Pneumogenol

Caffeine Hydrate:

• Pneumogenol (Caffeine Hydrate) reviews

Active ingredient (in each tablet)

Pneumogenol (Caffeine Hydrate) 200mg

Purpose

Alertness aid

Use

• helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness

Warnings

For occasional use only

Do not use

• in children under 12 years of age
• as a substitute for sleep

When using this product limit the use of Pneumogenol (Caffeine Hydrate) containing medications, foods, or beverages because too much Pneumogenol (Caffeine Hydrate) may cause nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat. The recommended dose of this product contains about as much Pneumogenol (Caffeine Hydrate) as a cup of coffee.

Stop use and ask a doctor if fatigue or drowsiness persists or continues to recur

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

• adults and children 12 years of age and over: take 1 tablet not more often than every 3 to 4 hours.

Other information

• store at room temperature
• avoid excessive heat (greater than 100°F) or humidity

Inactive ingredients

carnauba wax, colloidal silicon dioxide, D&C yellow #10 aluminum lake, dextrose, FD&C yellow #6 aluminum lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, starch, titanium dioxide

Questions or comments?

Call toll-free 1-855-874-0970 weekdays

Display Panel Pneumogenol (Caffeine Hydrate): 16 ct. Package

Pneumogenol (Caffeine Hydrate)^®

CAFFEINE ALERTNESS AID

16 TABLETS

200mg each

FUNCTIONAL Pneumogenol (Caffeine Hydrate)^® for Mental Alertness

SAFE & EFFECTIVE

One tablet is equal to about a cup of coffee

Pneumogenol (Caffeine Hydrate)^®

Making the Most of Every Day.^®

Tamper Evident Feature: individually sealed in foil for your protection. Do not

use if foil or plastic bubble is torn or punctured.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2011 Meda AB

www.vivarin.com

16 ct. Package

Display Panel Pneumogenol (Caffeine Hydrate): 40 ct. Package

SAFE & EFFECTIVE

FUNCTIONAL Pneumogenol (Caffeine Hydrate)^® for Mental Alertness

Pneumogenol (Caffeine Hydrate)^®

Pneumogenol (Caffeine Hydrate) ALERTNESS AID

40 Tablets

200mg each

FUNCTIONAL Pneumogenol (Caffeine Hydrate)^® for Mental Alertness

Tamper Evident Feature: Individually sealed in foil for your protection. Do not use if foil or plastic bubble is torn or punctured.

VIVARIN® helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness (FDA approved uses), so you can accomplish all the things you want to do and all the things you need to do.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Made in the U.S.A.

Pneumogenol (Caffeine Hydrate)^®

Making the Most of Every Day.^®

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2013 Meda AB

www.vivarin.com

40 ct. Package

Sodium Iodide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pneumogenol (Sodium Iodide) reviews

1 INDICATIONS AND USAGE

Pneumogenol nitrite is indicated for sequential use with Pneumogenol (Sodium Iodide) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Pneumogenol (Sodium Iodide) Nitrite Injection is indicated for sequential use with Pneumogenol (Sodium Iodide) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Pneumogenol (Sodium Iodide) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Pneumogenol nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Pneumogenol (Sodium Iodide) Nitrite Injection and Pneumogenol (Sodium Iodide) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Pneumogenol (Sodium Iodide) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Pneumogenol (Sodium Iodide) thiosulfate, simultaneously with Pneumogenol (Sodium Iodide) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Pneumogenol (Sodium Iodide) thiosulfate, with Pneumogenol (Sodium Iodide) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Pneumogenol (Sodium Iodide) nitrite, followed by Pneumogenol (Sodium Iodide) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate.

