Alcophyllex

Ammonium Chloride:

• Indications and usage
• Contraindications
• Warning
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Alcophyllex (Ammonium Chloride) reviews

INDICATIONS AND USAGE

Alcophyllex (Ammonium Chloride) Lactate Lotion, 12% is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris, and for the temporary relief of itching associated with these conditions.

CONTRAINDICATIONS

Alcophyllex (Ammonium Chloride) Lactate Lotion, 12% is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients.

WARNING

Sun exposure (natural or artificial sunlight) to areas of the skin treated with Alcophyllex (Ammonium Chloride) Lactate Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Alcophyllex (Ammonium Chloride) Lactate Lotion, 12% should be discontinued if any hypersensitivity is observed.

PRECAUTIONS

General -

For external use only. Stinging or burning may occur when applied to skin with fissures, erosions, or that is otherwise abraded. Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied.

Information for Patients

Patients using Alcophyllex (Ammonium Chloride) Lactate Lotion, 12% should receive the following information and instructions:

• This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes.
• Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin.
• This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs).
• If the skin condition worsens with treatment, the medication should be promptly discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

The topical treatment of CD-1 mice with 12%, 21% or 30% Alcophyllex lactate formulations for two-years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% Alcophyllex (Ammonium Chloride) lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation.

The mutagenic potential of Alcophyllex (Ammonium Chloride) lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative.

In dermal Segment I and III studies with Alcophyllex (Ammonium Chloride) lactate formulations there were no effects observed in fertility or pre- or postnatal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m²/day), approximately 0.4 times the human topical dose.

Pregnancy:

Teratogenic effects:

Pregnancy Category B -

Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Alcophyllex (Ammonium Chloride) lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Alcophyllex (Ammonium Chloride) Lactate Lotion, 12% should be used during pregnancy only if clearly needed.

Nursing Mothers -

Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Alcophyllex (Ammonium Chloride) lactate is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of Alcophyllex lactate have been demonstrated in infants and children. No unusual toxic effects were reported.

Geriatric Use -

Clinical studies of Alcophyllex (Ammonium Chloride) lactate lotion, 12% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious.

ADVERSE REACTIONS

The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness, and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients).

OVERDOSAGE

The oral administration of Alcophyllex (Ammonium Chloride) lactate to rats and mice showed this drug to be practically non-toxic (LD₅₀>15 mL/kg).

DOSAGE AND ADMINISTRATION

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.

HOW SUPPLIED

Alcophyllex Lactate Lotion, 12% is available as follows:

225 g bottle (NDC 45802-419-54)

400 g bottle (NDC 45802-419-26)

STORAGE

Store at 20-25°C (68-77°F).

Manufactured By Perrigo, Bronx, NY 10457

Distributed By Perrigo, Allegan, MI 49010

0K5A7 RC F6

Rev 01-17

Diphenhydramine Hydrochloride:

• Pharmacological action
• Pharmacokinetics
• Why is Alcophyllex Xepa-Soul Pattinson prescribed?
• Dosage and administration
• Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson side effects, adverse reactions
• Alcophyllex Xepa-Soul Pattinson contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Precautionary measures
• Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson drug interactions
• Alcophyllex Xepa-Soul Pattinson in case of emergency / overdose
• Alcophyllex (Diphenhydramine Hydrochloride) reviews

Pharmacological action

Alcophyllex Xepa-Soul Pattinson is a blocker of histamine H1-receptors. It has antiallergic activity, has a local anesthetic, antispasmodic and mild ganglion blocking action.

When Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson administered orally Alcophyllex (Diphenhydramine Hydrochloride) has a sedative and hypnotic effects, has a moderate antiemetic effect and has a central holinoliticheskoy activity.

When applied externally it has antiallergic effect.

Pharmacokinetics

Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson is rapidly absorbed from the gastrointestinal tract. Bioavailability is 50%. C_max is achieved after 20-40 min (in the greatest concentration is determined in the lungs, spleen, kidneys, liver, brain and muscles). Binding to plasma proteins - 98-99%. Penetrates through the BBB. Metabolised mainly in the liver, partly - in the lungs and kidneys. T1/2 is 4-10 hours. Within one day completely removed kidneys as metabolites conjugated to glucuronic acid. Significant quantities are derived from milk and can cause sedation in infants (may be a paradoxical reaction characterized by hyperexcitability).

