurarine, quinine may also potentiate neuromuscular blockade when used with these drugs [see Drug Interactions (7.2) ].

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Limptar (Quinine Sulfate) include anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, and pruritus.

A number of other serious adverse reactions reported with quinine, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), thrombocytopenia, immune thrombocytopenic purpura (ITP), blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis may also be due to hypersensitivity reactions.

Limptar (Quinine Sulfate) should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4) ].

5.7 Atrial Fibrillation and Flutter

Limptar should be used with caution in patients with atrial fibrillation or atrial flutter. A paradoxical increase in ventricular response rate may occur with quinine, similar to that observed with quinidine. If digoxin is used to prevent a rapid ventricular response, serum digoxin levels should be closely monitored, because digoxin levels may be increased with use of quinine [see Drug Interactions (7.2) ].

5.8 Hypoglycemia

Quinine stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.

6 ADVERSE REACTIONS

Most common adverse reactions are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking quinine: headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, disturbance in color perception, vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction.

To report SUSPECTED ADVERSE REACTIONS, contact Mutual Pharmaceutical Company, Inc. at 1-888-351-3786 or drugsafetyLimptar (Quinine Sulfate)urlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

Quinine can adversely affect almost every body system. The most common adverse events associated with quinine use are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking quinine. Symptoms of mild cinchonism include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. More severe symptoms of cinchonism are vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction. Most symptoms of cinchonism are reversible and resolve with discontinuation of quinine.

The following ADVERSE REACTIONS have been reported with Limptar (Quinine Sulfate). Most of these reactions are thought to be uncommon, but the actual incidence is unknown:

General: fever, chills, sweating, flushing, asthenia, lupus-like syndrome, and hypersensitivity reactions.

Hematologic: agranulocytosis, hypoprothrombinemia, thrombocytopenia, disseminated intravascular coagulation, hemolytic anemia; hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, petechiae, ecchymosis, hemorrhage, coagulopathy, blackwater fever, leukopenia, neutropenia, pancytopenia, aplastic anemia, and lupus anticoagulant.

Neuropsychiatric: headache, diplopia, confusion, altered mental status, seizures, coma, disorientation, tremors, restlessness, ataxia, acute dystonic reaction, aphasia, and suicide.

Dermatologic: cutaneous rashes, including urticarial, papular, or scarlatinal rashes, pruritus, bullous dermatitis, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption, photosensitivity reactions, allergic contact dermatitis, acral necrosis, and cutaneous vasculitis.

Respiratory: asthma, dyspnea, pulmonary edema.

Cardiovascular: chest pain, vasodilatation, hypotension, postural hypotension, tachycardia, bradycardia, palpitations, syncope, atrioventricular block, atrial fibrillation, irregular rhythm, unifocal premature ventricular contractions, nodal escape beats, U waves, QT prolongation, ventricular fibrillation, ventricular tachycardia, torsades de pointes, and cardiac arrest.

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, gastric irritation, and esophagitis.

Hepatobiliary: granulomatous hepatitis, hepatitis, jaundice, and abnormal liver function tests.

Metabolic: hypoglycemia and anorexia.

Musculoskeletal: myalgias and muscle weakness.

Renal: hemoglobinuria, renal failure, renal impairment, and acute interstitial nephritis.

Special Senses: visual disturbances, including blurred vision with scotomata, sudden loss of vision, photophobia, diplopia, night blindness, diminished visual fields, fixed pupillary dilatation, disturbed color vision, optic neuritis, blindness, vertigo, tinnitus, hearing impairment, and deafness.

7 DRUG INTERACTIONS

Interacting Drug Interaction
Drugs known to prolong QT interval. Limptar (Quinine Sulfate) prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).

7.1 Effects of Drugs and Other Substances on Quinine Pharmacokinetics

Quinine is a P-gp substrate and is primarily metabolized by CYP3A4. Other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 may contribute to the metabolism of quinine [see Clinical Pharmacology (12.3) ].

Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Concomitant administration of these antacids with Limptar (Quinine Sulfate) should be avoided.

Antiepileptics (AEDs) (carbamazepine, phenobarbital, and phenytoin): Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with Limptar (Quinine Sulfate).

Cholestyramine: In 8 healthy subjects who received Limptar (Quinine Sulfate) 600 mg with or without 8 grams of cholestyramine resin, no significant difference in quinine pharmacokinetic parameters was seen.

Cigarette Smoking (CYP1A2 inducer): In healthy male heavy smokers, the mean quinine AUC following a single 600 mg dose was 44% lower, the mean Cmax was 18% lower, and the elimination half-life was shorter (7.5 hours versus 12 hours) than in their non-smoking counterparts. However, in malaria patients who received the full 7-day course of quinine therapy, cigarette smoking produced only a 25% decrease in median quinine AUC and a 16.5% decrease in median Cmax, suggesting that the already reduced clearance of quinine in acute malaria could have diminished the metabolic induction effect of smoking. Because smoking did not appear to influence the therapeutic outcome in malaria patients, it is not necessary to increase the dose of quinine in the treatment of acute malaria in heavy cigarette smokers.