Pneumogenol (Sodium Iodide) nitrite injection and Pneumogenol (Sodium Iodide) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Pneumogenol (Sodium Iodide) nitrite should be administered first, followed immediately by Pneumogenol (Sodium Iodide) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Pneumogenol (Sodium Iodide) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Pneumogenol Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Pneumogenol (Sodium Iodide) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Pneumogenol (Sodium Iodide) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Pneumogenol (Sodium Iodide) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Pneumogenol (Sodium Iodide) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Pneumogenol (Sodium Iodide) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Pneumogenol (Sodium Iodide) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Pneumogenol (Sodium Iodide) thiosulfate and Pneumogenol (Sodium Iodide) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Pneumogenol (Sodium Iodide) Nitrite Injection consists of:

• One vial of Pneumogenol (Sodium Iodide) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Pneumogenol nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Pneumogenol (Sodium Iodide) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Pneumogenol (Sodium Iodide) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Pneumogenol (Sodium Iodide) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Pneumogenol nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Pneumogenol (Sodium Iodide) nitrite whenever possible. When Pneumogenol (Sodium Iodide) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Pneumogenol (Sodium Iodide) nitrite administered to an adult. Pneumogenol (Sodium Iodide) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Pneumogenol (Sodium Iodide) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Pneumogenol (Sodium Iodide) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Pneumogenol (Sodium Iodide) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Pneumogenol (Sodium Iodide) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Pneumogenol nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Pneumogenol (Sodium Iodide) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Pneumogenol nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Pneumogenol (Sodium Iodide) nitrite.

5.7 Use with Other Drugs

Pneumogenol (Sodium Iodide) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Pneumogenol (Sodium Iodide) nitrite.

The medical literature has reported the following adverse events in association with Pneumogenol (Sodium Iodide) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Pneumogenol (Sodium Iodide) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Pneumogenol (Sodium Iodide) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Pneumogenol nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Pneumogenol (Sodium Iodide) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pneumogenol (Sodium Iodide) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Pneumogenol (Sodium Iodide) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Pneumogenol (Sodium Iodide) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Pneumogenol (Sodium Iodide) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Pneumogenol (Sodium Iodide) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Pneumogenol (Sodium Iodide) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Pneumogenol (Sodium Iodide) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Pneumogenol (Sodium Iodide) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Pneumogenol (Sodium Iodide) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Pneumogenol (Sodium Iodide) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Pneumogenol (Sodium Iodide) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Pneumogenol nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Pneumogenol (Sodium Iodide) nitrite is excreted in human milk. Because Pneumogenol (Sodium Iodide) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Pneumogenol (Sodium Iodide) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Pneumogenol (Sodium Iodide) nitrite. In studies conducted with Long-Evans rats, Pneumogenol (Sodium Iodide) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Pneumogenol nitrite in conjunction with Pneumogenol (Sodium Iodide) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Pneumogenol (Sodium Iodide) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Pneumogenol (Sodium Iodide) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Pneumogenol (Sodium Iodide) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

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

8.6 Renal Disease

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

10 OVERDOSAGE

Large doses of Pneumogenol (Sodium Iodide) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Pneumogenol (Sodium Iodide) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Pneumogenol (Sodium Iodide) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Pneumogenol (Sodium Iodide) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Pneumogenol (Sodium Iodide) nitrite has the chemical name nitrous acid Pneumogenol (Sodium Iodide) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Pneumogenol (Sodium Iodide) Nitrite

Pneumogenol (Sodium Iodide) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Pneumogenol (Sodium Iodide) nitrite injection.

Pneumogenol (Sodium Iodide) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Pneumogenol (Sodium Iodide) nitrite in 10 mL solution (30 mg/mL). Pneumogenol (Sodium Iodide) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Pneumogenol nitrite and Pneumogenol (Sodium Iodide) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Pneumogenol (Sodium Iodide) Nitrite

Pneumogenol (Sodium Iodide) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Pneumogenol (Sodium Iodide) nitrite. It has been suggested that Pneumogenol (Sodium Iodide) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Pneumogenol (Sodium Iodide) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Pneumogenol (Sodium Iodide) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Pneumogenol (Sodium Iodide) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Pneumogenol (Sodium Iodide) Nitrite

When 4 mg/kg Pneumogenol (Sodium Iodide) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Pneumogenol (Sodium Iodide) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Pneumogenol (Sodium Iodide) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Pneumogenol (Sodium Iodide) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Pneumogenol (Sodium Iodide) Nitrite