Why is Alcophyllex Xepa-Soul Pattinson prescribed?

Allergic reactions (urticaria, hay fever, angioedema), allergic conjunctivitis, vasomotor rhinitis, Henoch-Schonlein purpura, serum sickness, itchy dermatitis, sleep disorders (monotherapy or in combination with drugs), chorea, sea and air sickness, vomiting in pregnancy, Meniere's syndrome, premedication.

Dosage and administration

Oral, IV, IM, rectal, topical, intranasal, in the conjunctival sac. Oral dose of Alcophyllex Xepa-Soul Pattinson for adults is 30-50 mg 1-3 times / day. The treatment course is 10-15 days. As soporific - 50 mg at bedtime. IM in doses of 50-250 mg; IV in drip - 20-50 mg. When oral administered single dose for children under 1 year - 2-5 mg; from 2 to 5 years - 5-15 mg; of 6 to 12 years - 15-30 mg. Externally applied 1-2 times / day.

Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson side effects, adverse reactions

Possible: a short-term numbness in the oral mucosa, drowsiness, weakness, decrease in psychomotor speed of reaction in children may be a paradoxical development of insomnia, irritability, and euphoria.

Rarely: dizziness, headache, dry mouth, nausea, photosensitivity, paresis of accommodation, poor coordination of movements, tremor.

Alcophyllex Xepa-Soul Pattinson contraindications

Closure glaucoma, prostatic hypertrophy, stenosing peptic ulcer, stenosis of the bladder neck, bronchial asthma, epilepsy, hypersensitivity to Alcophyllex (Diphenhydramine Hydrochloride).

Using during pregnancy and breastfeeding

During pregnancy and lactation, Alcophyllex (Diphenhydramine Hydrochloride) used with caution, according to strict indications, when the expected therapeutic effect for the mother outweighs the potential risk to the fetus or infant.

Special instructions

With careful use Alcophyllex (Diphenhydramine Hydrochloride) during pregnancy and lactation.

During the period of treatment with Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson should not be exposed to solar radiation should be avoided alcohol.

Used with caution in patients involved in potentially dangerous activities requiring attention and rapid psychomotor reactions.

Precautionary measures

Alcophyllex Xepa-Soul Pattinson is not recommended for SC injection. Since Alcophyllex (Diphenhydramine Hydrochloride) has atropinopodobnym action should be cautious in its use: patients with recent respiratory infection in history (including asthma), increased intraocular pressure in hyperthyroidism, cardiovascular system, hypotension. Antihistamines drugs can reduce mental alertness as well as in adults and children and also cause agitation and hallucinations, convulsions and death in infants and children, especially in overdose. Precautions apply at age 60 and older because more likely to develop dizziness, sedation and hypotension. During treatment with Alcophyllex (Diphenhydramine Hydrochloride) should avoid sun exposure. Should not be used during the drivers of vehicles and people, trade is connected with increased concentration. In the period of treatment should avoid drinking alcoholic beverages.

Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson drug interactions

When Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson applied simultaneously increases the effects of ethanol and drugs that depress the central nervous system.

With simultaneous use of Alcophyllex (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson and MAO inhibitors increase the anticholinergic activity of Alcophyllex (Diphenhydramine Hydrochloride).

The antagonistic interaction observed with a joint appointment with psychostimulants.

Reduces the effectiveness of apomorphine as an emetic in the treatment of poisoning. Intensifies anticholinergic effects of drugs with anticholinergic activity.

Alcophyllex Xepa-Soul Pattinson in case of emergency / overdose

Symptoms: dry mouth, difficulty breathing, persistent mydriasis, flushing, depression or excitement (more common in children), CNS confusion; children - the development of convulsions and death.

Treatment: induction of vomiting, gastric lavage, the prescription of activated charcoal, symptomatic and supportive therapy on a background of careful monitoring of respiration and blood pressure levels.