Grapefruit juice (P-gp/CYP3A4 inhibitor): In a pharmacokinetic study involving 10 healthy subjects, the administration of a single 600 mg dose of Limptar (Quinine Sulfate) with grapefruit juice (full-strength or half-strength) did not significantly alter the pharmacokinetic parameters of quinine. Limptar (Quinine Sulfate) may be taken with grapefruit juice.

Histamine H2-receptor blockers [cimetidine, ranitidine (nonspecific CYP450 inhibitors)]: In healthy subjects who were given a single oral 600 mg dose of Limptar (Quinine Sulfate) after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for 7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of quinine decreased and the mean elimination half-life increased significantly when given with cimetidine but not with ranitidine. Compared to untreated controls, the mean AUC of quinine increased by 20% with ranitidine and by 42% with cimetidine (p<0.05) without a significant change in mean quinine Cmax. When quinine is to be given concomitantly with a histamine H2-receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with Limptar (Quinine Sulfate), patients should be monitored closely for adverse events associated with quinine.

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of quinine. Adjustment of Limptar (Quinine Sulfate) dosage is not necessary when isoniazid is given concomitantly.

Ketoconazole (CYP3A4 inhibitor): In a crossover study, healthy subjects (N=9) who received a single oral dose of quinine hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean quinine AUC that was higher by 45% and a mean oral clearance of quinine that was 31% lower than after receiving quinine alone. Although no change in the Limptar (Quinine Sulfate) dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with quinine.

Macrolide antibiotics (erythromycin, troleandomycin) (CYP3A4 inhibitors): In a crossover study (N=10), healthy subjects who received a single oral 600 mg dose of Limptar (Quinine Sulfate) with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87% higher mean quinine AUC, a 45% lower mean oral clearance of quinine, and a 81% lower formation clearance of the main metabolite, 3-hydroxyquinine, than when quinine was given alone.

Erythromycin was shown to inhibit the in vitro metabolism of quinine in human liver microsomes, an observation confirmed by an in vivo interaction study. In a crossover study (N=10), healthy subjects who received a single oral 500 mg dose of Limptar (Quinine Sulfate) with erythromycin (600 mg every 8 hours for four days) showed a decrease in quinine oral clearance (CL/F), an increase in half-life, and a decreased metabolite (3-hydroxyquinine) to quinine AUC ratio, as compared to when quinine was given with placebo.

Therefore, concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with Limptar (Quinine Sulfate) should be avoided [see Warnings and Precautions (5.3) ].

Oral contraceptives (estrogen, progestin): In 7 healthy females who were using single-ingredient progestin or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of Limptar (Quinine Sulfate) were not altered in comparison to those observed in 7 age-matched female control subjects not using oral contraceptives.

Rifampin (CYP3A4 inducer): In patients with uncomplicated P. falciparum malaria who received Limptar (Quinine Sulfate) 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of quinine between days 3 and 7 of therapy was 75% lower as compared to those who received quinine monotherapy. In healthy subjects (N=9) who received a single oral 600 mg dose of Limptar (Quinine Sulfate) after 2 weeks of pretreatment with rifampin 600 mg/day, the mean quinine AUC and Cmax decreased by 85% and 55%, respectively. Therefore, the concomitant administration of rifampin with Limptar (Quinine Sulfate) should be avoided [see Warnings and Precautions (5.4) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Limptar (Quinine Sulfate) with the 15th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean quinine AUC and Cmax, and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when quinine was given alone. Therefore, the concomitant administration of ritonavir with Limptar (Quinine Sulfate) capsules should be avoided [see also Drug Interactions (7.2) ].

Tetracycline: In 8 patients with acute uncomplicated P. falciparum malaria who were treated with oral Limptar (Quinine Sulfate) (600 mg every 8 hours for 7 days) in combination with oral tetracycline (250 mg every 6 hours for 7 days), the mean plasma quinine concentrations were about two-fold higher than in 8 patients who received quinine monotherapy. Although tetracycline may be concomitantly administered with Limptar (Quinine Sulfate), patients should be monitored closely for adverse reactions associated with Limptar (Quinine Sulfate).

Theophylline or aminophylline: In 20 healthy subjects who received multiple doses of Limptar (Quinine Sulfate) (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of theophylline, the quinine mean Cmax and AUC were increased by 13% and 14% respectively. Although no change in the Limptar (Quinine Sulfate) dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with quinine.

Urinary alkalizers (acetazolamide, sodium bicarbonate): Urinary alkalinizing agents may increase plasma quinine concentrations.

7.2 Effects of Quinine on the Pharmacokinetics of Other Drugs

Results of in vivo drug interaction studies suggest that quinine has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Quinine inhibits P-gp and has the potential to affect the transport of drugs that are P-gp substrates.

