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Trezix

Generic Name: acetaminophen, caffeine, dihydrocodeine bitartrate
Dosage Form: capsule

Acetaminophen, Caffeine and Dihydrocodeine Bitartrate         

320.5 mg / 30 mg / 16 mg
Rx Only                                                CIII

WARNING: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine

Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.

Hepatotoxicity
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen containing product.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION

Addiction, Abuse, and Misuse

Trezix™ exposes patients and other users to the risks of opioid addiction, abuse,
and misuse, which can lead to overdose and death. Assess each patient’s risk prior to
prescribing Trezix™, and monitor all patients regularly for the development of
these behaviors or conditions [see WARNINGS].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Trezix™. Monitor for respiratory depression, especially during initiation of Trezix™ or following a dose increase [see WARNINGS].

Accidental Ingestion

Accidental ingestion of even one dose of Trezix™, especially by children, can result in a fatal overdose of Trezix™ [see WARNINGS].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Trezix™ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS].

Cytochrome P450 3A4 Interaction

The concomitant use of Trezix™ with all cytochrome P450 3A4 inhibitors may result in an increase in Trezix™ plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in Trezix™ plasma concentration. Monitor patients receiving Trezix™ and any CYP3A4 inhibitor or inducer [see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions].

DESCRIPTION:

Trezix™ capsules are supplied in capsule form for oral administration.
Each red capsule contains:
Acetaminophen...........................................320.5 mg
Caffeine ..........................................................30 mg
Dihydrocodeine bitartrate ...............................16 mg

Acetaminophen (4'-hydroxyacetanilide), a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:


Caffeine (1,3,7-trimethylxanthine), a bitter, white crystalline powder or white glistening needles, is a central nervous system stimulant. It has the following structural formula:

Dihydrocodeine Bitartrate (4,5 _-epoxy-3-methoxy-17-methylmorphinan-6 _-ol (+)-tartrate), an odorless, fine white powder is an opioid analgesic. It has the following structural formula:

In addition, each capsule contains the following inactive ingredients: crospovidone, magnesium stearate, povidone, pregelatinized starch, stearic acid. The capsule is composed of FD&C Red #40, and gelatin. Imprinting ink is composed of ammonium hydroxide, isopropyl alcohol, n-butyl alcohol, pharmaceutical glaze (modified) in SD-45, propylene glycol, simethicone, and titanium dioxide.

CLINICAL PHARMACOLOGY:

Trezix™ capsules contain dihydrocodeine which is a semi-synthetic narcotic analgesic related to codeine, with multiple actions qualitatively similar to those of codeine; the most prominent of these involve the central nervous system and organs with smooth muscle components. The principal action of therapeutic value is analgesia.

This combination product also contains acetaminophen, a non-opiate, non-salicylate analgesic and antipyretic. This combination product contains caffeine as an analgesic adjuvant. Caffeine is also a CNS and cardiovascular stimulant.

INDICATIONS AND USAGE:

Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules are indicated for the management of moderate to moderately severe pain severe enough to require an opioid analgesic 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 [see WARNINGS], reserve Trezix™ for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]

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

CONTRAINDICATIONS:

Trezix™ is contraindicated in patients with:

  • Significant respiratory depression [see WARNINGS]
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS]

Dihydrocodeine-containing products are contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.

This combination product is contraindicated in patients with hypersensitivity to dihydrocodeine, codeine, acetaminophen, caffeine, or any of the inactive components listed above, or any situation where opioids are contraindicated including significant respiratory depression (in unmonitored settings or in the absence of resuscitative equipment), acute or severe bronchial asthma or hypercapnia, and paralytic ileus.

WARNINGS:

Addiction, Abuse, and Misuse
Trezix™ contains dihydrocodeine bitartrate , a Schedule III controlled substance. As an opioid,
Trezix™ exposes users to the risks of addiction, abuse, and misuse [see DRUG
ABUSE AND DEPENDENCE].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Trezix™. 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 Trezix™, and monitor all patients receiving Trezix™ for the development of these behaviors or 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 Trezix™, but use in such patients necessitates intensive counseling about the risks and proper use of Trezix™ 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 Trezix™ .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 [see PRECAUTIONS; Information for Patients]. 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.

