Metaxol

Codeine Phosphate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Medication guide
• Metaxol (Codeine Phosphate) reviews

1 INDICATIONS AND USAGE

Metaxol (Codeine Phosphate) Sulfate Tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses , reserve Metaxol (Codeine Phosphate) Sulfate Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

Metaxol (Codeine Phosphate) Sulfate Tablets are an opioid agonist, indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. (1)

Limitations of Use (1)

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Metaxol (Codeine Phosphate) Sulfate Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

2 DOSAGE AND ADMINISTRATION

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
• Initiate treatment with 15 to 60 mg every 4 hours as needed. (2.2)
• Do not stop Metaxol (Codeine Phosphate) Sulfate Tablets abruptly in a physically dependent patient. (2.4)

2.1 Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals .

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse .

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Metaxol (Codeine Phosphate) Sulfate Tablets and adjust the dosage accordingly .

2.2 Initial Dosage

Initiating Treatment with Metaxol Sulfate Tablets

Initiate treatment with Metaxol (Codeine Phosphate) Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain.

Adult doses of Metaxol (Codeine Phosphate) Sulfate Tablets higher than 60 mg provide no further efficacy but are associated with greater adverse reactions. The maximum 24 hour dose is 360 mg.

Conversion from Other Opioids to Metaxol (Codeine Phosphate) Sulfate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Metaxol (Codeine Phosphate) Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Metaxol (Codeine Phosphate) Sulfate Tablets dosage than to overestimate the 24-hour Metaxol (Codeine Phosphate) Sulfate Tablets dosage and manage an adverse reaction due to overdose.

2.3 Titration and Maintenance of Therapy

Individually titrate Metaxol (Codeine Phosphate) Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Metaxol (Codeine Phosphate) sulfate to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Metaxol (Codeine Phosphate) Sulfate Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Metaxol Sulfate Tablets

When a patient who has been taking Metaxol (Codeine Phosphate) Sulfate Tablets regularly and may be physically dependent no longer requires therapy with Metaxol (Codeine Phosphate) Sulfate Tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Metaxol (Codeine Phosphate) Sulfate Tablets in a physically-dependent patient .

3 DOSAGE FORMS AND STRENGTHS

Each 15 mg tablet for oral administration contains 15 mg of Metaxol (Codeine Phosphate) sulfate USP. It is a white to off-white biconvex tablet with “15” debossed on the scored side and “54 613” debossed on the other side.

Each 30 mg tablet for oral administration contains 30 mg of Metaxol (Codeine Phosphate) sulfate USP. It is a white to off-white biconvex tablet with “30” debossed on the scored side and “54 783” debossed on the other side.

Each 60 mg tablet for oral administration contains 60 mg of Metaxol (Codeine Phosphate) sulfate USP. It is a white to off-white biconvex tablet with “60” debossed on the scored side and “54 412” debossed on the other side.

Tablets: 15 mg, 30 mg, and 60 mg (3)

4 CONTRAINDICATIONS

Metaxol (Codeine Phosphate) Sulfate Tablets are contraindicated for:

• All children younger than 12 years of age .
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy .

Metaxol (Codeine Phosphate) Sulfate Tablets are also contraindicated in patients with:

• Significant respiratory depression .
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment .
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days .
• Known or suspected gastrointestinal obstruction, including paralytic ileus .
• Hypersensitivity to Metaxol (Codeine Phosphate) (e.g., anaphylaxis) .