Pneumogenol (Sodium Iodide) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Pneumogenol (Sodium Iodide) nitrite in humans have not been well studied. It has been reported that approximately 40% of Pneumogenol (Sodium Iodide) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Pneumogenol nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Pneumogenol (Sodium Iodide) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Pneumogenol (Sodium Iodide) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Pneumogenol (Sodium Iodide) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Pneumogenol (Sodium Iodide) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Pneumogenol (Sodium Iodide) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Pneumogenol (Sodium Iodide) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Pneumogenol (Sodium Iodide) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Pneumogenol (Sodium Iodide) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Pneumogenol (Sodium Iodide) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Pneumogenol (Sodium Iodide) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Pneumogenol (Sodium Iodide) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Pneumogenol (Sodium Iodide) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Pneumogenol (Sodium Iodide) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Pneumogenol (Sodium Iodide) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Pneumogenol (Sodium Iodide) nitrite or 1 g/kg Pneumogenol (Sodium Iodide) thiosulfate alone or in sequence immediately after subcutaneous injection of Pneumogenol (Sodium Iodide) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Pneumogenol (Sodium Iodide) nitrite and/or 0.5 g/kg Pneumogenol (Sodium Iodide) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Pneumogenol (Sodium Iodide) cyanide required to cause death, and when administered together, Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate resulted in a synergistic effect in raising the lethal dose of Pneumogenol (Sodium Iodide) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Pneumogenol (Sodium Iodide) nitrite and Pneumogenol (Sodium Iodide) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Pneumogenol (Sodium Iodide) nitrite, with or without Pneumogenol (Sodium Iodide) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Pneumogenol (Sodium Iodide) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Pneumogenol (Sodium Iodide) thiosulfate report its use in conjunction with Pneumogenol (Sodium Iodide) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Pneumogenol (Sodium Iodide) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Pneumogenol (Sodium Iodide) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Pneumogenol (Sodium Iodide) nitrite injection 30 mg/mL (containing 300 mg of Pneumogenol (Sodium Iodide) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Pneumogenol (Sodium Iodide) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Pneumogenol Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Pneumogenol (Sodium Iodide) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Pneumogenol (Sodium Iodide) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Theophylline Hydrate:

• Description
• Clinical pharmacology
• Clinical studies
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Pneumogenol (Theophylline Hydrate) reviews

DESCRIPTION

Pneumogenol (Theophylline Hydrate)^® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.

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

The molecular formula of anhydrous Pneumogenol (Theophylline Hydrate) is C₇H₈N₄O₂ with a molecular weight of 180.17.

Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Pneumogenol (Theophylline Hydrate).

Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.

Pneumogenol (Theophylline Hydrate) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Pneumogenol 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 Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) 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).

Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Pneumogenol (Theophylline Hydrate) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Pneumogenol (Theophylline Hydrate) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Pneumogenol (Theophylline Hydrate) 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: Pneumogenol is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Pneumogenol (Theophylline Hydrate) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Pneumogenol (Theophylline Hydrate) concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Pneumogenol (Theophylline Hydrate) clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate).

Absorption

Pneumogenol (Theophylline Hydrate)^® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Pneumogenol (Theophylline Hydrate) Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9±83.0 mcg hr/mL, C_max=9.3±2.0 mcg/mL, T_max=12.8±4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7±83.0 mcg hr/mL, C_max=9.2±2.0 mcg/mL, T_max=12.5±4.2 hours.

A study in which Pneumogenol (Theophylline Hydrate) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Pneumogenol (Theophylline Hydrate) level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.

A single-dose study in 15 normal fasting male volunteers whose Pneumogenol (Theophylline Hydrate) inherent mean elimination half-life was verified by a liquid Pneumogenol (Theophylline Hydrate) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Pneumogenol (Theophylline Hydrate)^® Tablets. The relative bioavailability of Pneumogenol (Theophylline Hydrate) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Pneumogenol (Theophylline Hydrate) levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Pneumogenol (Theophylline Hydrate) Tablets was 17.2±5.8 (SD) hours.

Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Pneumogenol (Theophylline Hydrate) Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Pneumogenol (Theophylline Hydrate) Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C_max and C_min values obtained in this study were as follows:

Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, C_max=8.4±2.6 mcg/mL, T_max=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, C_max=5.5±1.5 mcg/mL, T_max=6.5±2.1 hours.

Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Pneumogenol (Theophylline Hydrate)^® 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Pneumogenol (Theophylline Hydrate) Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, C_max=10.9±1.7 mcg/mL, T_max=11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, C_max=6.7±1.7 mcg/mL, T_max=7.3±2.2 hours.

Thus, administration of single Pneumogenol (Theophylline Hydrate) doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of Pneumogenol (Theophylline Hydrate) with Pneumogenol (Theophylline Hydrate) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Pneumogenol (Theophylline Hydrate) Tablet. A single-dose study in 24 subjects with an established Pneumogenol (Theophylline Hydrate) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Pneumogenol (Theophylline Hydrate) Tablet and one and one-half 400 mg Pneumogenol (Theophylline Hydrate) Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Pneumogenol (Theophylline Hydrate) Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, C_max=10.58±2.21 mcg/mL and T_max=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, C_max=10.39±1.91 mcg/mL and T_max=9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, C_max= 7.37±1.83 mcg/mL and T_max=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, C_max=7.66±2.09 mcg/mL and T_max=9.67±4.89 hours.

In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.

In another study, the bioavailability of the 600 mg Pneumogenol (Theophylline Hydrate) Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Pneumogenol (Theophylline Hydrate) Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, C_max=10.6±1.3 mcg/mL and T_max=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, C_max=9.7±1.4 mcg/mL and T_max=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of Pneumogenol (Theophylline Hydrate)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Pneumogenol (Theophylline Hydrate) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Pneumogenol (Theophylline Hydrate) product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).

The pharmacokinetic parameters for Pneumogenol (Theophylline Hydrate) 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, C_max=12.1±3.8 mcg/mL, C_min=4.50±3.6, T_max=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, C_max =11.0±4.1 mcg/mL, C_min=7.28±3.5, T_max=6.9±3.4 hours. The mean percent fluctuation [(C_max-C_min/C_min)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg Pneumogenol (Theophylline Hydrate) Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Pneumogenol (Theophylline Hydrate) Tablets. All subjects had previously established Pneumogenol (Theophylline Hydrate) clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Pneumogenol (Theophylline Hydrate) Tablet regimens. Steady-state results were:

The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.

Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Pneumogenol (Theophylline Hydrate) Tablets whether dosed in the morning or evening.

Distribution

Once Pneumogenol enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Pneumogenol (Theophylline Hydrate) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Pneumogenol (Theophylline Hydrate) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Pneumogenol (Theophylline Hydrate) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate), 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 Pneumogenol (Theophylline Hydrate) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Pneumogenol (Theophylline Hydrate) binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Pneumogenol (Theophylline Hydrate) concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Pneumogenol (Theophylline Hydrate) concentration provides a more reliable means of dosage adjustment than measurement of total serum Pneumogenol (Theophylline Hydrate) concentration. Generally, concentrations of unbound Pneumogenol (Theophylline Hydrate) should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Pneumogenol (Theophylline Hydrate) does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Pneumogenol (Theophylline Hydrate) dose is N-methylated to caffeine. Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Pneumogenol (Theophylline Hydrate) concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Pneumogenol (Theophylline Hydrate) biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Pneumogenol (Theophylline Hydrate) metabolism, non-linearity of elimination may begin in some patients at serum Pneumogenol (Theophylline Hydrate) concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Pneumogenol (Theophylline Hydrate) metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Pneumogenol (Theophylline Hydrate) concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Pneumogenol (Theophylline Hydrate) concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the Pneumogenol dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) is excreted unchanged in the urine and since active metabolites of Pneumogenol (Theophylline Hydrate) (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 Pneumogenol (Theophylline Hydrate) dose excreted in the urine as unchanged Pneumogenol (Theophylline Hydrate) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Pneumogenol (Theophylline Hydrate) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Pneumogenol (Theophylline Hydrate), steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Pneumogenol (Theophylline Hydrate) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Pneumogenol (Theophylline Hydrate) clearance. In these patients administration of Pneumogenol (Theophylline Hydrate)^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