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 [see OVERDOSAGE]. 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 Trezix™, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Trezix™.

To reduce the risk of respiratory depression, proper dosing and titration of Trezix™ are
essential [see DOSAGE AND ADMINISTRATION]. Overestimating the Trezix™ 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 Trezix™, especially by children, can result in respiratory depression and death due to an overdose of dihydrocodeine bitartrate .

Neonatal Opioid Withdrawal Syndrome
Prolonged use of Trezix™ 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. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients, Pregnancy].

Risks due to Interactions with Central Nervous System Depressants
Hypotension, profound sedation, respiratory depression, coma, and death may result if
Trezix™ is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., benzodiazepines and other sedatives/hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).

When considering the use of Trezix™ in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin Trezix™ is made, start with a lower dosage of Trezix™, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant [see PRECAUTIONS; Drug Interactions].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of Trezix™ 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: - Trezix™ 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 Trezix™ [see WARNINGS].

Elderly, Cachetic, 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 [see
WARNINGS].

Monitor such patients closely, particularly when initiating and titrating Trezix™ and
when Trezix™ is given concomitantly with other drugs that depress respiration [see
WARNINGS]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 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.

Hepatotoxicity:

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death.  Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Serious Skin Reactions
Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine:

Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see Precautions, Nursing Mothers].

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or  *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert dihydrocodeine into its active metabolite, dihydromorphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum dihydromorphine 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) [see Overdosage].

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly  sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Dihydrocodeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications].

When prescribing dihydrocodeine-containing products, 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 [see Overdosage].

Hypersensitivity/Anaphylaxis:
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen.  Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticarial, rash, pruritus, and vomiting.  There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention.  Instruct patients to discontinue Trezix™ immediately and seek medical care if they experience these symptoms.  Do not prescribe Trezix™ for patients with acetaminophen allergy.

Usage in Ambulatory Patients:
Dihydrocodeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

Respiratory Depression:
Respiratory depression is the most dangerous acute reaction produced by opioid agonist preparations, although it is rarely severe with usual doses. Opioids decrease the respiratory rate, tidal volume, minute ventilation, and sensitivity to carbon dioxide. Respiratory depression occurs most frequently in elderly or debilitated patients, usually after large initial doses in nontolerant patients, or when opioids are given in conjunction with other agents that depress respiration. This combination product should be used with caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale and in patients with a substantially decreased respiratory reserve, hypoxia hypercapnia, or respiratory depression. In such patients, alternative non-opioid analgesics should be considered, and opioids should be administered only under careful medical supervision at the lowest effective dose.

Head Injury:
This combination product should be used cautiously in the presence of head injury or increased intracranial pressure. The effects of opioids on pupillary response and consciousness may obscure neurologic signs of increases in intracranial pressure in patients with head injuries. The respiratory depressant effects including carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or other causes of increased intracranial pressures.

Hypotensive Effect:
Dihydrocodeine, like all opioid analgesics, may cause hypotension in patients whose ability to maintain blood pressure has been compromised by a depleted blood volume or who receive concurrent therapy with drugs such as phenothiazines or other agents which compromise vasomotor tone. Acetaminophen, caffeine and dihydrocodeine bitartrate capsules may produce orthostatic hypotension in ambulatory patients. This combination product should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Drug Dependence:
Dihydrocodeine can produce drug dependence of the codeine type and has the potential of being abused (See DRUG ABUSE AND DEPENDENCE).

PRECAUTIONS:

General:

Selection of patients for treatment with Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be governed by the same principles that apply to the use of similar opioid/non-opioid fixed combination analgesics. As with any such opioid analgesic, the dosing regimen should be adjusted for each patient (See DOSAGE AND ADMINISTRATION). This combination product should be used with caution in elderly or debilitated patients or those with any of the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); asthma; central nervous system depression or coma; chronic obstructive pulmonary disease; decreased respiratory reserve (including emphysema, severe obesity, cor pulmonale, or kyphoscoliosis); delirium tremens; head injury; hypotension; increased intracranial pressure; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis. The benefits and risks of using opioids in patients taking monoamine oxidase inhibitors and in those with a history of drug abuse should be carefully considered. The administration of an analgesic containing an opioid may obscure the diagnosis or clinical course in patients with acute abdominal conditions. This combination product may aggravate convulsions in patients with convulsive disorders and, like all opioids, may induce or aggravate seizures in some clinical settings.

