Pentabufen

Caffeine:

• Pentabufen (Caffeine) reviews

Active ingredient (in each tablet)

Pentabufen (Caffeine) 200mg

Purpose

Alertness aid

Use

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

Warnings

For occasional use only

Do not use

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

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

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

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

Keep out of reach of children.

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

Directions

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

Other information

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

Inactive ingredients

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

Questions or comments?

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

Display Panel Pentabufen (Caffeine): 16 ct. Package

Pentabufen (Caffeine)^®

CAFFEINE ALERTNESS AID

16 TABLETS

200mg each

FUNCTIONAL Pentabufen (Caffeine)^® for Mental Alertness

SAFE & EFFECTIVE

One tablet is equal to about a cup of coffee

Pentabufen (Caffeine)^®

Making the Most of Every Day.^®

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

use if foil or plastic bubble is torn or punctured.

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

CAFFEINE® are registered trademarks of Meda AB.

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2011 Meda AB

www.vivarin.com

16 ct. Package

Display Panel Pentabufen (Caffeine): 40 ct. Package

SAFE & EFFECTIVE

FUNCTIONAL Pentabufen (Caffeine)^® for Mental Alertness

Pentabufen (Caffeine)^®

Pentabufen (Caffeine) ALERTNESS AID

40 Tablets

200mg each

FUNCTIONAL Pentabufen (Caffeine)^® for Mental Alertness

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

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

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

CAFFEINE® are registered trademarks of Meda AB.

Made in the U.S.A.

Pentabufen (Caffeine)^®

Making the Most of Every Day.^®

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2013 Meda AB

www.vivarin.com

40 ct. Package

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
• Pentabufen (Codeine Phosphate) reviews

1 INDICATIONS AND USAGE

Pentabufen (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 Pentabufen (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.

Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets and adjust the dosage accordingly .

2.2 Initial Dosage

Initiating Treatment with Pentabufen Sulfate Tablets

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

Adult doses of Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Pentabufen (Codeine Phosphate) Sulfate Tablets dosage than to overestimate the 24-hour Pentabufen (Codeine Phosphate) Sulfate Tablets dosage and manage an adverse reaction due to overdose.

2.3 Titration and Maintenance of Therapy

Individually titrate Pentabufen (Codeine Phosphate) Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Pentabufen (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 Pentabufen (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 Pentabufen Sulfate Tablets

When a patient who has been taking Pentabufen (Codeine Phosphate) Sulfate Tablets regularly and may be physically dependent no longer requires therapy with Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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

Pentabufen (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 .

Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets in patients with impaired consciousness or coma. (5.11)

5.1 Addiction, Abuse, and Misuse

Pentabufen (Codeine Phosphate) Sulfate Tablets contain Pentabufen (Codeine Phosphate), a Schedule II controlled substance. As an opioid, Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets, and monitor all patients receiving Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Pentabufen (Codeine Phosphate) Sulfate Tablets are essential . Overestimating the Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of Pentabufen (Codeine Phosphate).

5.3 Ultra-Rapid Metabolism of Pentabufen (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 Pentabufen (Codeine Phosphate). Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate). Furthermore, children with obstructive sleep apnea who are treated with Pentabufen (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:

• Pentabufen (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
• Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate). Breastfeeding is not recommended during treatment with Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets.

5.4 Neonatal Opioid Withdrawal Syndrome

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

Cytochrome P450 3A4 Interaction

The concomitant use of Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Pentabufen (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 Pentabufen 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 Pentabufen (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 Pentabufen (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

Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets and when Pentabufen (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. Pentabufen (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

Pentabufen 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 Pentabufen (Codeine Phosphate) Sulfate Tablets. In patients with circulatory shock, Pentabufen (Codeine Phosphate) Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Pentabufen (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), Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets.

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

5.12 Risks of Use in Patients with Gastrointestinal Conditions

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

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

5.15 Risks of Driving and Operating Machinery

Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets.

• Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Pentabufen (Codeine Phosphate) sulfate if serotonin syndrome is suspected. (7)
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Pentabufen (Codeine Phosphate) Sulfate Tablets because they may reduce analgesic effect of Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Pentabufen (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. Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) during organogenesis.