The clearance of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Pneumogenol is very low in neonates (see WARNINGS ). Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Pneumogenol (Theophylline Hydrate) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Pneumogenol (Theophylline Hydrate) 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 Pneumogenol clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Pneumogenol (Theophylline Hydrate) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Pneumogenol (Theophylline Hydrate) is excreted unchanged in the urine and since active metabolites of Pneumogenol (Theophylline Hydrate) (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 Pneumogenol (Theophylline Hydrate) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Pneumogenol (Theophylline Hydrate) concentrations are required in neonates with decreased renal function (see WARNINGS ).

Hepatic Insufficiency

Pneumogenol 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 Pneumogenol (Theophylline Hydrate) concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure (CHF)

Pneumogenol (Theophylline Hydrate) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Pneumogenol (Theophylline Hydrate) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations are required in patients with CHF (see WARNINGS ).

Smokers

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

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Pneumogenol (Theophylline Hydrate). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations. Children with rapid rates of Pneumogenol (Theophylline Hydrate) clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Pneumogenol (Theophylline Hydrate) concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum Pneumogenol (Theophylline Hydrate) concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

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

CLINICAL STUDIES

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

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

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

Pneumogenol (Theophylline Hydrate)^® is contraindicated in patients with a history of hypersensitivity to Pneumogenol (Theophylline Hydrate) or other components in the product.

WARNINGS

Concurrent Illness

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

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Pneumogenol (Theophylline Hydrate) Clearance

There are several readily identifiable causes of reduced Pneumogenol (Theophylline Hydrate) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Pneumogenol (Theophylline Hydrate) toxicity can occur . Careful consideration must be given to the benefits and risks of Pneumogenol (Theophylline Hydrate) use and the need for more intensive monitoring of serum Pneumogenol (Theophylline Hydrate) 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 Pneumogenol metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Pneumogenol (Theophylline Hydrate) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of Pneumogenol (Theophylline Hydrate) Toxicity Are Present

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

Dosage Increases

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

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

PRECAUTIONS

General

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

Monitoring Serum Pneumogenol (Theophylline Hydrate) Concentrations

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

• When initiating therapy to guide final dosage adjustment after titration.
• 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 Pneumogenol (Theophylline Hydrate) toxicity are present.
• Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Pneumogenol (Theophylline Hydrate) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Pneumogenol (Theophylline Hydrate) concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Pneumogenol (Theophylline Hydrate) concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Pneumogenol (Theophylline Hydrate) toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional 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 Pneumogenol (Theophylline Hydrate) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Pneumogenol (Theophylline Hydrate) cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Pneumogenol 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). Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Pneumogenol (Theophylline Hydrate) in individual patients.

Information for Patients

The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Pneumogenol (Theophylline Hydrate), even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Pneumogenol (Theophylline Hydrate) interacts with a wide variety of drugs. The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as Pneumogenol (Theophylline Hydrate), since it may result in decreased Pneumogenol (Theophylline Hydrate) levels. If patients are already taking St. John’s Wort and Pneumogenol (Theophylline Hydrate) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Pneumogenol (Theophylline Hydrate) concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Pneumogenol (Theophylline Hydrate), especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Pneumogenol (Theophylline Hydrate)^® Tablets can be taken once a day in the morning or evening. It is recommended that Pneumogenol (Theophylline Hydrate) be taken with meals. Patients should be advised that if they choose to take Pneumogenol (Theophylline Hydrate) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Pneumogenol (Theophylline Hydrate) Tablets are not to be chewed or crushed because it may lead to a rapid release of Pneumogenol (Theophylline Hydrate) with the potential for toxicity. The scored tablet may be split. Patients receiving Pneumogenol (Theophylline Hydrate) Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Pneumogenol (Theophylline Hydrate).