Acetaminophen is relatively non-toxic at therapeutic doses, but should be used with caution in patients with severe renal or hepatic disease. Care should be observed when using large doses of acetaminophen in malnourished patients or those with a history of chronic alcohol abuse because they may be more susceptible to hepatic damage similar to that observed with toxic overdosage. Caffeine in high doses may produce central nervous system and cardiovascular stimulation and gastrointestinal irritation.

Drug Interactions:

Dihydrocodeine with Other Central Nervous System Depressants:
Patients receiving other opioid analgesics, sedatives or hypnotics, muscle relaxants, general anesthetics, centrally acting anti-emetics, phenothiazines or other tranquilizers, or alcohol concomitantly with this combination product may exhibit additive depressant effects on the central nervous system. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Dihydrocodeine with Monoamine Oxidase Inhibitors:
Dihydrocodeine, like all opioid analgesics, interacts with monoamine oxidase inhibitors causing central nervous system excitation and hypertension.

Dihydrocodeine with Mixed Agonist/Antagonist Opioid Analgesics:
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) may reduce the analgesic effect of this combination product.

Acetaminophen Drug Interactions:
Chronic and excessive consumption of alcohol may increase the hepatotoxic risk of acetaminophen. The potential for hepatotoxicity with acetaminophen also may be increased in patients receiving anticonvulsants that induce hepatic microsomal enzymes (including phenytoin, barbiturates, and carbamazepine) or isoniazide. Chronic ingestion of large doses of acetaminophen may slightly potentiate the effects of warfarin-
and indandione- derivative anticoagulants. Severe hypothermia is possible in patients receiving acetaminophen concomitantly with phenothiazines.

Caffeine Drug Interactions:
Caffeine may enhance the cardiac inotropic effects of beta-adrenergic stimulating agents. Co-administration of caffeine and disulfiram may lead to a substantial decrease in caffeine clearance. Caffeine may increase the metabolism of other drugs such as phenobarbital and aspirin. Caffeine accumulation may occur when products or foods containing caffeine are consumed concomitantly with quinolones such as ciprofloxacin.

Information for Patients/Caregivers:

Addiction, Abuse, and Misuse
Inform patients that the use of Trezix™ even when taken as recommended, can result
in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS]. Instruct patients not to share Trezix™ with others and to take steps to protect Trezix™ 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 Trezix™ or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS]. 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 [see WARNINGS]. Instruct patients to take steps to store Trezix™ securely and to dispose of unused Trezix™ by xxx-xxx-xxx-xxx

Interactions with Alcohol and Other CNS Depressants
Inform patients that potentially serious additive effects may occur if Trezix™ is used with alcohol or other CNS depressants and not to use such drugs unless supervised by a health care provider [see WARNINGS, PRECAUTIONS; Drug Interactions].

Serotonin Syndrome
Inform patients that Trezix™ 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 [see PRECAUTIONS; Drug Interactions].

Adrenal Insufficiency
Inform patients that Trezix™ 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 [see WARNINGS].

Pregnancy
Neonatal Opioid Withdrawal Syndrome
Inform patients that prolonged use of Trezix™ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy]

Embryo-Fetal Toxicity
Inform female patients of reproductive potential that Trezix™ can cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy].

Lactation
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers].

Disposal of Unused Trezix™
Advise patients to take advantage of programs that allow the public to take unused drugs to a central location for proper disposal. Call your local law enforcement agencies to see if they sponsor medicine take-back programs in your community. Contact your city’s or county government’s household trash and recycling service to learn about medication disposal options and guidelines for your area.
Transfer unused medicines to collectors registered with the Drug Enforcement Administration (DEA). Authorized sites may be retail, hospital or clinic pharmacies, and law enforcement locations. Some offer mail-back programs or collection receptacles (“drop-boxes”). Visit the DEA’s website or call 1-800-882-9539 for more information and to find an authorized collector in your community.