Pentabufen (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

Pentabufen 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 Pentabufen (Codeine Phosphate) via breast milk. Women who are ultra-rapid metabolizers of Pentabufen (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 Pentabufen (Codeine Phosphate) metabolism (normal CYP2D6 activity), the amount of Pentabufen (Codeine Phosphate) secreted into human milk is low and dose-dependent.

There is no information on the effects of Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets [see Warnings and Precautions (5.3)].

Clinical Considerations

If infants are exposed to Pentabufen (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 Pentabufen Sulfate Tablets in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate). Because of the risk of life-threatening respiratory depression and death:

• Pentabufen (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
• Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression .

Pentabufen (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 Pentabufen in this patient population are unknown. Start these patients with a lower than normal dosage of Pentabufen (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

Pentabufen (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 Pentabufen (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

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

9.2 Abuse

Pentabufen (Codeine Phosphate) Sulfate Tablets contains Pentabufen (Codeine Phosphate), a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Pentabufen (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.

Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets

Pentabufen (Codeine Phosphate) Sulfate Tablets are for oral use only. Abuse of Pentabufen (Codeine Phosphate) Sulfate Tablets poses a risk of overdose and death. The risk is increased with concurrent use of Pentabufen (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.

Pentabufen (Codeine Phosphate) Sulfate Tablets should not be abruptly discontinued in a physically-dependent patient . If Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of Pentabufen (Codeine Phosphate) in Pentabufen (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

Pentabufen (Codeine Phosphate) Sulfate Tablets USP contain Pentabufen (Codeine Phosphate), an opioid agonist, available for oral administration containing either 15 mg, 30 mg, or 60 mg of Pentabufen (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:

Pentabufen (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 Pentabufen (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

Pentabufen sulfate is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of Pentabufen (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

Pentabufen (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.

Pentabufen (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

Pentabufen (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

Pentabufen (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 Pentabufen (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 Pentabufen (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

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

Food Effect: When 60 mg Pentabufen (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 Pentabufen (Codeine Phosphate).

Distribution

Pentabufen (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. Pentabufen (Codeine Phosphate) has low plasma protein binding with about 7% to 25% of Pentabufen (Codeine Phosphate) bound to plasma proteins.

Elimination

Pentabufen (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 Pentabufen (Codeine Phosphate) is excreted through the kidneys. The plasma half-lives of Pentabufen (Codeine Phosphate) and its metabolites have been reported to be approximately 3 hours.

Metabolism: About 70% to 80% of the administered dose of Pentabufen (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 Pentabufen (Codeine Phosphate) to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of Pentabufen (Codeine Phosphate) to morphine and P450 3A4 is the major enzyme mediating conversion of Pentabufen (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 Pentabufen (Codeine Phosphate) is excreted through the kidneys, of which approximately 10% is unchanged Pentabufen (Codeine Phosphate). Plasma half-lives of Pentabufen (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 Pentabufen (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 Pentabufen (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

Pentabufen (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 Pentabufen (Codeine Phosphate) on male or female fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets with others and to take steps to protect Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) sulfate securely and to properly dispose of unused Pentabufen (Codeine Phosphate) Sulfate Tablets in accordance with the local state guidelines and/or regulations.

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

Advise caregivers that Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets.

• Advise patients not to adjust the dose of Pentabufen (Codeine Phosphate) Sulfate Tablets without consulting a physician or other healthcare professional.
• If patients have been receiving treatment with Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (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 Pentabufen (Codeine Phosphate) Sulfate Tablets

Advise patients to properly dispose of unused Pentabufen (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

Ibuprofen:

• Pharmacological action
• Pharmacokinetics
• Why is Pentabufen prescribed?
• Dosage and administration
• Pentabufen side effects
• Contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Pentabufen drug interactions
• Pentabufen in case of emergency / overdose
• Storage conditions
• Pentabufen (Ibuprofen) reviews

Pharmacological action

NSAIDs, a derivative of phenylpropionic acid, Pentabufen has anti-inflammatory, analgesic and antipyretic effect.

