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Trezix
Overview
What is Trezix?
TREZIX™ capsules are supplied in capsule form for oral administration.Each red capsule contains:Acetaminophen...........................................320.5 mgCaffeine ..........................................................30 mgDihydrocodeine 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:
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.
What does Trezix look like?
What are the available doses of Trezix?
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What should I talk to my health care provider before I take Trezix?
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How should I use 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 UseBecause of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses [see ], reserve TREZIX™ for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]
Important Dosage and Administration Instructions
Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see ].
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 ].
Initial Dosage
Initiating treatment with TREZIX™
Conversion from Other Opioids to TREZIX™
Titration and Maintenance of Therapy
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™
What interacts with Trezix?
- TREZIX™ is contraindicated for:
- All children younger than 12 years of age [see and ]
- Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see and ].
- TREZIX is also contraindicated in patients with:
- Significant respiratory depression [see ]
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see ]
- Known or suspected gastrointestinal obstruction, including paralytic ileus [see ]
- Hypersensitivity to codeine, acetaminophen, or any of the formulation excipients. (e.g., anaphylaxis) [see ]
- 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.
What are the warnings of Trezix?
Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets. If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride extended-release tablets immediately, discontinue tramadol hydrochloride extended-release tablets permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction
Addiction, Abuse, and Misuse
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 ]. 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
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™ areessential [see ]. 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.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children
Neonatal Opioid Withdrawal Syndrome
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
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.
If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of TREZIX™ until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
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. If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the TREZIX™ dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the TREZIX™ dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see ; ].
Hepatotoxicity
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
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 ].
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. Screenpatients 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 and ].
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
Patients with Chronic Pulmonary Disease:
Elderly, Cachetic, or Debilitated Patients:
Monitor such patients closely, particularly when initiating and titrating TREZIX™ andwhen TREZIX™ is given concomitantly with other drugs that depress respiration [see
]. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal Insufficiency
Serious Skin Reactions
Usage in Ambulatory Patients
Respiratory Depression
Head Injury
Hypersensitivity/Anaphylaxis
Hypotensive Effect
Drug Dependence
What are the precautions of Trezix?
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 ]. 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
- 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).
- 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.
- 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.
- Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.
- 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.
- Patients should be advised to report adverse experiences occurring during therapy.
- Patients should be advised not to adjust the dose of TREZIX™ capsules without consulting the prescribing professional.
- Patients should be advised that TREZIX™ capsules are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
- Advise patients that some people have a genetic variation that results in dihydrocodeine changing into dihydromorphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid dihydrocodeine metabolizer or not. These higher-than-normal levels of dihydromorphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. Dihydrocodeine-containing products are contraindicated in all children who undergo tonsillectomy and/or adenoidectomy.
Drug Interactions
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
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 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 ].
Clinical Considerations
If Infants are exposed to TREZIX 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.
Pediatric Use
- TREZIX is contraindicated for all children younger than 12 years of age [see ].
- TREZIX is contraindicated for post-operative pain management in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy [see ].
- 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 withhypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, andconcomitant use of other medications that cause respiratory depression [see ].
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:
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 ].
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.
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What are the side effects of Trezix?
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 ). 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
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Androgen deficiency
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Serotonin syndrome:
Adrenal insufficiency:
Anaphylaxis
Androgen deficiency:
What should I look out for while using Trezix?
TREZIX™ is contraindicated for:
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.
Addiction, Abuse, and Misuse
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 ]. 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
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™ areessential [see ]. 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.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children
CONTRAINDICATIONS
CONTRAINDICATIONS
OVERDOSAGE
Nursing Mothers
CYP2D6 Genetic Variability: Ultra-rapid metabolizer
Neonatal Opioid Withdrawal Syndrome
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
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.
If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of TREZIX™ until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
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. If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the TREZIX™ dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the TREZIX™ dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see ; ].
Hepatotoxicity
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
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 ].
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. Screenpatients 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 and ].
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
Patients with Chronic Pulmonary Disease:
Elderly, Cachetic, or Debilitated Patients:
Monitor such patients closely, particularly when initiating and titrating TREZIX™ andwhen TREZIX™ is given concomitantly with other drugs that depress respiration [see
]. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal Insufficiency
Serious Skin Reactions
Usage in Ambulatory Patients
Respiratory Depression
Head Injury
Hypersensitivity/Anaphylaxis
Hypotensive Effect
Drug Dependence
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What might happen if I take too much Trezix?
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
Signs and Symptoms
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.
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.
How should I store and handle Trezix?
Store at 25°C (77°F): excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. Store at 25°C (77°F): excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. 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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.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 OnlyManufactured for:13001 Rev. 4/2017Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.
Clinical Information
Chemical Structure
No Image foundClinical 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
Non-Clinical Toxicology
TREZIX™ is contraindicated for: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.
Addiction, Abuse, and Misuse
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 ]. 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
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™ areessential [see ]. 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.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children
CONTRAINDICATIONS
CONTRAINDICATIONS
OVERDOSAGE
Nursing Mothers
CYP2D6 Genetic Variability: Ultra-rapid metabolizer
Neonatal Opioid Withdrawal Syndrome
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
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.
If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of TREZIX™ until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
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. If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the TREZIX™ dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the TREZIX™ dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see ; ].
Hepatotoxicity
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
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 ].
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. Screenpatients 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 and ].
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
Patients with Chronic Pulmonary Disease:
Elderly, Cachetic, or Debilitated Patients:
Monitor such patients closely, particularly when initiating and titrating TREZIX™ andwhen TREZIX™ is given concomitantly with other drugs that depress respiration [see ]. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal Insufficiency
Serious Skin Reactions
Usage in Ambulatory Patients
Respiratory Depression
Head Injury
Hypersensitivity/Anaphylaxis
Hypotensive Effect
Drug Dependence
CYP2D6 Inhibitors
Array
CYP3A4 Inhibitors
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
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
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 ].
Serotonergic Drugs
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 with Mixed Agonist/Antagonist Opioid Analgesics
Acetaminophen Drug Interactions
Caffeine Drug Interactions
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 ). 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
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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