Patients receiving Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be given the following information:

  1. Do not take Trezix™ if you are allergic to any of its ingredients.
  2. If you develop signs of allergy such as a rash or difficulty breathing stop taking Trezix™ and contact your healthcare provider immediately.
  3. Do not take more than 4000 milligrams of acetaminophen per day.  Call your doctor if you took more than the recommended dose.
  4. Patients should be advised that Trezix™ capsules may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
  5. Patients should be advised to report adverse experiences occurring during therapy.
  6. Patients should be advised not to adjust the dose of Trezix™ capsules without consulting the prescribing professional.
  7. Patients should not combine Trezix™ capsules with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.
  8. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
  9. Patients should be advised that Trezix™ capsules are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

Advise patients that some people have a genetic variation that results in dihydrocodeine changing into dihydromorphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid dihydrocodeine metabolizer or not. These higher-than-normal levels of dihydromorphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this  population due to respiratory depression. Dihydrocodeine-containing products are contraindicated in all children who undergo tonsillectomy  and/or adenoidectomy. Advise caregivers of children receiving dihydrocodeine-containing products for other reasons to monitor for signs of
respiratory depression.

Advise patients that nursing mothers taking dihydrocodeine can also have higher dihydromorphine levels in their breast milk if they are  ultra-rapid metabolizers. These higher levels of dihydromorphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Advise nursing mothers to watch for signs of dihydromorphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby’s doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

Pregnancy:

Teratogenic Effects – Pregnancy Category C. Animal reproduction studies have not been conducted with Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules. It is also not known whether this combination product can cause fetal harm when administered to pregnant women or can affect reproduction capacity in males and females. This combination product should be given to pregnant women only if clearly needed, especially during the first trimester.

Labor and Delivery:

Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules are not recommended for use by women during and immediately before labor and delivery because oral opioids may cause respiratory depression in the newborn.

Nursing Mothers:

Dihydrocodeine bitartrate is secreted into human milk. In women with normal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of dihydrocodeine. These women achieve higher-than-expected serum levels of dihydrocodeine’s active metabolite, dihydromorphine, leading to higher-than-expected levels of dihydromorphine in breast milk and potentially dangerously high serum dihydromorphine levels in their breastfed infants. Therefore, maternal use of dihydrocodeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The risk of infant exposure to dihydrocodeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when dihydrocodeine is administered to a nursing woman. If a dihydrocodeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using dihydrocodeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of dihydrocodeine-containing products during breastfeeding (See Warnings).

Acetaminophen and caffeine are also excreted in breast milk in small amounts. Because of the potential for serious adverse reactions in nursing infants from this combination product, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

Safety and effectiveness of Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules in pediatric patients have not been established.

Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine.

Dihydrocodeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS].

Geriatric Use:

Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be given with caution to the elderly.

Hepatic Impairment:

Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be given with caution to patients with hepatic insufficiency. Since dihydrocodeine is metabolized by the liver and since acetaminophen potentially causes hepatotoxicity, the effects of this combination product should be monitored closely in such patients.

Renal Impairment:

Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be used with caution and at reduced dosage in the presence of impaired renal function.

Pancreatic/Biliary Tract Disease:

Opioids may cause spasms of the sphincter of Oddi and should be used with caution in patients with biliary tract disease including pancreatitis.

ADVERSE REACTIONS:

Dihydrocodeine:
The most frequently observed adverse reactions include light-headedness, dizziness, drowsiness, headache, fatigue, sedation, sweating, nausea, vomiting, constipation, pruritus, and skin reactions. With the exception of constipation, tolerance develops to most of these effects. Other reactions that have been observed with dihydrocodeine or other opioids include respiratory depression, orthostatic hypotension, cough suppression, confusion, diarrhea, miosis, abdominal pain, dry mouth, indigestion, anorexia, spasm of biliary tract, and urinary retention. Physical and psychological dependence are possibilities. Hypersensitivity reactions (including anaphylactoid reactions), hallucinations, vivid dreams, granulomatous interstitial nephritis, severe narcosis and acute renal failure have been reported rarely during dihydrocodeine administration.