Anticonvulsants : A single 600 mg oral dose of Limptar (Quinine Sulfate) increased the mean plasma Cmax, and AUC0–24 of single oral doses of carbamazepine (200 mg) and phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine, phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in Cmax were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by quinine. If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of anticonvulsant drug concentrations is recommended. Additionally, patients should be monitored closely for adverse reactions associated with these anticonvulsants.

Astemizole (CYP3A4 substrate): Elevated plasma astemizole concentrations were reported in a subject who experienced torsades de pointes after receiving three doses of Limptar (Quinine Sulfate) for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of Limptar (Quinine Sulfate) with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine) should also be avoided [see Warnings and Precautions (5.3) ].

Atorvastatin (CYP3A4 substrate): Rhabdomyolysis with acute renal failure secondary to myoglobinuria was reported in a patient taking atorvastatin administered with a single dose of quinine. Quinine may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of Limptar (Quinine Sulfate) with atorvastatin or other HMG-CoA reductase inhibitors ("statins") that are CYP3A4 substrates (e.g., simvastatin, lovastatin) should carefully weigh the potential benefits and risks of each medication. If Limptar (Quinine Sulfate) is used concomitantly with any of these statins, lower starting and maintenance doses of the statin should be considered. Patients should also be monitored closely for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy. If marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values >10 times the upper limit of normal) is diagnosed or suspected, atorvastatin or other statin should be discontinued.

Desipramine (CYP2D6 substrate): Quinine (750 mg/day for 2 days) decreased the metabolism of desipramine in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers. Lower doses (80 mg to 400 mg) of quinine did not significantly affect the pharmacokinetics of other CYP2D6 substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies have not been performed, antimalarial doses (greater than or equal to 600 mg) of quinine may inhibit the metabolism of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol, paroxetine). Patients taking medications that are CYP2D6 substrates with Limptar (Quinine Sulfate) should be monitored closely for adverse reactions associated with these medications.

Digoxin (P-gp substrate): In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with quinine (750 mg/day), a 33% increase in mean steady state AUC of digoxin and a 35% reduction in the steady state biliary clearance of digoxin were observed compared to digoxin alone. Thus, if Limptar (Quinine Sulfate) is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary [see Warnings and Precautions (5.7) ].

Halofantrine: Although not studied clinically, quinine was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Limptar (Quinine Sulfate) is likely to increase plasma halofantrine concentrations [see Warnings and Precautions (5.3) ].

Mefloquine: In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose of Limptar (Quinine Sulfate), the AUC of mefloquine was increased by 22% compared to mefloquine alone. In this study, the QTc interval was significantly prolonged in the subjects who received mefloquine and Limptar (Quinine Sulfate) 24 hours apart. The concomitant administration of mefloquine and Limptar (Quinine Sulfate) may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures [see Warnings and Precautions (5.3) ].

Midazolam (CYP3A4 substrate): In 23 healthy subjects who received multiple doses of Limptar (Quinine Sulfate) 324 mg three times daily × 7 days with a single oral 2 mg dose of midazolam, the mean AUC and Cmax of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with Limptar (Quinine Sulfate) 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, quinine potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received quinine 1800 mg daily. Quinine may also enhance the neuromuscular blocking effects of succinylcholine and tubocurarine [see Warnings and Precautions (5.5) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Limptar (Quinine Sulfate) with the 15th dose of ritonavir (200 mg every 12 hours for 9 days), the mean ritonavir AUC, Cmax, and elimination half-life were slightly but not significantly increased compared to when ritonavir was given alone. However, due to the significant effect of ritonavir on quinine pharmacokinetics, the concomitant administration of Limptar (Quinine Sulfate) capsules with ritonavir should be avoided [see also Drug Interactions (7.1) ].

Theophylline or aminophylline (CYP1A2 substrate): In 19 healthy subjects who received multiple doses of Limptar (Quinine Sulfate) 648 mg every 8 hours x 7 days with a single 300 mg oral dose of theophylline, the mean theophylline AUC was 10% lower than when theophylline was given alone. There was no significant effect on mean theophylline Cmax. Therefore, if Limptar (Quinine Sulfate) is co-administered to patients receiving theophylline or aminophylline, plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations.

Warfarin and oral anticoagulants: Cinchona alkaloids, including quinine, may have the potential to depress hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin and other oral anticoagulants. Quinine may also interfere with the anticoagulant effect of heparin. Thus, in patients receiving these anticoagulants, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalization ratio (INR) should be closely monitored as appropriate, during concurrent therapy with Limptar (Quinine Sulfate).

7.3 Drug/Laboratory Interactions

Quinine may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.

Quinine may interfere with urine qualitative dipstick protein assays as well as quantitative methods (e.g., pyrogallol red-molybdate).

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Reduce dose and dosing frequency for patients with severe chronic renal impairment.
  • Hepatic impairment: Closely monitor for adverse events. Quinine should not be administered in patients with severe (Child-Pugh C) hepatic impairment (2.3, 8.7, 12.3).
  • Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk (8.1).
  • Nursing Mothers: Exercise caution when administering to a nursing woman (8.3).

