TREZIX- acetaminophen, caffeine, dihydrocodeine bitartrate capsule

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
ACETAMINOPHEN (UNII: 362O9ITL9D) (ACETAMINOPHEN - UNII:362O9ITL9D), CAFFEINE (UNII: 3G6A5W338E) (CAFFEINE - UNII:3G6A5W338E), DIHYDROCODEINE BITARTRATE (UNII: 8LXS95BSA9) (DIHYDROCODEINE - UNII:N9I9HDB855)
Available from:
Bryant Ranch Prepack
INN (International Name):
ACETAMINOPHEN
Composition:
ACETAMINOPHEN 320.5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules are indicated for the management of 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 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] - Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy [see WARNINGS] - Patients with known or suspected gastrointestinal obstruction, including paralytic ileus
Product summary:
Product: 63629-5637 NDC: 63629-5637-1 30 CAPSULE in a BOTTLE NDC: 63629-5637-2 60 CAPSULE in a BOTTLE NDC: 63629-5637-3 90 CAPSULE in a BOTTLE NDC: 63629-5637-4 120 CAPSULE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-5637-1, 63629-5637-2, 63629-5637-3, 63629-5637-4

TREZIX- acetaminophen, caffeine, dihydrocodeine bitartrate capsule

Bryant Ranch Prepack

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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.

Trezix can cause severe drowsiness, breathing problems (respiratory depression), coma and death

when taken with benzodiazepines or other medicines that depress consciousness.

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.

previously had an allergic reaction to dihydrocodeine or acetaminophen.

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. Use the

lowest dose possible for the shortest time needed.

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, dispose the unused Trezix in accordance with local state guidelines

and/or regulations.

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 Trezix:

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: 11/2016

Revised: 6/2017

Document Id: 0f379aba-f28b-40b4-a2fc-d807829f2c70

34391-3

Set id: f90f87cb-77ad-45f4-8b59-09459090d988

Version: 3

Effective Time: 20170615

Bryant Ranch Prepack

TREZIX- acetaminophen, caffeine, dihydrocodeine bitartrate capsule

Bryant Ranch Prepack

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TREZIX™ Capsules

Acetaminophen, Caffeine and Dihydrocodeine Bitartrate

320.5 mg / 30 mg / 16 mg

Rx Only CIII

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING

RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID

WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM

OF CODEINE TO MORPHINE; HEPATOTOXICITY; CYTOCHROME P450 2D6

INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES

OR OTHER CNS DEPRESSANTS

Addiction, Abuse and Misuse

TREZIX™ expose 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 and 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 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].

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 CYP2D6 polymorphism [see WARNINGS,

PRECAUTIONS; Information for Patients/Caregivers, Nursing mothers].

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 4,000 milligrams per day, and often involve more than

one acetaminophen-containing product [see WARNINGS].

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 codeine are complex. Use of cytochrome P450 3A4

inducers, 3A4 inhibitors, or 2D6 inhibitors with TREZIX™ requires careful consideration

of the effects on the parent drug, codeine, and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of TREZIX™ with all cytochrome P450 3A4 inhibitors or

discontinuation of a cytochrome P450 3A4 inducer may result in an increase in codeine

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 TREZIX™ with all cytochrome P450 3A4 inducers or

discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine 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 TREZIX™ and any CYP3A4 inhibitor or inducer for signs and

symptoms that may reflect opioid toxicity and opioid withdrawal when TREZIX™ are used

in conjunction with inhibitors and inducers of CYP3A4 [see WARNINGS, PRECAUTIONS;

Drug Interactions].

Cytochrome P450 2D6 Interaction

The concomitant use of TREZIX™ with all cytochrome P450 2D6 inhibitors may result in

an increase in codeine plasma concentrations and a decrease in the plasma concentration of

the active metabolite, morphine, which could result in an analgesic efficacy reduction or

symptoms of opioid withdrawal.

The discontinuation of a cytochrome P450 2D6 inhibitor may result in a decrease in codeine

plasma concentrations and an increase in the plasma concentration of the active metabolite,

morphine, which could which could increase or prolong adverse reactions and may cause

potentially fatal respiratory depression.

Follow patients receiving TREZIX™ and any CYP2D6 inhibitor for signs and symptoms

that may reflect opioid toxicity and opioid withdrawal when TREZIX™ are used in

conjunction with inhibitors of CYP2D6 [see WARNINGS, PRECAUTIONS; Drug

Interactions ].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression,

coma, and death [see WARNINGS, PRECAUTIONS; Drug Interactions].

Reserve concomitant prescribing of TREZIX™ and benzodiazepines or other CNS

depressants for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

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.

Effects on the Endocrine System

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal

changes 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 [see ADVERSE REACTIONS].

INDICATIONS AND USAGE

TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules are indicated for the

management of 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]

Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy

[see WARNINGS]

Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see

WARNINGS]

Patients with hypersensitivity to codeine, acetaminophen, or any of the formulation excipients. (e.g.,

anaphylaxis) [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 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].

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].