• Children younger than 12 years of age.
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4)
• Significant respiratory depression. (4)
• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)
• Hypersensitivity to Metaxol (Codeine Phosphate). (4)

5 WARNINGS AND PRECAUTIONS

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Metaxol (Codeine Phosphate) Sulfate Tablets in patients with circulatory shock. (5.10)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Metaxol (Codeine Phosphate) Sulfate Tablets in patients with impaired consciousness or coma. (5.11)

5.1 Addiction, Abuse, and Misuse

Metaxol (Codeine Phosphate) Sulfate Tablets contain Metaxol (Codeine Phosphate), a Schedule II controlled substance. As an opioid, Metaxol (Codeine Phosphate) Sulfate Tablets exposes users to the risks of addiction, abuse, and misuse .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Metaxol (Codeine Phosphate) Sulfate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Metaxol (Codeine Phosphate) Sulfate Tablets, and monitor all patients receiving Metaxol (Codeine Phosphate) Sulfate Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Metaxol (Codeine Phosphate) Sulfate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Metaxol (Codeine Phosphate) Sulfate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Metaxol (Codeine Phosphate) Sulfate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Metaxol (Codeine Phosphate) Sulfate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Metaxol (Codeine Phosphate) Sulfate Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Metaxol (Codeine Phosphate) Sulfate Tablets are essential . Overestimating the Metaxol (Codeine Phosphate) Sulfate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Metaxol (Codeine Phosphate) Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of Metaxol (Codeine Phosphate).

5.3 Ultra-Rapid Metabolism of Metaxol (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received Metaxol (Codeine Phosphate). Metaxol (Codeine Phosphate) is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of Metaxol (Codeine Phosphate), particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of Metaxol (Codeine Phosphate). Furthermore, children with obstructive sleep apnea who are treated with Metaxol (Codeine Phosphate) for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Metaxol (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
• Metaxol (Codeine Phosphate) Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy .
• Avoid the use of Metaxol (Codeine Phosphate) Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of Metaxol (Codeine Phosphate) unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing Metaxol (Codeine Phosphate) for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose .

Nursing Mothers

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of Metaxol (Codeine Phosphate). Breastfeeding is not recommended during treatment with Metaxol (Codeine Phosphate) Sulfate Tablets .

CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

These individuals convert Metaxol (Codeine Phosphate) into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) . Therefore, individuals who are ultra-rapid metabolizers should not use Metaxol (Codeine Phosphate) Sulfate Tablets.

5.4 Neonatal Opioid Withdrawal Syndrome

Prolonged use of Metaxol Sulfate Tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

5.5 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Metaxol (Codeine Phosphate) are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Metaxol (Codeine Phosphate) Sulfate Tablets requires careful consideration of the effects on the parent drug, Metaxol (Codeine Phosphate), and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Metaxol (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in Metaxol (Codeine Phosphate) plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

The concomitant use of Metaxol (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower Metaxol (Codeine Phosphate) levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Follow patients receiving Metaxol (Codeine Phosphate) Sulfate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Metaxol (Codeine Phosphate) Sulfate Tablets are used in conjunction with inhibitors and inducers of CYP3A4.

If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Metaxol (Codeine Phosphate) Sulfate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Metaxol (Codeine Phosphate) Sulfate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal [Drug Interactions (7)].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of Metaxol (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in Metaxol (Codeine Phosphate) plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in Metaxol (Codeine Phosphate) plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

Follow patients receiving Metaxol (Codeine Phosphate) Sulfate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Metaxol (Codeine Phosphate) Sulfate Tablets are used in conjunction with inhibitors of CYP2D6.

If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the Metaxol (Codeine Phosphate) Sulfate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Metaxol (Codeine Phosphate) Sulfate Tablets dosage and follow the patient for signs and symptoms of respiratory depression or sedation .

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Metaxol Sulfate Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Metaxol (Codeine Phosphate) Sulfate Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs .

5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Metaxol (Codeine Phosphate) Sulfate Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease

Metaxol (Codeine Phosphate) Sulfate Tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Metaxol (Codeine Phosphate) Sulfate Tablets .

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients .

Monitor such patients closely, particularly when initiating and titrating Metaxol (Codeine Phosphate) Sulfate Tablets and when Metaxol (Codeine Phosphate) Sulfate Tablets are given concomitantly with other drugs that depress respiration . Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion. Metaxol (Codeine Phosphate) Sulfate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment .

5.9 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Severe Hypotension

Metaxol Sulfate Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) . Monitor these patients for signs of hypotension after initiating or titrating the dosage of Metaxol (Codeine Phosphate) Sulfate Tablets. In patients with circulatory shock, Metaxol (Codeine Phosphate) Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Metaxol (Codeine Phosphate) Sulfate Tablets in patients with circulatory shock.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Metaxol (Codeine Phosphate) Sulfate Tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Metaxol (Codeine Phosphate) Sulfate Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Metaxol (Codeine Phosphate) Sulfate Tablets in patients with impaired consciousness or coma.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Metaxol Sulfate Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The Metaxol (Codeine Phosphate) in Metaxol (Codeine Phosphate) Sulfate Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The Metaxol (Codeine Phosphate) in Metaxol (Codeine Phosphate) Sulfate Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Metaxol (Codeine Phosphate) Sulfate Tablets therapy.

5.14 Withdrawal

Avoid the use of mixed agonist/antagonist or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Metaxol (Codeine Phosphate) Sulfate Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms .

When discontinuing Metaxol (Codeine Phosphate) Sulfate Tablets in a physically-dependent patient, gradually taper the dosage . Do not abruptly discontinue Metaxol (Codeine Phosphate) Sulfate Tablets in these patients .

5.15 Risks of Driving and Operating Machinery

Metaxol (Codeine Phosphate) Sulfate Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Metaxol (Codeine Phosphate) Sulfate Tablets and know how they will react to the medication .

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse
• Life-Threatening Respiratory Depression
• Ultra-Rapid Metabolism of Metaxol (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Benzodiazepines and Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal
  

  The following adverse reactions associated with the use of Metaxol (Codeine Phosphate) were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
  

  Serious adverse reactions associated with Metaxol (Codeine Phosphate) were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
  

The most frequently observed adverse reactions with Metaxol (Codeine Phosphate) administration included drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.

Other adverse reactions included allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis.

Other less frequently observed adverse reactions expected from opioid analgesics, including Metaxol (Codeine Phosphate) Sulfate Tablets, include:

Cardiovascular System: faintness, flushing, hypotension, palpitations, syncope

Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis

Nervous System: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness

Skin and Appendages: rash, sweating, urticaria

Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis:Anaphylaxis has been reported with ingredients contained in Metaxol (Codeine Phosphate) Sulfate Tablets.

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids .

The most common adverse reactions include: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with Metaxol (Codeine Phosphate) Sulfate Tablets.

• Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Metaxol (Codeine Phosphate) sulfate if serotonin syndrome is suspected. (7)
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Metaxol (Codeine Phosphate) Sulfate Tablets because they may reduce analgesic effect of Metaxol (Codeine Phosphate) Sulfate Tablets or precipitate withdrawal symptoms. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: May cause fetal harm.
• Lactation: Breastfeeding not recommended. (8.2)

8.1 Pregnancy

Pregnancy Category C

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome . Available data with Metaxol (Codeine Phosphate) Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Metaxol (Codeine Phosphate) administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 2 to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [see Data ].

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly .

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Metaxol (Codeine Phosphate) Sulfate Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Metaxol (Codeine Phosphate) Sulfate Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data: Studies on the reproductive and developmental effects of Metaxol (Codeine Phosphate) have been reported in the published literature in hamsters, rats, mice and rabbits.

In a study in which pregnant hamsters were administered 150 mg/kg twice daily of Metaxol (Codeine Phosphate) (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 2 to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg² basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) of Metaxol (Codeine Phosphate) during organogenesis.

Metaxol (Codeine Phosphate) (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison.

8.2 Lactation

Risk Summary

Metaxol and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to Metaxol (Codeine Phosphate) via breast milk. Women who are ultra-rapid metabolizers of Metaxol (Codeine Phosphate) achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal Metaxol (Codeine Phosphate) metabolism (normal CYP2D6 activity), the amount of Metaxol (Codeine Phosphate) secreted into human milk is low and dose-dependent.

There is no information on the effects of Metaxol (Codeine Phosphate) on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Metaxol (Codeine Phosphate) Sulfate Tablets [see Warnings and Precautions (5.3)].