8.1 Pregnancy

Pregnancy Category C

There are extensive published data but few well-controlled studies of Limptar (Quinine Sulfate) in pregnant women. Published data on over 1,000 pregnancy exposures to quinine did not show an increase in teratogenic effects over the background rate in the general population; however, the majority of these exposures were not in the first trimester. In developmental and reproductive toxicity studies, central nervous system (CNS) and ear abnormalities and increased fetal deaths occurred in some species when pregnant animals received quinine at doses about 1 to 4 times the human clinical dose. Quinine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

P. falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population. Pregnant women with P. falciparum malaria have an increased incidence of fetal loss (including spontaneous abortion and stillbirth), preterm labor and delivery, intrauterine growth retardation, low birth weight, and maternal death. Therefore, treatment of malaria in pregnancy is important.

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, particularly in pregnant women.

Quinine crosses the placenta with measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting quinine therapy, umbilical cord plasma quinine concentrations were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord plasma to maternal plasma quinine concentrations was 0.32 ± 0.14. Quinine levels in the fetus may not be therapeutic. If congenital malaria is suspected after delivery, the infant should be evaluated and treated appropriately.

A study from Thailand (1999) of women with P. falciparum malaria who were treated with oral Limptar (Quinine Sulfate) 10 mg/kg 3 times daily for 7 days at anytime in pregnancy reported no significant difference in the rate of stillbirths at >28 weeks of gestation in women treated with quinine (10 of 633 women [1.6%]) as compared with a control group without malaria or exposure to antimalarial drugs during pregnancy (40 of 2201 women [1.8%]). The overall rate of congenital malformations (9 of 633 offspring [1.4%]) was not different for women who were treated with Limptar (Quinine Sulfate) compared with the control group (38 of 2201 offspring [1.7%]). The spontaneous abortion rate was higher in the control group (10.9%) than in women treated with Limptar (Quinine Sulfate) (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An epidemiologic survey that included 104 mother-child pairs exposed to quinine during the first 4 months of pregnancy, found no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]). Rare and isolated case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses of quinine.

In animal developmental studies conducted in multiple animal species, pregnant animals received quinine by the subcutaneous or intramuscular route at dose levels similar to the maximum recommended human dose (MRHD; 32 mg/kg/day) based on body surface area (BSA) comparisons. There were increases in fetal death in utero in rabbits at maternal doses ≥ 100 mg/kg/day and in dogs at ≥ 15 mg/kg/day corresponding to dose levels approximately 0.5 and 0.25 times the MRHD respectively based on BSA comparisons. Rabbit offspring had increased rates of degenerated auditory nerve and spiral ganglion and increased rates of CNS anomalies such as anencephaly and microcephaly at a dose of 130 mg/kg/day corresponding to a maternal dose approximately 1.3 times the MRHD based on BSA comparison. Guinea pig offspring had increased rates of hemorrhage and mitochondrial change in the cochlea at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. There were no teratogenic findings in rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons.

In a pre- postnatal study in rats, an estimated oral dose of Limptar (Quinine Sulfate) of 20 mg/kg/day corresponding to approximately 0.1 times the MRHD based on BSA comparison resulted in offspring with impaired growth, lower body weights at birth and during the lactation period, and delayed physical development of teeth eruption and eye opening during the lactation period.

8.2 Labor and Delivery

There is no evidence that quinine causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, quinine may stimulate the pregnant uterus.

8.3 Nursing Mothers

There is limited information on the safety of quinine in breastfed infants. No toxicity was reported in infants in a single study where oral Limptar (10 mg/kg every 8 hours for 1 to 10 days) was administered to 25 lactating women. It is estimated from this study that breastfed infants would receive less than 2 to 3 mg per day of quinine base (< 0.4% of the maternal dose) via breast milk [see Clinical Pharmacology (12.3) ].

Although quinine is generally considered compatible with breastfeeding, the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a nursing woman.

If malaria is suspected in the infant, appropriate evaluation and treatment should be provided. Plasma quinine levels may not be therapeutic in infants of nursing mothers receiving Limptar (Quinine Sulfate).

8.4 Pediatric Use

The safety and efficacy of Limptar (Quinine Sulfate) in pediatric patients under the age of 16 has not been established.