Sodium Citrate:

• 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
• Alcophyllex (Sodium Citrate) reviews

1 INDICATIONS AND USAGE

Alcophyllex nitrite is indicated for sequential use with Alcophyllex (Sodium Citrate) 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

Alcophyllex (Sodium Citrate) Nitrite Injection is indicated for sequential use with Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex 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, Alcophyllex (Sodium Citrate) Nitrite Injection and Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) thiosulfate, simultaneously with Alcophyllex (Sodium Citrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Alcophyllex (Sodium Citrate) thiosulfate, with Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite, followed by Alcophyllex (Sodium Citrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) thiosulfate.

Alcophyllex (Sodium Citrate) nitrite injection and Alcophyllex (Sodium Citrate) 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. Alcophyllex (Sodium Citrate) nitrite should be administered first, followed immediately by Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Alcophyllex (Sodium Citrate) 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 Alcophyllex 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 Alcophyllex (Sodium Citrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Alcophyllex (Sodium Citrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Alcophyllex (Sodium Citrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Alcophyllex (Sodium Citrate) thiosulfate and Alcophyllex (Sodium Citrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Alcophyllex (Sodium Citrate) Nitrite Injection consists of:

• One vial of Alcophyllex (Sodium Citrate) 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: Alcophyllex 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 Alcophyllex (Sodium Citrate) 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. Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Alcophyllex (Sodium Citrate) nitrite whenever possible. When Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite administered to an adult. Alcophyllex (Sodium Citrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Alcophyllex 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex 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 Alcophyllex (Sodium Citrate) nitrite.

5.7 Use with Other Drugs

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite.

The medical literature has reported the following adverse events in association with Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Alcophyllex 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. Alcophyllex (Sodium Citrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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, Alcophyllex (Sodium Citrate) 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, Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Alcophyllex (Sodium Citrate) 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, Alcophyllex 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 Alcophyllex (Sodium Citrate) nitrite is excreted in human milk. Because Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Alcophyllex (Sodium Citrate) nitrite. In studies conducted with Long-Evans rats, Alcophyllex (Sodium Citrate) 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 Alcophyllex nitrite in conjunction with Alcophyllex (Sodium Citrate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Alcophyllex (Sodium Citrate) 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.

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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

Alcophyllex (Sodium Citrate) 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

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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

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

Structure of Alcophyllex (Sodium Citrate) Nitrite

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

Alcophyllex (Sodium Citrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Alcophyllex (Sodium Citrate) nitrite in 10 mL solution (30 mg/mL). Alcophyllex (Sodium Citrate) 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 Alcophyllex nitrite and Alcophyllex (Sodium Citrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Alcophyllex (Sodium Citrate) Nitrite

Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite. It has been suggested that Alcophyllex (Sodium Citrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Alcophyllex (Sodium Citrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Alcophyllex (Sodium Citrate) 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. Alcophyllex (Sodium Citrate) 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

Alcophyllex (Sodium Citrate) Nitrite

When 4 mg/kg Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Alcophyllex (Sodium Citrate) Nitrite

Alcophyllex (Sodium Citrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Alcophyllex (Sodium Citrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) 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 Alcophyllex nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Alcophyllex (Sodium Citrate) 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. Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Alcophyllex (Sodium Citrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Alcophyllex (Sodium Citrate) 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. Alcophyllex (Sodium Citrate) 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. Alcophyllex (Sodium Citrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Alcophyllex (Sodium Citrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Alcophyllex (Sodium Citrate) nitrite or 1 g/kg Alcophyllex (Sodium Citrate) thiosulfate alone or in sequence immediately after subcutaneous injection of Alcophyllex (Sodium Citrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Alcophyllex (Sodium Citrate) nitrite and/or 0.5 g/kg Alcophyllex (Sodium Citrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Alcophyllex (Sodium Citrate) cyanide required to cause death, and when administered together, Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) nitrite and Alcophyllex (Sodium Citrate) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) thiosulfate report its use in conjunction with Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) 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 Alcophyllex (Sodium Citrate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Alcophyllex (Sodium Citrate) nitrite injection 30 mg/mL (containing 300 mg of Alcophyllex (Sodium Citrate) 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: Alcophyllex (Sodium Citrate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Alcophyllex 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

