Trezix

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

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].

CYP2D6 InhibitorsDihydrocodeine in TREZIX™ is metabolized by CYP2D6 to form dihydromorphine . The concomitant use of TREZIX™ and CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine, fluoxetine, bupropion, quinidine) 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

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 dihydromorphine 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.

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.

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].

Dihydrocodeine bitartrate and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of dihydrocodeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants.  In women with normal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent. There is no information on the effects of the dihydrocodeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TREZIX™ [see WARNINGS].

Clinical Considerations

If Infants are exposed to TREZIX^​TM​ through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when 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.

Safety and effectiveness of TREZIX™ in pediatric patients have not been established.

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

• TREZIX^​TM​ is contraindicated for all children younger than 12 years of age [see CONTRAINDICATIONS].
• TREZIX^​TM​ is contraindicated for post-operative pain management in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS].
• Avoid the use of TREZIX™ in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with
  hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and
  concomitant use of other medications that cause respiratory depression [see WARNINGS].

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].

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.

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.
• Taking Trezix with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decrease awareness, breathing problems, coma and death.
• 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.

Important Information Guiding Use in Pediatric Patients:

• Do not give Trezix to a child younger than 12 years of age.

• Do not give Trezix to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids.

• Avoid giving Trezix to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems

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.
• have been told by your healthcare provider that you are a “rapid metabolizer” of certain medicines.

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. Not recommended; 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: 12/2017

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:

[image: MM1]
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:
[image: MM2]

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:
[image: MM3]
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.

NDC 66992-840-10

TREZIX^TM 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: 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. 7/2017

WraSer PHARMACEUTICALS

[image: MM4]

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. 4/2017

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