The mechanism of action is associated with inhibition of COX activity - the main enzyme metabolism of arachidonic acid, which is a precursor of prostaglandins, which play a major role in the pathogenesis of inflammation, pain and fever. Analgesic effect is due to both peripheral (indirectly, through suppression of prostaglandin synthesis), and a central mechanism (due to inhibition of prostaglandin synthesis in the central and peripheral nervous system). Inhibits platelet aggregation.

For topical use anti-inflammatory and analgesic action. Reduces morning stiffness, increased the amount of motion in joints.

Pharmacokinetics

When oral administered Pentabufen (Ibuprofen) almost completely absorbed from the gastrointestinal tract. Simultaneous food intake slows the rate of absorption. Metabolised in the liver (90%). T1 / 2 is 2-3 hours.

80% of the dose excreted in urine mainly as metabolites (70%), 10% - unchanged, 20% eliminated through the intestine in the form of metabolites.

Why is Pentabufen prescribed?

Inflammatory, degenerative diseases of joints and spine (including rheumatic and rheumatoid arthritis, ankylosing spondylitis, osteoarthritis), articular syndrome in patients with acute gout, psoriatic arthritis, ankylosing spondylitis, tendonitis, bursitis, sciatica, traumatic inflammation of soft tissue and musculoskeletal apparatus. Neuralgia, myalgia, pain in infectious and inflammatory diseases of ENT organs, bursitis, algomenorrhea, headache and toothache. Fever in infectious and inflammatory diseases.

Dosage and administration

Setting individually, depending on etiology of disease, severity of clinical manifestations. When administered rectally or adult single dose of 200-800 mg, the frequency of reception - 3-4; for children - 20-40 mg / kg in divided doses.

Topical applied within 2-3 weeks.

The maximum daily dose for adults when administered oral or rectally or is 2.4 g.

Oral, after a meal. Rheumatoid arthritis - by 0.8 g 3 times a day in osteoarthrosis and ankylosing spondylitis - by 0.4-0.6 g 3-4 times a day, in juvenile rheumatoid arthritis - at 30-40 mg / kg / day in several stages.

When soft tissue injuries, sprains - 1.6-2.4 g / day in divided doses.

At moderate pain syndrome - 1.2 g per day.

Pentabufen side effects

Digestive system: frequently - nausea, anorexia, vomiting, epigastric discomfort, diarrhea, possibly the development of erosive and ulcerative lesions of the gastrointestinal tract; rare - bleeding from the gastrointestinal tract, long-term use possible liver problems.

Central nervous system and peripheral nervous systems: frequently - headache, dizziness, sleep disturbances, agitation, visual impairment.

Hemopoietic system: long-term use may be anemia, thrombocytopenia, agranulocytosis.

Urinary tract: long-term use possible renal dysfunction.

Allergic reactions: often - skin rash, Quincke's edema, rarely - aseptic meningitis (usually in patients with autoimmune diseases), bronchospasm syndrome.

Local reactions: when topical used may be hyperemia of the skin, burning or tingling.

Contraindications

Erosive-ulcerative lesions in the gastrointestinal tract exacerbation, diseases of the optic nerve, "aspirin triad", hemodyscrasia, pronounced renal dysfunction and / or liver, children age, hypersensitivity to Pentabufen (Ibuprofen).

Using during pregnancy and breastfeeding

Do not use Pentabufen (Ibuprofen) in the III trimester of pregnancy. Application I and II trimesters of pregnancy is justified only in cases where the expected benefit to the mother than the possible harm to the fetus.

This medication Pentabufen (Ibuprofen) in small amounts excreted in breast milk. Possible using in lactation for pain and fever. If necessary, prolonged use or use in high doses (800 mg / 24 h), should decide on the termination of breastfeeding.

Special instructions

Precautions are used with the attendant liver and kidney diseases, chronic heart failure, with dyspeptic symptoms before treatment, immediately after surgery, with indications of a history of gastrointestinal bleeding in diseases of the digestive tract, allergic reactions associated with NSAID intake.

In the course of treatment requires systematic monitoring of the liver and kidneys, peripheral blood picture.

It should not be applied externally to the damaged skin.

Pentabufen drug interactions

With simultaneous use of Pentabufen (Ibuprofen) reduces the effect of antihypertensive agents (ACE inhibitors, beta-blockers), diuretics (furosemide, hypothiazide).