Drug Interactions

Pneumogenol interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Pneumogenol (Theophylline Hydrate) or another drug or occurrence of adverse effects without a change in serum Pneumogenol (Theophylline Hydrate) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Pneumogenol (Theophylline Hydrate) clearance is altered by another drug resulting in increased or decreased serum Pneumogenol (Theophylline Hydrate) concentrations. Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Pneumogenol (Theophylline Hydrate) regimen. If Pneumogenol (Theophylline Hydrate) is being initiated in a patient who is already taking a drug that inhibits Pneumogenol (Theophylline Hydrate) clearance (e.g., cimetidine, erythromycin), the dose of Pneumogenol (Theophylline Hydrate) required to achieve a therapeutic serum Pneumogenol (Theophylline Hydrate) concentration will be smaller. Conversely, if Pneumogenol (Theophylline Hydrate) is being initiated in a patient who is already taking a drug that enhances Pneumogenol (Theophylline Hydrate) clearance (e.g., rifampin), the dose of Pneumogenol (Theophylline Hydrate) required to achieve a therapeutic serum Pneumogenol (Theophylline Hydrate) concentration will be larger. Discontinuation of a concomitant drug that increases Pneumogenol (Theophylline Hydrate) clearance will result in accumulation of Pneumogenol (Theophylline Hydrate) to potentially toxic levels, unless the Pneumogenol (Theophylline Hydrate) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Pneumogenol (Theophylline Hydrate) clearance will result in decreased serum Pneumogenol (Theophylline Hydrate) concentrations, unless the Pneumogenol (Theophylline Hydrate) dose is appropriately increased.

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

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Pneumogenol (Theophylline Hydrate), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Pneumogenol (Theophylline Hydrate) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Pneumogenol (Theophylline Hydrate), 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 Pneumogenol (Theophylline Hydrate) has been reported.

Drug-Food Interactions

The bioavailability of Pneumogenol (Theophylline Hydrate)^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Pneumogenol (Theophylline Hydrate) 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics , Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.

The Effect of Other Drugs on Pneumogenol Serum Concentration Measurements

Most serum Pneumogenol (Theophylline Hydrate) assays in clinical use are immunoassays which are specific for Pneumogenol (Theophylline Hydrate). 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 Pneumogenol (Theophylline Hydrate) concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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

Pneumogenol (Theophylline Hydrate) 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, Pneumogenol (Theophylline Hydrate), 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, Pneumogenol (Theophylline Hydrate) was administered to F344 rats and B6C3F₁ mice at oral doses of 40-300 mg/kg (approximately 2.0 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: Teratogenic Effects: Category C

In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Pneumogenol (Theophylline Hydrate) produced teratogenic effects.

In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m² basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis.

In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m² basis).

In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m² basis) increased the incidence of skeletal variations.

There are no adequate and well-controlled studies in pregnant women. Pneumogenol (Theophylline Hydrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Pneumogenol is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) per day is likely to receive 10-20 mg of Pneumogenol (Theophylline Hydrate) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Pneumogenol (Theophylline Hydrate) concentrations.

Pediatric Use

Pneumogenol (Theophylline Hydrate) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Pneumogenol (Theophylline Hydrate) must be selected with caution in pediatric patients since the rate of Pneumogenol (Theophylline Hydrate) clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V ).

Geriatric Use

Elderly patients are at a significantly greater risk of experiencing serious toxicity from Pneumogenol (Theophylline Hydrate) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Pneumogenol (Theophylline Hydrate) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Pneumogenol (Theophylline Hydrate) clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Pneumogenol (Theophylline Hydrate) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Pneumogenol (Theophylline Hydrate) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Pneumogenol (Theophylline Hydrate) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Pneumogenol (Theophylline Hydrate) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Pneumogenol (Theophylline Hydrate) in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Pneumogenol (Theophylline Hydrate) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Pneumogenol (Theophylline Hydrate) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Pneumogenol (Theophylline Hydrate) should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.