8.5 Geriatric Use

Clinical studies of Limptar did not include sufficient numbers of subjects aged 65 and over to determine whether they respond to treatment differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Clearance of quinine is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh C), quinine oral clearance (CL/F) is decreased, volume of distribution (Vd/F) is increased, and half-life is prolonged, relative to subjects with normal liver function. Therefore, quinine is not indicated in patients with severe hepatic impairment and alternate therapy should be administered [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

Close monitoring is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, as exposure to quinine may be increased relative to subjects with normal liver function [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Quinine overdose can be associated with serious complications, including visual impairment, hypoglycemia, cardiac arrhythmias, and death. Visual impairment can range from blurred vision and defective color perception, to visual field constriction and permanent blindness. Cinchonism occurs in virtually all patients with quinine overdose. Symptoms range from headache, nausea, vomiting, abdominal pain, diarrhea, tinnitus, vertigo, hearing impairment, sweating, flushing, and blurred vision, to deafness, blindness, serious cardiac arrhythmias, hypotension, and circulatory collapse. Central nervous system toxicity (drowsiness, disturbances of consciousness, ataxia, convulsions, respiratory depression and coma) has also been reported with quinine overdose, as well as pulmonary edema and adult respiratory distress syndrome.

Most toxic reactions are dose-related; however, some reactions may be idiosyncratic because of the variable sensitivity of patients to the toxic effects of quinine. A lethal dose of quinine has not been clearly defined, but fatalities have been reported after the ingestion of 2 to 8 grams in adults.

Quinine, like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of quinine is due to its negative inotropic action, and to its effect on cardiac conduction, resulting in decreased rates of depolarization and conduction, and increased action potential and effective refractory period. ECG changes observed with quinine overdose include sinus tachycardia, PR prolongation, T wave inversion, bundle branch block, an increased QT interval, and a widening of the QRS complex. Quinine's alpha-blocking properties may result in hypotension and further exacerbate myocardial depression by decreasing coronary perfusion. Quinine overdose has been also associated with hypotension, cardiogenic shock, and circulatory collapse, ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, idioventricular rhythm, and torsades de pointes, as well as bradycardia, and atrioventricular block [see Warnings and Precautions (5), Clinical Pharmacology (12.3) ].

Quinine is rapidly absorbed, and attempts to remove residual Limptar (Quinine Sulfate) from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease plasma quinine concentrations [see Clinical Pharmacology (12.3) ].

Forced acid diuresis, hemodialysis, charcoal column hemoperfusion, and plasma exchange were not found to be effective in significantly increasing quinine elimination in a series of 16 patients.

11 DESCRIPTION

Limptar (Quinine Sulfate) (quinine sulfate) is a cinchona alkaloid chemically described as cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C20H24N2O2)2-H2SO4-2H2O and a molecular weight of 782.96.

The structural formula of Limptar (Quinine Sulfate) is:

Limptar (Quinine Sulfate) occurs as a white, crystalline powder that darkens on exposure to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, alcohol, chloroform, and ether.

Limptar (Quinine Sulfate) is supplied for oral administration as capsules containing 324 mg of the active ingredient Limptar (Quinine Sulfate) USP, equivalent to 269 mg free base. Inactive ingredients: corn starch, magnesium stearate, and talc.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Quinine is an antimalarial agent [see Clinical Pharmacology ].

12.2 Pharmacodynamics

QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with Limptar (Quinine Sulfate) 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms.

Prolongation of the PR and QRS interval was also noted in subjects receiving Limptar (Quinine Sulfate). The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. [see Warnings and Precautions (5.3) ].

12.3 Pharmacokinetics

Absorption

The oral bioavailability of quinine is 76 to 88% in healthy adults. Quinine exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of Limptar, the mean quinine Tmax was longer, and mean AUC and Cmax were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below.

Healthy Subjects

(N = 23)

Mean ± SD

Uncomplicated P. falciparum Malaria Patients

(N = 15)

Mean ± SD

Dose (mg/kg)Limptar (Quinine Sulfate) dose was 648 mg (approximately 8.7 mg/kg) in healthy subjects; and 10 mg/kg in patients with malaria 8.7 10
Tmax (h) 2.8 ± 0.8 5.9 ± 4.7
Cmax (mcg/mL) 3.2 ± 0.7 8.4
AUC0–12 (mcg*h/mL) 28.0 73.0

Limptar (Quinine Sulfate) capsules may be administered without regard to meals. When a single oral 324 mg capsule of Limptar (Quinine Sulfate) was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean Tmax of quinine was prolonged to about 4.0 hours, but the mean Cmax and AUC0-24h were similar to those achieved when Limptar (Quinine Sulfate) capsule was given under fasted conditions [see Dosage and Administration (2.1) ].

Distribution

In patients with malaria, the volume of distribution (Vd/F) decreases in proportion to the severity of the infection. In published studies with healthy subjects who received a single oral 600 mg dose of Limptar (Quinine Sulfate), the mean Vd/F ranged from 2.5 to 7.1 L/kg.

Quinine is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of quinine is increased to 78 to 95%, corresponding to the increase in α1-acid glycoprotein that occurs with malaria infection.

Intra-erythrocytic levels of quinine are approximately 30 to 50% of the plasma concentration.

Quinine penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2 to 7% of plasma concentration.

In one study, quinine concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of quinine concentrations in maternal plasma. The estimated total dose of quinine secreted into breast milk was less than 2 to 3 mg per day [see Use in Specific Populations (8.1, 8.3) ].