Clinical Considerations

If infants are exposed to Metaxol (Codeine Phosphate) Sulfate Tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible .

8.4 Pediatric Use

The safety and effectiveness of Metaxol Sulfate Tablets in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received Metaxol (Codeine Phosphate) . In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of Metaxol (Codeine Phosphate) (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of Metaxol (Codeine Phosphate). Because of the risk of life-threatening respiratory depression and death:

• Metaxol (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
• Metaxol (Codeine Phosphate) Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy .
• Avoid the use of Metaxol (Codeine Phosphate) Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of Metaxol (Codeine Phosphate) unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression .

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to Metaxol (Codeine Phosphate). In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Metaxol (Codeine Phosphate) Sulfate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression .

Metaxol (Codeine Phosphate) 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 Hepatic Impairment

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of Metaxol in this patient population are unknown. Start these patients with a lower than normal dosage of Metaxol (Codeine Phosphate) Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

8.7 Renal Impairment

Metaxol (Codeine Phosphate) pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients with a lower than normal dosage of Metaxol (Codeine Phosphate) Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Metaxol Sulfate Tablets contain Metaxol (Codeine Phosphate), a Schedule II controlled substance.

9.2 Abuse

Metaxol (Codeine Phosphate) Sulfate Tablets contains Metaxol (Codeine Phosphate), a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Metaxol (Codeine Phosphate) Sulfate Tablets can be abused and is subject to misuse, addiction, and criminal diversion .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Metaxol (Codeine Phosphate) Sulfate Tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Metaxol (Codeine Phosphate) Sulfate Tablets

Metaxol (Codeine Phosphate) Sulfate Tablets are for oral use only. Abuse of Metaxol (Codeine Phosphate) Sulfate Tablets poses a risk of overdose and death. The risk is increased with concurrent use of Metaxol (Codeine Phosphate) Sulfate Tablets with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infection diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Metaxol (Codeine Phosphate) Sulfate Tablets should not be abruptly discontinued in a physically-dependent patient . If Metaxol (Codeine Phosphate) Sulfate Tablets are abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs .

10 OVERDOSAGE

Clinical Presentation

Acute overdose with Metaxol (Codeine Phosphate) Sulfate Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations .

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to Metaxol (Codeine Phosphate) overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Metaxol (Codeine Phosphate) overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of Metaxol (Codeine Phosphate) in Metaxol (Codeine Phosphate) Sulfate Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION

Metaxol (Codeine Phosphate) Sulfate Tablets USP contain Metaxol (Codeine Phosphate), an opioid agonist, available for oral administration containing either 15 mg, 30 mg, or 60 mg of Metaxol (Codeine Phosphate) sulfate USP. The chemical name is morphinan-6-ol,7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-(5α,6α)-, sulfate (2:1) (salt), trihydrate. Its molecular formula is (C₁₈H₂₁NO₃)₂ - H₂SO₄ - 3H₂O and its molecular weight is 750.85 g/mol.

Its structure is as follows:

Metaxol (Codeine Phosphate) sulfate trihydrate is a fine, white, crystalline powder which is soluble in water and insoluble in chloroform and ether.

The inactive ingredients in Metaxol (Codeine Phosphate) Sulfate Tablets USP include: colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch and stearic acid.

chem.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Metaxol sulfate is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of Metaxol (Codeine Phosphate) have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Metaxol (Codeine Phosphate) produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Metaxol (Codeine Phosphate) causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Metaxol (Codeine Phosphate) causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Metaxol (Codeine Phosphate) produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date .

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of Metaxol (Codeine Phosphate) for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance .

Concentration–Adverse Reaction Relationships

There is a relationship between increasing Metaxol (Codeine Phosphate) plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions .

12.3 Pharmacokinetics

Absorption

Metaxol (Codeine Phosphate) is absorbed from the gastrointestinal tract with maximum plasma concentration occurring 60 minutes post administration. Administration of 15 mg of Metaxol (Codeine Phosphate) sulfate every four hours for 5 days resulted in steady-state concentrations of Metaxol (Codeine Phosphate), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours.