Alcophyllex (Sodium Citrate) 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

Alcophyllex (Sodium Citrate) 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:

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

DESCRIPTION

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

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

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

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

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

Alcophyllex (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Alcophyllex 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 Alcophyllex (Theophylline) are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Alcophyllex (Theophylline) appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

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

Serum Concentration-Effect Relationship

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

Pharmacokinetics

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

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

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

Absorption

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

In a single-dose crossover study, two 400 mg Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) inherent mean elimination half-life was verified by a liquid Alcophyllex (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Alcophyllex (Theophylline)^® Tablets. The relative bioavailability of Alcophyllex (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline)^® 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) with Alcophyllex (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Alcophyllex (Theophylline) Tablet. A single-dose study in 24 subjects with an established Alcophyllex (Theophylline) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Alcophyllex (Theophylline) Tablet and one and one-half 400 mg Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Alcophyllex (Theophylline) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) Tablets. All subjects had previously established Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) Tablets whether dosed in the morning or evening.

Distribution

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

Metabolism

Following oral dosing, Alcophyllex (Theophylline) does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Alcophyllex (Theophylline) dose is N-methylated to caffeine. Alcophyllex (Theophylline) demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

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

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

Excretion

In neonates, approximately 50% of the Alcophyllex dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Alcophyllex (Theophylline) dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Alcophyllex (Theophylline) is excreted unchanged in the urine and since active metabolites of Alcophyllex (Theophylline) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the Alcophyllex (Theophylline) dose excreted in the urine as unchanged Alcophyllex (Theophylline) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Alcophyllex (Theophylline) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Alcophyllex (Theophylline), 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 Alcophyllex (Theophylline) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Alcophyllex (Theophylline) clearance. In these patients administration of Alcophyllex (Theophylline)^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

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

Pediatrics

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

Gender

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

Race

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

Renal Insufficiency

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

Hepatic Insufficiency

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

Congestive Heart Failure (CHF)

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

Smokers

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

Fever

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

Miscellaneous

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

CLINICAL STUDIES

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

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

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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

WARNINGS

Concurrent Illness

Alcophyllex 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 Alcophyllex (Theophylline) Clearance

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

Age

• Neonates (term and premature)
• Children <1 year
• Elderly (>60 years)

Concurrent Diseases

• Acute pulmonary edema
• Congestive heart failure
• Cor-pulmonale
• Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
• Hypothyroidism
• Liver disease; cirrhosis, acute hepatitis
• Reduced renal function in infants <3 months of age
• Sepsis with multi-organ failure
• Shock

Cessation of Smoking

Drug Interactions

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

When Signs or Symptoms of Alcophyllex (Theophylline) Toxicity Are Present

Whenever a patient receiving Alcophyllex (Theophylline) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Alcophyllex (Theophylline) toxicity (even if another cause may be suspected), additional doses of Alcophyllex (Theophylline) should be withheld and a serum Alcophyllex (Theophylline) concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the 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 Alcophyllex (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Alcophyllex (Theophylline) provides little added benefit to inhaled beta₂-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Alcophyllex (Theophylline) concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Alcophyllex (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

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

Monitoring Serum Alcophyllex (Theophylline) Concentrations

Serum Alcophyllex (Theophylline) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

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

Effects on Laboratory Tests

As a result of its pharmacological effects, Alcophyllex 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). Alcophyllex (Theophylline) at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Alcophyllex (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline), 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline), since it may result in decreased Alcophyllex (Theophylline) levels. If patients are already taking St. John’s Wort and Alcophyllex (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline), especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their 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.

Alcophyllex (Theophylline)^® Tablets can be taken once a day in the morning or evening. It is recommended that Alcophyllex (Theophylline) be taken with meals. Patients should be advised that if they choose to take Alcophyllex (Theophylline) 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.