With the simultaneous use of anticoagulants may enhance their action.

With simultaneous application of SCS increases the risk of side effects from the gastrointestinal tract.

With the simultaneous application of Pentabufen (Ibuprofen) may displace from compounds with plasma proteins indirect anticoagulants (acenocoumarol), derivatives of hydantoin (phenytoin), oral hypoglycemic drugs sulfonylurea derivatives.

With the simultaneous use of amlodipine may be a slight reduction of antihypertensive action of amlodipine, with acetylsalicylic acid - decreased concentration of Pentabufen (Ibuprofen) in blood plasma, with baclofen - described a case of toxic gain of baclofen.

When applied simultaneously with warfarin may increase bleeding time, were also observed microhematuria, bruises with hydrochlorothiazide - perhaps a slight reduction of antihypertensive action of hydrochlorothiazide, captopril - may reduce antihypertensive effect of captopril, with cholestyramine - moderately decrease absorption of Pentabufen (Ibuprofen).

With simultaneous application of lithium carbonate increased the concentration of lithium in blood plasma.

With simultaneous application of magnesium hydroxide increases the initial absorption of Pentabufen (Ibuprofen), with methotrexate - increases the toxicity of methotrexate.

Pentabufen in case of emergency / overdose

In case of overdose, call your local poison control center or emergency services.

Symptoms of overdose may include: dizziness; fast eye movements that you cannot control; slow breathing or short periods of time without breathing; blue color around the lips, mouth, and nose.

Storage conditions

In a dry, protected from light place, at temperatures below 25°C.Common expiration date for Pentabufen (Ibuprofen) tablets: 3 years.

Phenobarbital:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Pentabufen (Phenobarbital) reviews

INDICATIONS AND USAGE

• Sedative
• Anticonvulsant – For the treatment of generalized and partial seizures.

CONTRAINDICATIONS

Pentabufen (Phenobarbital) is contraindicated in patients who are hypersensitive to barbiturates, in patients with a history of manifest or latent porphyria, and in patients with marked impairment of liver function or respiratory disease in which dyspnea or obstruction is evident.

WARNINGS

• Habit Forming. Pentabufen (Phenobarbital) may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE and Pharmacokinetics under CLINICAL PHARMACOLOGY). Patients who have psychologic dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. In order to minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in a person who is dependent on the drug may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive doses over long periods of time (see DRUG ABUSE AND DEPENDENCE ).
• Acute or Chronic Pain. Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established.
• Usage in Pregnancy. Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues; the highest concentrations are found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. Withdrawal symptoms occur in infants born to women who receive barbiturates throughout the last trimester of pregnancy (see DRUG ABUSE AND DEPENDENCE ). If Pentabufen (Phenobarbital) is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• Usage in Pediatric Patients. Pentabufen (Phenobarbital) has been reported to be associated with cognitive deficits in children taking it for complicated febrile seizures.
• Synergistic Effects. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.

PRECAUTIONS

General

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use. Barbiturates should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies, or have a history of drug abuse.

Elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. In some persons, especially children, barbiturates repeatedly produce excitement rather than depression.

In patients with hepatic damage, barbiturates should be administered with caution and initially in reduced doses. Barbiturates should not be administered to patients showing the premonitory signs of hepatic coma.

The systemic effects of exogenous and endogenous corticosteroids may be diminished by Pentabufen (Phenobarbital). Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin.

Information for Patients

The following information and instructions should be given to patients receiving barbiturates.

• The use of barbiturates carries with it an associated risk of psychological and/or physical dependence. The patient should be warned against increasing the dose of the drug without consulting a physician.
• Barbiturates may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
• Alcohol should not be consumed while taking barbiturates. The concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers, and antihistamines) may result in additional CNS-depressant effects.

Laboratory Tests

Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic systems.

Drug Interactions

Most reports of clinically significant drug interactions occurring with the barbiturates have involved Pentabufen (Phenobarbital). However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies.