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 codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or

2D6 inhibitors with TREZIX™ requires careful consideration of the effects on the parent drug,

codeine, and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of TREZIX™ 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 codeine 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 TREZIX™ with all cytochrome P450 3A4 inducers or discontinuation of a

cytochrome P450 3A4 inhibitor may result in lower codeine 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 TREZIX™ and any CYP3A4 inhibitor or inducer for signs and symptoms that

may reflect opioid toxicity and opioid withdrawal when TREZIX™ are used in conjunction with

inhibitors and inducers of CYP3A4 [see WARNINGS, PRECAUTIONS; Drug Interactions].

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

The concomitant use of TREZIX™ with all cytochrome P450 2D6 inhibitors (e.g., amiodarone,

quinidine) may result in an increase in codeine 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

codeine plasma concentration and an increase in active metabolite morphine plasma concentration which

could which could increase or prolong adverse reactions and may cause potentially fatal respiratory

depression.

Follow patients receiving TREZIX™ and any CYP2D6 inhibitor for signs and symptoms that may reflect

opioid toxicity and opioid withdrawal when TREZIX™ are used in conjunction with inhibitors of

CYP2D6 [see PRECAUTIONS; Drug Interactions].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of

TREZIX™ 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 [see PRECAUTIONS; Drug Interactions].

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

TREZIX™ is 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 [see PRECAUTIONS; Drug Interactions and PRECAUTIONS; Information for

Patients].

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.

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,

urticaria, 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 obstructivepulmonary 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.

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™.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if

TREZIX™ is used with benzodiazepines or other CNS depressants, including alcohol, and not to use

these concomitantly unless supervised by a health care provider [see WARNINGS and

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 female patients of reproductive potential 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 patients that nursing mothers taking dihydrocodeine can 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 which includes increased sleepiness (more than

usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to seek

immediate medical care 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) [see PRECAUTIONS;

Nursing Mothers].

Disposal of Unused TREZIX™

Advise patients to properly dispose of unused TREZIX™. 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 the local state guidelines and/or

regulations.

Patients receiving TREZIX™ capsules should be given the following information:

1. Do not take TREZIX™ if you are allergic to any of its ingredients. If you develop signs of allergy

such as a rash or difficulty breathing stop taking TREZIX™ and contact your healthcare provider

immediately.

2. Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more

than the recommended dose.

3. 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.

4. Patients should be advised to report adverse experiences occurring during therapy.

5. Patients should be advised not to adjust the dose of TREZIX™ capsules without consulting the

prescribing professional.

6. 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.

7. 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.

Drug Interactions

CYP3A4 Inhibitors

The concomitant use of TREZIX™ with CYP3A4 inhibitors such as macrolide antibiotics (e.g.,

erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), may

result in an increase in dihydrocodeine plasma concentration with subsequently greater metabolism by

cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse

reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added

after a stable dose of TREZIX™ is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower

dihydrocodeine plasma levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with

resultant lower dihyromorphine levels, resulting in decreased opioid efficacy or a withdrawal

syndrome in patients who had developed physical dependence to dihydrocodeine. If concomitant use

with CYP3A4 inhibitor is necessary, consider dosage reduction of TREZIX™ until stable drug effects

are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the TREZIX™ dosage until stable drug

effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 Inducers

The concomitant use of TREZIX™ and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin),

can result in lower dihydrocodeine levels, greater dihydronorcodeine levels, and less metabolism via

2D6 with resultant lower dihyromorphine levels, resulting in decreased efficacy or a withdrawal

syndrome in patients who had developed physical dependence to dihydrocodeine.

After stopping a CYP3A4 inducer, as the effects of the inhibitor decline, the dihydrocodeine plasma

concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in

greater dihyromorphine levels, which could increase or prolong both the therapeutic effects and

adverse reactions, and may cause serious respiratory depression.

If concomitant use with CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs

of opioid withdrawal and consider increasing the TREZIX™ dosage as needed.

If a CYP3A4 inducer is discontinued, consider TREZIX™ dosage reduction and monitor for signs of

respiratory depression and sedation at frequent intervals.

CYP2D6 Inhibitors

Dihydrocodeine in TREZIX™ is metabolized by CYP2D6 to form dihydromorphine . The concomitant

use of TREZIX™ and CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine bupropion) can

increase the plasma concentration of dihydrocodeine, but can decrease the plasma concentration of

active metabolite dihydromorphine which could result in reduced analgesic efficacy or symptoms of

opioid withdrawal, particularly when an inhibitor is added after a stable dose of TREZIX™ is achieved.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the dihydrocodeine plasma

concentration will decrease but the active metabolite dihydromorphine plasma concentration will

increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory

depression.

If concomitant use with a CYP2D6 inhibitor is necessary or if a CYP2D6 inhibitor is discontinued after

concomitant use, consider dosage adjustment of TREZIX™ and monitor patients closely at frequent

intervals.

If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or

signs and symptoms of opioid withdrawal and consider increasing the TREZIX™ as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the TREZIX™ and monitor the patient for

signs and symptoms of respiratory depression or sedation.