Acetaminophen:
Acetaminophen in therapeutic doses rarely causes adverse reactions. The most serious adverse reaction is hepatoxicity from overdosage (see OVERDOSAGE). Thrombocytopenia, leukopenia, pancytopenia, neutropenia, thrombocytopenic purpura, and agranulocytosis have been reported in patients receiving acetaminophen or p-aminophenol derivatives. Hypersensitivity reactions including urticarial or erythematous skin reactions, laryngeal edema, angioedema, or anaphylactoid reactions are rare.

Caffeine:
Adverse reactions associated with caffeine use include anxiety, anxiety neurosis, excitement, headaches, insomnia, irritability, lightheadedness, restlessness, tenseness, tremor, extrasystoles, palpitations, tachycardia, diarrhea, nausea, stomach pain, vomiting, diuresis, urticaria, scintillating scotoma, and tinnitus.

Postmarketing Experience

  • serotonin syndrome
  • adrenal insufficiency

Androgen deficiency
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms of hypogonadism, such as impotence, erectile dysfunction, or amenorrhea. The causal role of opioids in the
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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

DRUG ABUSE AND DEPENDENCE:

Controlled Substance
Trezix™ contains dihydrocodeine bitartrate, a Schedule III controlled substance.
Abuse
Trezix™ contains dihydrocodeine bitartrate, a substance with a high potential for abuse similar to other Schedule III opioids. Trezix™ can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries 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 health care 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. Health care 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.
Trezix™, 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 Trezix™
This combination product is subject to the provisions of the Controlled Substance Act and has been placed in Schedule III.

Dihydrocodeine can produce drug dependence of the codeine type and therefore has the potential of being abused. Like other opioid analgesics, dihydrocodeine may produce subjected effects other than analgesia (e.g., euphoria, relaxation), which may contribute to abuse by some patients. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of dihydrocodeine, and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral opioid analgesic medications. Symptoms of dihydrocodeine withdrawal consist of irritability, restlessness, insomnia, diaphoresis, anxiety and palpitations. Prolonged, high intake of caffeine may produce tolerance and habituation. Physical signs of withdrawal, such as headaches, irritation, nervousness, anxiety, and dizziness may occur upon abrupt discontinuation.

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 (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of
continued opioid usage.
Trezix™ should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If Trezix™ is abruptly discontinued in a physicallydependent 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 [see PRECAUTIONS; Pregnancy].

OVERDOSAGE:

Following an acute overdosage with Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules, toxicity may result from the dihydrocodeine or the acetaminophen. Toxicity due to the caffeine is less likely, due to the relatively small amounts in this formulation.

Clinical Presentation
Acute overdose with Trezix™ 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.

Signs and Symptoms: Toxicity from dihydrocodeine poisoning include the opioid triad of: pinpoint pupils, respiratory depression, and loss of consciousness. Convulsions, cardiovascular collapse, and death may occur. A single case of acute rhabdomyolysis associated with an overdose of dihydrocodeine has been reported. In acetaminophen overdosage: dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post ingestion. Acute caffeine poisoning may cause insomnia, restlessness, tremor, delirium, tachycardia, and extrasystoles.

Because overdose information on this combination product is limited, it is unclear which of the signs and symptoms of toxicity would manifest in any particular overdose situation.

Treatment
A single or multiple drug overdose with Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules is a potentially lethal polydrug overdose, and consultation with a regional Poison Control Center is recommended.  Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, and vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to dihydrocodeine, parenteral naloxone is a specific and effective antagonist. Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation.  Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading.  To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected.  Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication.  Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

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 Trezix™ overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Trezix™ overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of dihydrocodeine bitartrate in Trezix™ , carefully monitor the patient until spontaneous respiration is reliably re-established. 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.

DOSAGE AND ADMINISTRATION:

Important Dosage and Administration Instructions
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 [see WARNINGS].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Trezix™ and adjust the dosage accordingly [see WARNINGS].

Initial Dosage
The usual adult dosage is two (2) Trezix™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules orally every four (4) hours, as needed. Dosage should be adjusted according to the severity of the pain and the response of the patient. No more than two (2) capsules should be taken in a 4-hour period. No more than five (5) doses, or ten (10) capsules should be taken in a 24-hour period.