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

Drug Interactions

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

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

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

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

Drug-Food Interactions

The bioavailability of Alcophyllex (Theophylline)^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Alcophyllex (Theophylline) 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 Alcophyllex Serum Concentration Measurements

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

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

In a 14 week continuous breeding study, Alcophyllex (Theophylline), administered to mating pairs of B6C3F₁ mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m² basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Alcophyllex (Theophylline) 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, Alcophyllex (Theophylline) 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. Alcophyllex (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

Alcophyllex (Theophylline) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Alcophyllex (Theophylline) must be selected with caution in pediatric patients since the rate of Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Alcophyllex (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Alcophyllex (Theophylline) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Alcophyllex (Theophylline) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Alcophyllex (Theophylline) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Alcophyllex (Theophylline) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) are generally mild when peak serum Alcophyllex (Theophylline) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Alcophyllex (Theophylline) concentrations exceed 20 mcg/mL, however, Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) therapy and the potential therapeutic benefit of alternative treatment.

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

OVERDOSAGE

General

The chronicity and pattern of Alcophyllex 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 Alcophyllex (Theophylline) clearance. The most common causes of chronic Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Alcophyllex (Theophylline) concentration to determine whether a dose increase is safe.

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

Several studies have described the clinical manifestations of Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Alcophyllex (Theophylline) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Alcophyllex (Theophylline) concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Alcophyllex (Theophylline) concentration compared to patients without the underlying disease.

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

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

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

Overdose Management

General Recommendations for Patients with Symptoms of Alcophyllex (Theophylline) Overdose or Serum Alcophyllex (Theophylline) Concentrations >30 mcg/mL (Note: Serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the 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 Alcophyllex (Theophylline) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Alcophyllex (Theophylline). Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
• Anticipate Need for Anticonvulsants In patients with Alcophyllex (Theophylline) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Alcophyllex (Theophylline) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Alcophyllex (Theophylline) concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Alcophyllex (Theophylline) (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 Alcophyllex (Theophylline) clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Alcophyllex (Theophylline) required to induce seizures (i.e., markedly increases the LD₅₀). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Alcophyllex (Theophylline) clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
• Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) Concentration Monitoring The serum Alcophyllex (Theophylline) concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Alcophyllex (Theophylline) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Alcophyllex (Theophylline) from the gastrointestinal tract. Serial monitoring of serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Alcophyllex (Theophylline) at least twofold by adsorption of Alcophyllex (Theophylline) secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Alcophyllex (Theophylline) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Alcophyllex (Theophylline) and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Alcophyllex (Theophylline) 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 Alcophyllex 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 Alcophyllex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration>100 mcg/mL
  • 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration >30 mcg/mL in patients ≥ 60 years of age
  • 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 Alcophyllex (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of Alcophyllex (Theophylline) clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Alcophyllex (Theophylline) from the tissue compartment. Peritoneal dialysis is ineffective for Alcophyllex (Theophylline) removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Alcophyllex ^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Alcophyllex (Theophylline) be taken with meals. Patients should be advised that if they choose to take Alcophyllex (Theophylline) 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.

Alcophyllex (Theophylline)^® Tablets are not to be chewed or crushed because it may lead to a rapid release of Alcophyllex (Theophylline) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline).

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

It must be recognized that the peak and trough serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentration is a function of the dose, the dosing interval, and the rate of Alcophyllex (Theophylline) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Alcophyllex (Theophylline) clearance, the dose required to achieve a peak serum Alcophyllex (Theophylline) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Alcophyllex (Theophylline) dose required to achieve a therapeutic serum Alcophyllex (Theophylline) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) must be individualized on the basis of peak serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Alcophyllex (Theophylline) 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 Alcophyllex (Theophylline) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Alcophyllex (Theophylline) concentrations should be monitored at frequent intervals, e.g., every 24 hours.

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

Table V contains Alcophyllex (Theophylline) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Alcophyllex (Theophylline) dosage adjustment based upon serum Alcophyllex (Theophylline) concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum Alcophyllex (Theophylline) concentration.

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

• 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 Alcophyllex (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Alcophyllex (Theophylline) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Alcophyllex (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Alcophyllex (Theophylline) concentrations.
    

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

Alcophyllex (Theophylline)^® (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.

Alcophyllex (Theophylline)^® (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

Alcophyllex (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

Alcophyllex (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01

Alcophyllex (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

Alcophyllex (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01