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS

depressants, including alcohol, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle

relaxants, general anesthetics, antipsychotics and other opioids, can increase the risk of hypotension,

respiratory depression, profound sedation, coma, and death. .

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment

options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely

for signs of respiratory depression and sedation [see WARNINGS].

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system,

such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors

(SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the

serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase

(MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous

methylene blue) [see PRECAUTIONS; Information for Patients].

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and

dose adjustment. Discontinue TREZIX™ immediately if serotonin syndrome is suspected.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 [see ADVERSE REACTIONS].

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.

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 [see WARNINGS].

Labor and 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. TREZIX™ is not recommended for use in pregnant women during

or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid

analgesics, including TREZIX™, and 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.

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].

Infants exposed to Acetaminophen and Codeine Tablets through breast milk 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 breast-feeding is stopped.

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

Elderly patients (aged 65 years or older) may have increased sensitivity to TREZIX™. 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 TREZIX™ slowly in

geriatric patients and monitor closely for signs of central nervous system and central nervous system

depression [see WARNINGS].

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: 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 TREZIX™.

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

[see CLINICAL PHARMACOLOGY].

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™

TREZIX™ is for oral use only. Abuse of TREZIX™ poses a risk of overdose and death. The risk is

increased with concurrent use of TREZIX™ with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis

and HIV.

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 includes 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 of Overdose

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.

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.

For respiratory depression due to 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.

DOSAGE AND ADMINISTRATION

Important Dosage and Administration Instructions

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

goals [see WARNINGS].

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

Initiating treatment with TREZIX™

The usual adult dosage is two (2) TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate)

capsules orally every four (4) hours, as needed. No more than five (5) doses, or ten (10) capsules

should be taken in a 24-hour period.

Conversion from Other Opioids to TREZIX™

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 TREZIX™. It is safer to

underestimate a patient’s 24-hour TREZIX™ dosage than to overestimate the 24-hour TREZIX™

dosage and manage an adverse reaction due to overdose.

Titration and Maintenance of Therapy

Individually titrate TREZIX™ to a dose that provides adequate analgesia and minimizes adverse

reactions. Continually reevaluate patients receiving TREZIX™ 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 [see WARNINGS]. 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 TREZIX™ 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.

Discontinuation of TREZIX™

When a patient who has been taking TREZIX™ regularly and may be physically dependent no longer

requires therapy with TREZIX™, 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

TREZIX™ in a physically-dependent patient [see WARNINGS, DRUG ABUSE AND DEPENDENCE].

HOW SUPPLIED

Product: 63629-5637

NDC: 63629-5637-1 30 CAPSULE in a BOTTLE

NDC: 63629-5637-2 60 CAPSULE in a BOTTLE

NDC: 63629-5637-3 90 CAPSULE in a BOTTLE

NDC: 63629-5637-4 120 CAPSULE in a BOTTLE

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.

Trezix can cause severe drowsiness, breathing problems (respiratory depression), coma and death

when taken with benzodiazepines or other medicines that depress consciousness.

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.

previously had an allergic reaction to dihydrocodeine or acetaminophen.

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. Use the

lowest dose possible for the shortest time needed.

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, dispose the unused Trezix in accordance with local state guidelines

and/or regulations.

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 Trezix:

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:

11/2016

TREZIX (ACETAMINOPHEN, CAFFEINE, DIHYDROCODEINE BITARTRATE) CAPSULE

TREZIX

acetaminophen, caffeine, dihydrocodeine bitartrate capsule

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -

56 37(NDC:6 6 9 9 2-8 40 )

Route of Administration

ORAL

DEA Sche dule

CIII

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ACETAMINO PHEN (UNII: 36 2O9 ITL9 D) (ACETAMINOPHEN - UNII:36 2O9 ITL9 D)

ACETAMINOPHEN

320 .5 mg

CAFFEINE (UNII: 3G6 A5W338 E) (CAFFEINE - UNII:3G6 A5W338 E)

CAFFEINE

30 mg

DIHYDRO CO DEINE BITARTRATE (UNII: 8 LXS9 5BSA9 ) (DIHYDROCODEINE -

UNII:N9 I9 HDB8 55)

DIHYDROCODEINE

BITARTRATE

16 mg

Bryant Ranch Prepack

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SPO VIDO NE, UNSPECIFIED (UNII: 2S78 30 E56 1)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

STARCH, CO RN (UNII: O8 232NY3SJ)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

GELATIN, UNSPECIFIED (UNII: 2G8 6 QN327L)

Product Characteristics

Color

re d

S core

no sco re

S hap e

CAPSULE

S iz e

20 mm

Flavor

Imprint Code

TREZIX

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -56 37-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /0 4/20 15

2

NDC:6 36 29 -56 37-2

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /0 4/20 15

3

NDC:6 36 29 -56 37-3

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/13/20 15

4

NDC:6 36 29 -56 37-4

120 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

10 /26 /20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 478 5

12/0 1/20 14

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -56 37) , RELABEL(6 36 29 -56 37)

Revised: 6/2017

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