HOW SUPPLIED:

Trezix™ capsules, containing acetaminophen 320.5 mg, caffeine 30 mg and dihydrocodeine bitartrate 16 mg, are supplied in bottles of 100 capsules (NDC #66992-840-10).

Capsules are imprinted “Trezix” on the red cap in white ink.

Store at 20°C to 25°C (68°F to 77°F). [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container with a child-resistant closure. Protect from moisture.

Rx Only

Manufactured for:
WraSer Pharmaceuticals LLC
Ridgeland, MS 39157

13001 Rev. April 2016

Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.

Medication Guide
Trezix (Tre~zix)
Capsules, CIII

Trezix is:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage moderate to moderately severe pain, when otherpain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Trezix:

  • Get emergency help right away if you take too much Trezix (overdose). When you first start taking Trezix, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Never give anyone else your Trezix. They could die from taking it. Store Trezix away from children and in a safe place to prevent stealing or abuse. Selling or giving away Trezix is against the law.

Do not take Trezix if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.

Before taking Trezix, tell your healthcare provider if you have a history of:

  • head injury, seizures ● liver, kidney, thyroid problems
  • problems urinating ● pancreas or gallbladder problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of Trezix during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Trezix passes into breast milk and may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Trezix with certain other medicines can cause serious side effects that could lead to death.

When taking Trezix:

  • Do not change your dose. Take Trezix exactly as prescribed by your healthcare provider.
  • Take your prescribed dose of 2 Trezix capsules orally every 4 hours, as needed. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • If you have been taking Trezix regularly, do not stop taking Trezix without talking to your healthcare provider.
  • After you stop taking Trezix, Call your local law enforcement agencies to see if they sponsor medicine take-back programs in your community.

While taking Trezix DO NOT:

  • Drive or operate heavy machinery, until you know how Trezix affects you. Trezix can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Trezix may cause you to overdose and die.

The possible side effects of [established name]:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of Trezix. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

Manufactured for: WraSer Pharmaceuticals, 121 Marketridge Drive, Ridgeland, MS 39157, www.wraser.com or call1-888-252-3901

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: April 2016

Trezix 100 Count Bottle

NDC 66992-840-10

TrezixTM CIII

(acetaminophen, caffeine and dihydrocodeine bitartrate capsules 320.5mg/30mg/16mg)

Rx ONLY

100 CAPSULES

DESCRIPTION:                                                                  
Each red capsule contains:
Acetaminophen .................................. 320.5 mg
Caffeine ................................................... 30 mg
Dihydrocodeine Bitartrate ....................... 16 mg

USUAL DOSAGE: See package insert for full prescribing information.

WARNING: Keep this and all medications out of the reach of children.

ATTENTION DISPENSER: ï»¿Dispense the accompanying Medication Guide to each patient.

For additional Medication Guides, please visit www.Trezixrx.com

Dispense in a tight, light-resistant container with a child-resistant closure. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Manufactured for:
WraSer Pharmaceuticals
Ridgeland, MS 39157
www.wraser.com

13001 Rev. 4/16

WraSer PHARMACEUTICALS

Trezix 
acetaminophen, caffeine, dihydrocodeine bitartrate capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:66992-840
Route of Administration ORAL DEA Schedule CIII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 320.5 mg
CAFFEINE (CAFFEINE) CAFFEINE 30 mg
DIHYDROCODEINE BITARTRATE (DIHYDROCODEINE) DIHYDROCODEINE BITARTRATE 16 mg
Inactive Ingredients
Ingredient Name Strength
CROSPOVIDONE  
MAGNESIUM STEARATE  
POVIDONE  
STARCH, CORN  
STEARIC ACID  
FD&C RED NO. 40  
GELATIN  
Product Characteristics
Color red Score no score
Shape CAPSULE Size 20mm
Flavor Imprint Code Trezix
Contains         
Packaging
# Item Code Package Description
1 NDC:66992-840-10 100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA204785 12/01/2014
Labeler - WraSer LLC (121828334)
Registrant - WraSer LLC (121828334)
Establishment
Name Address ID/FEI Operations
Tedor Pharma Inc. 122644417 manufacture(66992-840)
Revised: 07/2016
 
WraSer LLC



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