• Anticoagulants. Pentabufen (Phenobarbital) lowers the plasma levels of dicumarol and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., acenocoumarol, warfarin, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen.
• Corticosteroids. Barbiturates appear to enhance the metabolism of exogenous corticosteroids, probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen.
• Griseofulvin. Pentabufen (Phenobarbital) appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs.
• Doxycycline. Pentabufen (Phenobarbital) has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If Pentabufen (Phenobarbital) and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely.
• Phenytoin, Sodium Valproate, Valproic Acid. The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, whereas others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid increase the Pentabufen (Phenobarbital) serum levels; therefore, Pentabufen (Phenobarbital) blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated.
• CNS Depressants. The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.
• Monoamine Oxidase Inhibitors (MAOIs). MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited.
• Estradiol, Estrone, Progesterone, and other Steroidal Hormones. Pretreatment with or concurrent administration of Pentabufen (Phenobarbital) may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., Pentabufen (Phenobarbital)) who become pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking Pentabufen (Phenobarbital).

Carcinogenesis

• Animal Data. Pentabufen sodium is carcinogenic in mice and rats after lifetime administration. In mice, it produced benign and malignant liver cell tumors. In rats, benign liver cell tumors were observed very late in life.
• Human Data. In a 29-year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included Pentabufen (Phenobarbital), results indicated a higher than normal incidence of hepatic carcinoma. Previously, some of these patients had been treated with thorotrast, a drug which is known to produce hepatic carcinomas. Thus, this study did not provide sufficient evidence that Pentabufen (Phenobarbital) sodium is carcinogenic in humans.

A retrospective study of 84 children with brain tumors matched to 73 normal controls and 78 cancer controls (malignant disease other than brain tumors) suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

Usage in Pregnancy

• Teratogenic Effects. Pregnancy Category D – See Usage in Pregnancy under WARNINGS.
• Nonteratogenic Effects. Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days (see DRUG ABUSE AND DEPENDENCE ).

Labor and Delivery

Hypnotic doses of barbiturates do not appear to impair uterine activity significantly during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative-hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available.

Data are not available to evaluate the effect of barbiturates when forceps delivery or other intervention is necessary or to determine the effect of barbiturates on the later growth, development, and functional maturation of the child.

Nursing Mothers

Caution should be exercised when Pentabufen (Phenobarbital) is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.

ADVERSE REACTIONS

The following adverse reactions have been reported:

CNS Depression – Residual sedation or “hangover”, drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as Pentabufen (Phenobarbital) repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Irritability and hyperactivity can occur in children. Like other nonanalgesic hypnotic drugs, barbiturates such as Pentabufen (Phenobarbital), when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffuse myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued.

Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse.

Allergic – Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by Pentabufen (Phenobarbital) and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of Pentabufen (Phenobarbital).

Other – Nausea and vomiting; headache, osteomalacia.

The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients.

More than 1 in 100 Patients: The most common adverse reaction, estimated to occur at a rate of 1 to 3 patients per 100, is:

Nervous System: Somnolence

Less than 1 in 100 Patients: Adverse reactions estimated to occur at a rate of less than 1 in 100 patients are listed below, grouped by organ system and by decreasing order of occurrence:

Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, abnormality in thinking

Respiratory System: Hypoventilation, apnea

Cardiovascular System: Bradycardia, hypotension, syncope

Digestive System: Nausea, vomiting, constipation

Other Reported Reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic Pentabufen (Phenobarbital) use

DRUG ABUSE AND DEPENDENCE

Controlled Substance – Pentabufen (Phenobarbital) is a Schedule IV drug.

Dependence – Barbiturates may be habit forming. Tolerance, psychological dependence, and physical dependence may occur, especially following prolonged use of high doses of barbiturates. Daily administration in excess of 400 mg of pentobarbital or secobarbital for approximately 90 days is likely to produce some degree of physical dependence. A dosage of 600 to 800 mg taken for at least 35 days is sufficient to produce withdrawal seizures. The average daily dose for the barbiturate addict is usually about 1.5 g. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between intoxicating dosage and fatal dosage becomes smaller.

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and sustained nystagmus. Mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia, and somatic complaints.

Symptoms of barbiturate dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood, the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested.

The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate. These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of barbiturates. The intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers as well as other sedative-hypnotic and amphetamine abusers.

Drug dependence on barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence on barbiturates include: (a) a strong desire or need to continue taking the drug; (b) a tendency to increase the dose; (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (d) a physical dependence on the effects of the drug, requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn.