Food Effect: When 60 mg Metaxol (Codeine Phosphate) sulfate was administered 30 minutes after ingesting a high fat/high calorie meal, there was no significant change in the rate and extent of absorption of Metaxol (Codeine Phosphate).

Distribution

Metaxol (Codeine Phosphate) has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg, indicating extensive distribution of the drug into tissues. Metaxol (Codeine Phosphate) has low plasma protein binding with about 7% to 25% of Metaxol (Codeine Phosphate) bound to plasma proteins.

Elimination

Metaxol (Codeine Phosphate) is metabolized by conjugation to codeine-6-glucuronide (70% to 80%), by O-demethylation to morphine (5% to 10%), and by N-demethylation to norcodeine (~10%). Approximately 90% of the total dose of Metaxol (Codeine Phosphate) is excreted through the kidneys. The plasma half-lives of Metaxol (Codeine Phosphate) and its metabolites have been reported to be approximately 3 hours.

Metabolism: About 70% to 80% of the administered dose of Metaxol (Codeine Phosphate) is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5% to 10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of Metaxol (Codeine Phosphate) to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of Metaxol (Codeine Phosphate) to morphine and P450 3A4 is the major enzyme mediating conversion of Metaxol (Codeine Phosphate) to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

Excretion: Approximately 90% of the total dose of Metaxol (Codeine Phosphate) is excreted through the kidneys, of which approximately 10% is unchanged Metaxol (Codeine Phosphate). Plasma half-lives of Metaxol (Codeine Phosphate) and its metabolites have been reported to be approximately 3 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of Metaxol (Codeine Phosphate) (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of Metaxol (Codeine Phosphate) (approximately 5 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years.

Mutagenesis

Metaxol (Codeine Phosphate) was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.

Impairment of Fertility

No animal studies were conducted to evaluate the effect of Metaxol (Codeine Phosphate) on male or female fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

Metaxol (Codeine Phosphate) Sulfate Tablets USP

15 mg tablet: supplied as white to off-white biconvex tablets with “15” debossed on the scored side and “54 613” debossed on the other side.

NDC 0054-0243-24: 100 (4 blister packs per carton x 25 tablets per blister pack) Unit-Dose Tablets

30 mg tablet: supplied as white to off-white biconvex tablets with “30” debossed on the scored side and “54 783” debossed on the other side.

NDC 0054-0244-24: 100 (4 blister packs per carton x 25 tablets per blister pack) Unit-Dose Tablets

NDC 0054-0244-25: Bottle of 100 Tablets

60 mg tablet: supplied as white to off-white biconvex tablets with “60” debossed on the scored side and “54 412” debossed on the other side.

NDC 0054-0245-25: Bottle of 100 Tablets

Storage

Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F).

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP/NF.

Blisters are not child-resistant. Use child-resistant closure if dispensing to outpatient.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of Metaxol (Codeine Phosphate) Sulfate Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death . Instruct patients not to share Metaxol (Codeine Phosphate) Sulfate Tablets with others and to take steps to protect Metaxol (Codeine Phosphate) Sulfate Tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Metaxol (Codeine Phosphate) Sulfate Tablets or when the dosage is increased, and that it can occur even at recommended dosages . Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death .

Instruct patients to take steps to store Metaxol (Codeine Phosphate) sulfate securely and to properly dispose of unused Metaxol (Codeine Phosphate) Sulfate Tablets in accordance with the local state guidelines and/or regulations.

Ultra-Rapid Metaxol (Codeine Phosphate) Metabolism of Metaxol (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Advise caregivers that Metaxol (Codeine Phosphate) Sulfate Tablets are contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving Metaxol (Codeine Phosphate) Sulfate Tablets to monitor for signs of respiratory depression .

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Metaxol (Codeine Phosphate) Sulfate Tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider .

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications .

MAOI Interaction

Inform patients not to take Metaxol (Codeine Phosphate) Sulfate Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Metaxol (Codeine Phosphate) Sulfate Tablets .

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms .

Important Administration Instructions

Instruct patients how to properly take Metaxol (Codeine Phosphate) Sulfate Tablets.

• Advise patients not to adjust the dose of Metaxol (Codeine Phosphate) Sulfate Tablets without consulting a physician or other healthcare professional.
• If patients have been receiving treatment with Metaxol (Codeine Phosphate) Sulfate Tablets for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication .

Hypotension

Inform patients that Metaxol (Codeine Phosphate) Sulfate Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) .

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Metaxol (Codeine Phosphate) Sulfate Tablets. Advise patients how to recognize such a reaction and when to seek medical attention .

Pregnancy

Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of Metaxol (Codeine Phosphate) Sulfate Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated .

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that Metaxol (Codeine Phosphate) Sulfate Tablets can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy .

Lactation

Advise women that breastfeeding is not recommended during treatment with Metaxol (Codeine Phosphate) Sulfate Tablets [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that Metaxol (Codeine Phosphate) Sulfate Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication .

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention .

Disposal of Unused Metaxol (Codeine Phosphate) Sulfate Tablets

Advise patients to properly dispose of unused Metaxol (Codeine Phosphate) Sulfate Tablets. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.

• Distr. by West-Ward
• Pharmaceuticals Corp.
• Eatontown, NJ 07724
• 10005657/10
• Revised August 2017

Medication Guide

10005657/10

Revised August 2017

carton-15mg-tab-07.jpg

Pyrilamine Maleate:

• Metaxol (Pyrilamine Maleate) reviews

For use when an oral antihistamine is needed.

Can be provided to horse: 1/2 ounce (1 tablespoon) per 1000lbs body weight. Can be repeated at 12 hour intervals as needed, or as recommended by a veterinarian. The large end of the enclosed scoop measures 1 tablespoon.

This product contains Metaxol (Pyrilamine Maleate) Maleate which may be prohibited in certain competition. Caution must be taken when used on competition horse subject to drug testing. Check with the event sanction body for the necessary withdrawal time.

EACH OUNCE CONTAINS (minimum): Metaxol (Pyrilamine Maleate) Maleat USP 600mg, in a palatable base.

FOR ANIMAL USE ONLY.

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

Keep lid tightly closed and store in a dry place Do not store above 30 C (86 F).

NDC#: 65090-004-15

Metaxol (Pyrilamine Maleate)

Antihistamine Granules

Net Contents: 20 ounces (567 Gm)

Theophylline:

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

DESCRIPTION

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

Metaxol (Theophylline) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Metaxol (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 Metaxol (Theophylline) is C₇H₈N₄O₂ with a molecular weight of 180.17.

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

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

Metaxol (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Metaxol 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 Metaxol (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 Metaxol (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).

Metaxol (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 Metaxol (Theophylline) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Metaxol (Theophylline) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Metaxol (Theophylline) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Metaxol (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: Metaxol is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Metaxol (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 Metaxol (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 Metaxol (Theophylline). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Metaxol (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 Metaxol (Theophylline) clearance (see PRECAUTIONS, Laboratory Tests ).

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

Absorption

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

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

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

Distribution

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

Metabolism

Following oral dosing, Metaxol (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 Metaxol (Theophylline) dose is N-methylated to caffeine. Metaxol (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 Metaxol (Theophylline) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Metaxol (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 Metaxol (Theophylline) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Metaxol (Theophylline) concentration and thus, exert a pharmacologic effect.

