Theophylline in Dextrose

THEOPHYLLINE IN DEXTROSE- theophylline anhydrous and dextrose monohydrate injection, solution
B. Braun Medical Inc.

Do not admix with other drugs.

DESCRIPTION

Theophylline in 5% Dextrose Injection USP is sterile, nonpyrogenic solution intended for intravenous administration, prepared from theophylline and dextrose in Water for Injection USP.

Composition — Each 100 mL contains:
Solution	Anhydrous Theophylline USP	Hydrous Dextrose USP	pH	Calculated Osmolarity mOsmol/liter
Water for Injection USP, qs
0.08% Theophylline in 5% Dextrose Injection USP	80 mg	5 g	4.7 (3.5–6.5)	255

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

The formulas of the active ingredients are:

The molecular formula of anhydrous theophylline is C₇ H₈ N₄ O₂ with a molecular weight of 180.17.

The molecular formula of hydrous dextrose is C₆ H₁₂ O₆ •H₂ O with a molecular weight of 198.17.

Not made with natural rubber latex, PVC or DEHP.

The plastic container is made from a multilayered film specifically developed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.

The closure system has two ports; the one for the administration set has a tamper evident plastic protector. Refer to the Directions for Use of the container.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

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

Serum Concentration-Effect Relationship

Bronchodilation occurs over the serum theophylline concentration range of 5–20 mcg/mL. Clinically important improvement in symptom control and pulmonary function has been found in most studies to require serum theophylline concentrations greater than 10 mcg/mL. At serum theophylline concentrations greater than 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining average serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics

Overview

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, Laboratory tests).

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

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

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