Metabolism

Quinine is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2´-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug.

In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that quinine is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of quinine.

Elimination/Excretion

Quinine is eliminated primarily via hepatic biotransformation. Approximately 20% of quinine is excreted unchanged in urine. Because quinine is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline.

In various published studies, healthy subjects who received a single oral 600 mg dose of Limptar (Quinine Sulfate) exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours.

In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of Limptar (Quinine Sulfate), the mean total clearance of quinine was slower (approximately 0.09 L/h/kg) during the acute phase of the infection, and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase.

Extracorporeal Elimination: Administration of multiple-dose activated charcoal (50 grams administered 4 hours after quinine dosing followed by 3 further doses over the next 12 hours) decreased the mean quinine elimination half-life from 8.2 to 4.6 hours, and increased the mean quinine clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of Limptar (Quinine Sulfate). Likewise, in 5 symptomatic patients with acute quinine poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean quinine elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive activated charcoal [see Overdosage (10) ].

In 6 patients with quinine poisoning, forced acid diuresis did not change the half-life of quinine elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged quinine recovered in the urine, in comparison to 8 patients not treated in this manner [see Overdosage (10) ].

Specific Populations

Pediatric Patients: The pharmacokinetics of quinine in children (1.5 to 12 years old) with uncomplicated P. falciparum malaria appear to be similar to that seen in adults with uncomplicated malaria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of quinine were reduced in pediatric patients with malaria as compared to the healthy pediatric controls. Table 2 below provides a comparison of the mean ± SD pharmacokinetic parameters of quinine in pediatric patients vs. healthy pediatric controls.

Healthy Pediatric Controlsage 1.5 to 12 years

(N = 5)

Mean ± SD

P. falciparum Malaria Pediatric Patients

(N = 15)

Mean ± SD

Tmax (h) 2.0 4.0
Cmax (mcg/mL) 3.4 ± 1.18 7.5 ± 1.1
Half-life (h) 3.2 ± 0.3 12.1 ± 1.4
Total CL (L/h/kg) 0.30 ± 0.04 0.06 ± 0.01
Vd (L/kg) 1.43 ± 0.18 0.87 ± 0.12

Geriatric Patients: Following a single oral dose of 600 mg Limptar (Quinine Sulfate), the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean Tmax and Cmax were similar in elderly and younger subjects after a single oral dose of Limptar (Quinine Sulfate) 600 mg. The mean oral clearance of quinine was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of quinine between the two age groups, elderly subjects excreted a larger proportion of the dose in urine as unchanged drug than younger subjects (16.6% vs. 11.2%).

After a single 648 mg dose or at steady state, following Limptar (Quinine Sulfate) 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of quinine was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state Cmax (±SD) and AUC0-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral Limptar (Quinine Sulfate) 648 mg three times daily. The steady state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects.

Renal Impairment: Following a single oral 600 mg dose of Limptar (Quinine Sulfate) in otherwise healthy subjects with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine = 9.6 mg/dL), the median AUC was higher by 195% and the median Cmax was higher by 79% than in subjects with normal renal function (mean serum creatinine = 1 mg/dL). The mean plasma half-life in subjects with severe chronic renal impairment was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with malaria and severe chronic renal failure, a dosage regimen consisting of one loading dose of 648 mg Limptar (Quinine Sulfate) followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to quinine [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Limptar (Quinine Sulfate) are not known.

Negligible to minimal amounts of circulating quinine in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of quinine is removed in 1 hour. Plasma quinine concentrations do not change during or shortly after hemofiltration in subjects with CRF [see Overdosage (10) ].

Hepatic Impairment: In otherwise healthy subjects with mild hepatic impairment (Child-Pugh A; N=10), who received a single 500 mg dose of Limptar (Quinine Sulfate), there was no significant difference in quinine pharmacokinetic parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate hepatic impairment (Child-Pugh B; N=9) who received a single oral 600 mg dose of Limptar (Quinine Sulfate), the mean AUC increased by 55% without a significant change in mean Cmax, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of quinine was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of quinine [see Use in Specific Populations (8.7) ].

In subjects with severe hepatic impairment (Child-Pugh C; N=10), quinine oral clearance (CL/F) was reduced as was formation of the primary 3-hydroxyquinine metabolite. Volume of distribution (Vd/F) was higher and the plasma elimination half-life was increased. Therefore, quinine is not indicated in this population and alternate therapy should be administered [see Dosage and Administration (2.3) ].

12.4 Microbiology

Mechanism of Action

Quinine inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of Limptar (Quinine Sulfate) is not completely understood.

Activity In Vitro and In Vivo

Limptar (Quinine Sulfate) acts primarily on the blood schizont form of P. falciparum. It is not gametocidal and has little effect on the sporozoite or pre-erythrocytic forms.

Drug Resistance

Strains of P. falciparum with decreased susceptibility to quinine can be selected in vivo. P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of quinine have not been conducted.