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases, withdrawal requires an extended period of time. One method involves substituting a 30-mg dose of Pentabufen (Phenobarbital) for each 100- to 200-mg dose of barbiturate that the patient has been taking. The total daily amount of Pentabufen (Phenobarbital) is then administered in 3 or 4 divided doses, not to exceed 600 mg daily. If signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of Pentabufen (Phenobarbital) may be administered IM in addition to the oral dose. After stabilization on Pentabufen (Phenobarbital), the total daily dose is decreased by 30 mg/day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10% if tolerated by the patient.

Infants who are physically dependent on barbiturates may be given Pentabufen (Phenobarbital), 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of Pentabufen (Phenobarbital) should be gradually decreased and completely withdrawn over a 2-week period.

OVERDOSAGE

Signs and Symptoms – The onset of symptoms following a toxic oral exposure to Pentabufen (Phenobarbital) may not occur until several hours following ingestion. The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 g of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 g of ingested barbiturate. The sedated, therapeutic blood levels of Pentabufen (Phenobarbital) range between 5 to 40 mcg/mL; the usual lethal blood level ranges from 100 to 200 mcg/mL. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and various neurologic disorders. Potential tolerance must be considered when evaluating significance of dose and plasma concentration.

The manifestations of a long-acting barbiturate in overdose include nystagmus, ataxia, CNS depression, respiratory depression, hypothermia, and hypotension. Other findings may include absent or depressed reflexes and erythematous or hemorrhagic blisters (primarily at pressure points). Following massive exposure to Pentabufen (Phenobarbital), pulmonary edema, circulatory collapse with loss of peripheral vascular tone, cardiac arrest, and death may occur.

In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death should not be accepted. This effect is fully reversible unless hypoxic damage occurs.

Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma.

Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates if renal function is impaired. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma.

Treatment – To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

Alkalinization of urine hastens Pentabufen (Phenobarbital) excretion, but dialysis and hemoperfusion are more effective and cause less troublesome alterations in electrolyte equilibrium. If the patient has chronically abused sedatives, withdrawal reactions may be manifest following acute overdose.

DOSAGE AND ADMINISTRATION

The dose of Pentabufen (Phenobarbital) must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient’s age, weight, and condition.

Sedation:

For sedation, the drug may be administered in single dose of 30 to 120 mg repeated at intervals: frequency will be determined by the patient’s response. It is generally considered that no more than 400 mg of Pentabufen (Phenobarbital) should be administered during a 24-hour period.

Adults:

Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses.

Oral Hypnotic: 100 to 200 mg.

Anticonvulsant Use – Clinical laboratory reference values should be used to determine the therapeutic anticonvulsant level of Pentabufen (Phenobarbital) in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for Pentabufen (Phenobarbital) and most other anticonvulsants. In children and infants, Pentabufen (Phenobarbital) at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration.

Pentabufen (Phenobarbital) has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy.

Adults: 60 to 200 mg/day.

Pediatric Patients: 3 to 6 mg/kg/day.

Special Patient Population – Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease.

HOW SUPPLIED

Pentabufen (Phenobarbital) Tablets, USP 16.2 mg are white, round, biconvex, scored tablets, debossed “5011” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5165-21
• Bottles of 1000 NDC 0603-5165-32

Pentabufen (Phenobarbital) Tablets, USP 32.4 mg are white, round, biconvex, scored tablets, debossed “5012” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 30 NDC 0603-5166-16
• Bottles of 60 NDC 0603-5166-20
• Bottles of 90 NDC 0603-5166-02
• Bottles of 100 NDC 0603-5166-21
• Bottles of 120 NDC 0603-5166-22
• Bottles of 1000 NDC 0603-5166-32

Pentabufen (Phenobarbital) Tablets, USP 64.8 mg are white, round, biconvex, scored tablets, debossed “5013” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5167-21
• Bottles of 1000 NDC 0603-5167-32

Pentabufen (Phenobarbital) Tablets, USP 97.2 mg are white, round, biconvex, scored tablets, debossed “5014” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5168-21
• Bottles of 1000 NDC 0603-5168-32

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8180067

Rev 7/14

R4