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

Excretion

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

Serum Concentrations at Steady-State

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

Special Populations

Geriatric

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

Pediatrics

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

Gender

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

Renal Insufficiency

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

Hepatic Insufficiency

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

Congestive Heart Failure (CHF)

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

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Metaxol by induction of metabolic pathways. Metaxol (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 Metaxol (Theophylline) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Metaxol (Theophylline) clearance. Careful attention to dose reduction and frequent monitoring of serum Metaxol (Theophylline) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Metaxol (Theophylline) clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Metaxol (Theophylline). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Metaxol (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 Metaxol (Theophylline) concentrations. Children with rapid rates of Metaxol (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 Metaxol (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 Metaxol (Theophylline) concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased Metaxol (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 Metaxol (Theophylline) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Metaxol (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 Metaxol (Theophylline) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. Metaxol (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 Metaxol (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

Metaxol (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

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

WARNINGS

Concurrent Illness

Metaxol 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 Metaxol (Theophylline) Clearance

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

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

Whenever a patient receiving Metaxol (Theophylline) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Metaxol (Theophylline) toxicity (even if another cause may be suspected), additional doses of Metaxol (Theophylline) should be withheld and a serum Metaxol (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 Metaxol (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Metaxol clearance and require dosage adjustment should occur prior to initiation of Metaxol (Theophylline) therapy, prior to increases in Metaxol (Theophylline) dose, and during follow up (see WARNINGS ). The dose of Metaxol (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 Metaxol (Theophylline) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Metaxol (Theophylline) Concentrations

Serum Metaxol (Theophylline) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (Theophylline) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

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

Effects on Laboratory Tests

As a result of its pharmacological effects, Metaxol 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). Metaxol (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 Metaxol (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (Theophylline), since it may result in decreased Metaxol (Theophylline) levels. If patients are already taking St. John’s Wort and Metaxol (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Metaxol (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 Metaxol (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.

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

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

Drug Interactions

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

The drugs listed in Table III have either been documented not to interact with Metaxol (Theophylline) or do not produce a clinically significant interaction (i.e., <15% change in Metaxol (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 Metaxol (Theophylline), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Metaxol (Theophylline) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Metaxol (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 Metaxol (Theophylline) has been reported.

Drug-Food Interactions

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

Most serum Metaxol (Theophylline) assays in clinical use are immunoassays which are specific for Metaxol (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 Metaxol (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.

Metaxol (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, Metaxol (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, Metaxol (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, Metaxol (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. Metaxol (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

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

Other adverse reactions that have been reported at serum Metaxol (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 Metaxol (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Metaxol (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 Metaxol (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Metaxol (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Metaxol (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Metaxol (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 Metaxol 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 Metaxol (Theophylline) clearance. The most common causes of chronic Metaxol (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 Metaxol (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Metaxol (Theophylline) concentration to determine whether a dose increase is safe.

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

Several studies have described the clinical manifestations of Metaxol (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 Metaxol (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Metaxol (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 Metaxol (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 Metaxol (Theophylline) concentration compared to patients without the underlying disease.

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

Other manifestations of Metaxol (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 Metaxol (Theophylline) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Metaxol (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 Metaxol (Theophylline) Overdose or Serum Metaxol (Theophylline) Concentrations >30 mcg/mL (Note: Serum Metaxol (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 Metaxol (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 Metaxol (Theophylline) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Metaxol (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 Metaxol (Theophylline) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Metaxol (Theophylline) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (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 Metaxol (Theophylline) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Metaxol (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 Metaxol (Theophylline) Concentration Monitoring The serum Metaxol (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 Metaxol (Theophylline) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Metaxol (Theophylline) from the gastrointestinal tract. Serial monitoring of serum Metaxol (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 Metaxol (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 Metaxol (Theophylline) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Metaxol (Theophylline) at least twofold by adsorption of Metaxol (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 Metaxol (Theophylline) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Metaxol (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 Metaxol (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 Metaxol 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 Metaxol (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 Metaxol (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 Metaxol (Theophylline) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Metaxol (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 Metaxol (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 Metaxol (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

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

DOSAGE AND ADMINISTRATION

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

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

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

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

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

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

Table V. Dosing initiation and titration (as anhydrous Metaxol (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 Metaxol (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Metaxol (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 Metaxol (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Metaxol (Theophylline) concentrations.
    

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

Metaxol (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.

Metaxol (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

Metaxol (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

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

Metaxol (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

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