Mutagenesis

Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila, the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative.

Impairment of Fertility

Published studies indicate that quinine produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the MRHD based on body surface area (BSA) comparisons. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. There was no effect on testes weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the MRHD respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of quinine TID for one week, sperm motility was decreased and percent sperm with abnormal morphology was increased; sperm count and serum testosterone were unaffected.

14 CLINICAL STUDIES

Quinine has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1300 references to the treatment of malaria with quinine, and from these, 21 randomized, active-controlled studies were identified which evaluated oral quinine monotherapy or combination therapy for treatment of uncomplicated P. falciparum malaria. Over 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 patients received oral quinine. The following conclusions were drawn from review of these studies:

In areas where multi-drug resistance of P. falciparum is increasing, such as Southeast Asia, cure rates with 7 days of oral quinine monotherapy were at least 80%; while cure rates for 7 days of oral quinine combined with an antimicrobial agent (tetracycline or clindamycin) were greater than 90%. In areas where multi-drug resistance of the parasite was not as widespread, cure rates with 7 days of quinine monotherapy ranged from 86 to 100%. Cure was defined as initial clearing of parasitemia within 7 days without recrudescence by day 28 after treatment initiation. P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh, and quinine may not be as effective in those areas.

Completion of a 7-day oral quinine treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of quinine combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral quinine in conjunction with tetracycline, doxycycline, or clindamycin for treatment of uncomplicated P. falciparum malaria is limited, and these shorter course combination regimens may not be as effective as the longer regimens.

16 HOW SUPPLIED / STORAGE AND HANDLING

16.1 How Supplied

Limptar capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102:

Bottles of 30 NDC 13310-153-07
Bottles of 100 NDC 13310-153-01
Bottles of 500 NDC 13310-153-05
Bottles of 1000 NDC 13310-153-10

16.2 Storage

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide

17.1 Dosing Instructions

Patients should be instructed to:

  • Take all of the medication as directed.
  • Take no more of the medication than the amount prescribed.
  • Take with food to minimize possible gastrointestinal irritation.

If a dose is missed, patients should also be instructed not to double the next dose. If more than 4 hours has elapsed since the missed dose, the patient should wait and take the next dose as previously scheduled.

17.2 FDA-Approved Medication Guide

MEDICATION GUIDE

Limptar (Quinine Sulfate)®

(kwol-a-kwin)

(Quinine sulfate) Capsules

Read the Medication Guide that comes with Limptar (Quinine Sulfate) ® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Limptar (Quinine Sulfate) ® when you start taking it and at regular checkups. Limptar (Quinine Sulfate) ® is not approved for the treatment of night-time leg cramps.

What is the most important information I should know about Limptar (Quinine Sulfate)®?

Limptar (Quinine Sulfate)® used to treat or prevent leg cramps may cause serious side effects or even death.

  • Limptar (Quinine Sulfate) ® may cause your blood cell (platelet) count to drop causing serious bleeding problems. In some people, serious kidney problems can happen.
  • Limptar (Quinine Sulfate)® may cause problems with your heart rhythm that can lead to death.
  • Limptar (Quinine Sulfate)® may cause serious allergic reactions.

Call your healthcare provider right away if you have:

  • easy bruising
  • severe nose bleed
  • blood in urine or stool
  • bleeding gums
  • appearance of unusual purple, brown or red spots on your skin (bleeding under your skin)
  • rash
  • hives
  • severe itching
  • severe flushing
  • swelling of your face
  • trouble breathing
  • chest pain
  • rapid heartbeat
  • irregular heart rhythm
  • weakness
  • sweating
  • nervousness

Taking Limptar (Quinine Sulfate)® with some other medicines can increase the chance of serious side effects. Tell your healthcare provider if you take any other medicines.

Certain medicines can cause the blood levels of Limptar (Quinine Sulfate) ® to be too high or too low in your body. It is important for you to tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Limptar (Quinine Sulfate)® and other medicines may affect each other causing serious side effects or death. Even medicines that you may take for a short period of time, such as antibiotics, can mix in your blood with Limptar (Quinine Sulfate)® and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

What is Limptar (Quinine Sulfate)®?

Limptar (Quinine Sulfate) ® is a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum.

Limptar (Quinine Sulfate)® is Not approved to:

  • Prevent malaria
  • Treat severe or complicated malaria
  • Prevent or treat night-time leg cramps

It is not known if Limptar (Quinine Sulfate)® is safe and works in children younger than 16 years old.

Who should not take Limptar (Quinine Sulfate)®?

Do not take Limptar (Quinine Sulfate)® if you have:

  • certain heart rhythm problems (atrial fibrillation) or abnormal electrocardiogram (ECG) (QT prolongation).
  • low levels of an enzyme called Glucose-6-phosphate dehydrogenase (G6PD).
  • an autoimmune disease (myasthenia gravis) that leads to muscle weakness.
  • had allergic reactions to quinine, quinidine, or mefloquine (Lariam®).
  • had serious side effects to quinine (QUALAQUIN®), such as low platelets, which are necessary for your blood to clot.
  • an inflammation of the nerve important for vision (optic neuritis).