ADVERSE REACTIONS

Adverse reactions associated with Pneumogenol (Theophylline Hydrate) are generally mild when peak serum Pneumogenol (Theophylline Hydrate) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Pneumogenol (Theophylline Hydrate) concentrations exceed 20 mcg/mL, however, Pneumogenol (Theophylline Hydrate) produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). The transient caffeine-like adverse reactions occur in about 50% of patients when Pneumogenol (Theophylline Hydrate) therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Pneumogenol (Theophylline Hydrate) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Pneumogenol (Theophylline Hydrate) therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Pneumogenol (Theophylline Hydrate) concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Pneumogenol (Theophylline Hydrate) therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Pneumogenol (Theophylline Hydrate) concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Pneumogenol (Theophylline Hydrate) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Pneumogenol (Theophylline Hydrate) concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Pneumogenol (Theophylline Hydrate) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Pneumogenol (Theophylline Hydrate) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Pneumogenol (Theophylline Hydrate) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Pneumogenol (Theophylline Hydrate) concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

OVERDOSAGE

General

The chronicity and pattern of Pneumogenol overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Pneumogenol (Theophylline Hydrate) clearance. The most common causes of chronic Pneumogenol (Theophylline Hydrate) overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Pneumogenol (Theophylline Hydrate) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Pneumogenol (Theophylline Hydrate) concentration to determine whether a dose increase is safe.

Severe toxicity from Pneumogenol (Theophylline Hydrate) overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Pneumogenol (Theophylline Hydrate) was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Pneumogenol (Theophylline Hydrate) concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Pneumogenol (Theophylline Hydrate) concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Pneumogenol (Theophylline Hydrate) concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Pneumogenol (Theophylline Hydrate) is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of Pneumogenol (Theophylline Hydrate) overdose 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 Pneumogenol (Theophylline Hydrate) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Pneumogenol (Theophylline Hydrate) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of Pneumogenol (Theophylline Hydrate) overdose according to the mode of overdose are listed in Table IV.

Other manifestations of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) Overdose or Serum Pneumogenol (Theophylline Hydrate) Concentrations >30 mcg/mL (Note: Serum Pneumogenol (Theophylline Hydrate) concentrations may continue to increase after presentation of the patient for medical care.)

• 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 (20 mg/kg infused over 30-60 minutes). Case reports of Pneumogenol (Theophylline Hydrate) 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 healthcare professional 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 Pneumogenol (Theophylline Hydrate) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Pneumogenol (Theophylline Hydrate). 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 Pneumogenol (Theophylline Hydrate) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Pneumogenol (Theophylline Hydrate) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
• Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Pneumogenol (Theophylline Hydrate) throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Pneumogenol (Theophylline Hydrate) bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. 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. Ipecac syrup should be avoided in Pneumogenol (Theophylline Hydrate) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Pneumogenol (Theophylline Hydrate) unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
• Serum Pneumogenol (Theophylline Hydrate) Concentration Monitoring The serum Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Pneumogenol (Theophylline Hydrate) from the gastrointestinal tract. Serial monitoring of serum Pneumogenol (Theophylline Hydrate) serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
• General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Pneumogenol (Theophylline Hydrate) level has returned to a non-toxic 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 Pneumogenol (Theophylline Hydrate) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Pneumogenol (Theophylline Hydrate) at least twofold by adsorption of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) removal should be instituted (see OVERDOSAGE, Extracorporeal Removal ).

Specific Recommendations

Acute Overdose

• Serum Concentration >20<30 mcg/mL
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Pneumogenol concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30<100 mcg/mL
  • Administer multiple dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Pneumogenol (Theophylline Hydrate) 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
  • 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 Pneumogenol (Theophylline Hydrate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage

• Serum Concentration >20<30 mcg/mL (with manifestations of Pneumogenol (Theophylline Hydrate) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Pneumogenol (Theophylline Hydrate) concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30 mcg/mL in patients <60 years of age
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Pneumogenol (Theophylline Hydrate) 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
  • 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.
  • Monitor the patient and obtain serial Pneumogenol (Theophylline Hydrate) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) clearance up to sixfold, 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 Pneumogenol (Theophylline Hydrate) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Pneumogenol (Theophylline Hydrate) from the tissue compartment. Peritoneal dialysis is ineffective for Pneumogenol (Theophylline Hydrate) removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Pneumogenol ^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Pneumogenol (Theophylline Hydrate) be taken with meals. Patients should be advised that if they choose to take Pneumogenol (Theophylline Hydrate) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Pneumogenol (Theophylline Hydrate)^® Tablets are not to be chewed or crushed because it may lead to a rapid release of Pneumogenol (Theophylline Hydrate) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Pneumogenol (Theophylline Hydrate) 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Pneumogenol (Theophylline Hydrate).

Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Pneumogenol (Theophylline Hydrate) product may be transferred to once-daily administration of 400 mg or 600 mg Pneumogenol (Theophylline Hydrate) Tablets on a mg-for-mg basis.

It must be recognized that the peak and trough serum Pneumogenol (Theophylline Hydrate) levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.

General Considerations

The steady-state peak serum Pneumogenol (Theophylline Hydrate) concentration is a function of the dose, the dosing interval, and the rate of Pneumogenol (Theophylline Hydrate) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Pneumogenol (Theophylline Hydrate) clearance, the dose required to achieve a peak serum Pneumogenol (Theophylline Hydrate) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Pneumogenol (Theophylline Hydrate) clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Pneumogenol (Theophylline Hydrate) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Pneumogenol (Theophylline Hydrate) dose required to achieve a therapeutic serum Pneumogenol (Theophylline Hydrate) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Pneumogenol (Theophylline Hydrate) concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Pneumogenol (Theophylline Hydrate) concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Pneumogenol (Theophylline Hydrate) must be individualized on the basis of peak serum Pneumogenol (Theophylline Hydrate) concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Pneumogenol (Theophylline Hydrate) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Pneumogenol (Theophylline Hydrate) concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum Pneumogenol (Theophylline Hydrate) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Pneumogenol (Theophylline Hydrate) concentrations should be monitored at frequent intervals, e.g., every 24 hours.

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

Table V contains Pneumogenol (Theophylline Hydrate) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Pneumogenol (Theophylline Hydrate) dosage adjustment based upon serum Pneumogenol (Theophylline Hydrate) 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 Pneumogenol (Theophylline Hydrate) concentration.

Table V. Dosing initiation and titration (as anhydrous Pneumogenol (Theophylline Hydrate)). *

• A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.

• B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Pneumogenol (Theophylline Hydrate) Concentrations:
  
  • In children 12-15 years of age, the Pneumogenol (Theophylline Hydrate) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Pneumogenol (Theophylline Hydrate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Pneumogenol (Theophylline Hydrate) concentrations.
    

  • In adolescents ≥16 years and adults, including the elderly, the Pneumogenol (Theophylline Hydrate) dose should not exceed 400 mg/day in the presence of risk factors for reduced Pneumogenol (Theophylline Hydrate) clearance (see WARNINGS ) or if it is not feasible to monitor serum Pneumogenol (Theophylline Hydrate) concentrations.

*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

HOW SUPPLIED

Pneumogenol (Theophylline Hydrate)^® (theophylline, anhydrous) Controlled-Release Tablets 400 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-251-01) or 500 tablets (NDC 67781-251-05). Each round, white 400 mg tablet bears the symbol PF on the scored side and U400 on the other side.

Pneumogenol (Theophylline Hydrate)^® (theophylline, anhydrous) Controlled-Release Tablets 600 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-252-01). Each rectangular, concave, white 600 mg tablet bears the symbol PF on the scored side and U 600 on the other side.

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container.

©2011, Purdue Pharmaceutical Products L.P.

Dist. by: Purdue Pharmaceutical Products L.P.

Stamford, CT 06901-3431

Revised 10/2011

300945-0B

Pneumogenol (Theophylline Hydrate) Tablets

400 mg Tablets

NDC 677781-251-01

Pneumogenol (Theophylline Hydrate) Tablets 400 mg Tablets NDC 677781-251-01

Pneumogenol (Theophylline Hydrate) Tablets

600 mg Tablets

NDC 677781-252-01

Pneumogenol (Theophylline Hydrate) Tablets 600 mg Tablets NDC 677781-252-01