What should I tell my healthcare provider before starting Limptar (Quinine Sulfate)®?

Before you take Limptar (Quinine Sulfate)®, tell your healthcare provider if you:

  • Have heart problems.
  • Have kidney problems.
  • Have liver problems.
  • Have any other medical condition.
  • Are pregnant or could be pregnant. Treatment of malaria is important because it can be a serious disease for a pregnant woman and her unborn baby. Your healthcare provider can tell you more about the benefits and risks of taking this medication during pregnancy. Low blood sugar (hypoglycemia) can be seen in pregnant women while taking Limptar (Quinine Sulfate)®. This can include sweating, weakness, nausea, vomiting, or confusion. You and your healthcare provider can decide if Limptar (Quinine Sulfate) ® is right for you.
  • Are breast-feeding. Small amounts of Limptar (Quinine Sulfate) ® can pass into your breast milk. You and your healthcare provider can decide if you should breastfeed while taking Limptar (Quinine Sulfate) ® .

Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins and herbal supplements.

How should I take Limptar (Quinine Sulfate)®?

  • Take Limptar (Quinine Sulfate) ® exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you how many Limptar (Quinine Sulfate)® capsules to take and when to take them.
  • To lower the chance of stomach upset, take Limptar (Quinine Sulfate)® with food.
  • Finish all the Limptar (Quinine Sulfate) ® that is prescribed even if you feel better. Do not stop taking the medication without talking to your healthcare provider.
  • Do not take more than the amount prescribed. Do not take more than 2 capsules at one time or more than 3 doses in one day. If you take more than the prescribed dose, call your healthcare provider right away.
  • If you forget to take Limptar (Quinine Sulfate)®, do not double the next dose. If it has been more than 4 hours since the missed dose, just wait and take the regular dose at the next scheduled time. Call your healthcare provider if you are not sure what to do.
  • If you take too much Limptar (Quinine Sulfate)®, call your healthcare provider or go to the nearest emergency room right away.

Call your healthcare provider right away if:

  • If you feel worse, or if you do not start feeling better within 1 or 2 days of starting to take Limptar (Quinine Sulfate)®.
  • If your fever comes back after finishing treatment with Limptar (Quinine Sulfate)®.

What are the possible side effects of Limptar (Quinine Sulfate)®?

Limptar (Quinine Sulfate)® may cause serious side effects.

  • See "What is the most important information I should know about Limptar (Quinine Sulfate) ®" section.
  • Low blood sugar (hypoglycemia). This can include sweating, weakness, nausea, vomiting, or confusion.

Common side effects with Limptar (Quinine Sulfate) ® include:

  • headache
  • sweating
  • flushing
  • nausea
  • ringing in your ears
  • diarrhea
  • deafness
  • hearing loss
  • dizziness (vertigo)
  • blurred vision
  • changes in how you see color
  • vomiting
  • stomach pain
  • blindness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Limptar (Quinine Sulfate) ® . For more information, ask your healthcare provider or pharmacist.

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

How should I store Limptar (Quinine Sulfate)®?

  • Keep the capsules in a tightly closed container.
  • Do not refrigerate or freeze.
  • Store at 20°C to 25°C (68ºF to 77°F).

Keep Limptar (Quinine Sulfate)® and all medicines out of the reach of children.

General Information about Limptar (Quinine Sulfate)®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Limptar (Quinine Sulfate) ® for a condition for which it was not prescribed. Do not give Limptar (Quinine Sulfate) ® to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Limptar (Quinine Sulfate) ® . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Limptar (Quinine Sulfate) ® that is written for healthcare professionals.

For more information, go to www. QUALAQUIN.com or call 1-888-351-3786.

What are the ingredients in Limptar (Quinine Sulfate)®?

Active Ingredients: Limptar (Quinine Sulfate), USP

Inactive Ingredients: Corn starch, magnesium stearate, talc

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:

AR SCIENTIFIC, INC.

Philadelphia, PA 19124 USA

by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Philadelphia, PA 19124 USA

Rev 23, April 2013

PRINCIPAL DISPLAY PANEL - 324 mg Capsule Bottle Label

100 CAPSULES

NDC 13310-153-01

Limptar (Quinine Sulfate) ®

Limptar (Quinine Sulfate)

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only

Limptar pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Limptar available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Limptar destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Limptar Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Limptar pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."AMINOPHYLLINE INJECTION, SOLUTION [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."QUALAQUIN (QUININE SULFATE) CAPSULE [AR SCIENTIFIC INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."QUININE SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Limptar?

Depending on the reaction of the Limptar after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Limptar not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Limptar addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Limptar, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Limptar consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Limptar drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
> 601
100.0%

Visitor reviews


There are no reviews yet. Be the first to write one!


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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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