er 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.

ch 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. ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children life-threatening respiratory depression and death have occurred in children who received codeine. codeine is subject to variability in metabolism based upon cyp2d6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. based upon post-marketing reports, children less than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. for example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. because of the risk of life-threatening respiratory depression and death: • trezix™ is contraindicated for all children younger than 12 years of age [see contraindications ]. • trezix™ is contraindicated for post-operative management in pediatric patients younger than 18 years of age following 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. • as with adults, when prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see overdosage ]. nursing mothers at least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. breastfeeding is not recommended during treatment with trezix™ [see precautions ; nursing mothers ]. cyp2d6 genetic variability: ultra-rapid metabolizer some individuals may be ultra-rapid metabolizers because of a specific cyp2d6 genotype (e.g., gene duplications denoted as *1/*1xn or *1/*2xn). the prevalence of this cyp2d6 phenotype varies widely and has been estimated at 1 to 10% for whites (european, north american), 3 to 4% for blacks (african americans), 1 to 2% for east asians (chinese, japanese, korean), and may be greater than 10% in certain ethnic groups (i.e., oceanian, northern african, middle eastern, ashkenazi jews, puerto rican). these individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. this rapid conversion results in higher than expected serum morphine levels. even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see overdosage ]. therefore, individuals who are ultra-rapid metabolizers should not use codeine. 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 ]. 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. 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. if concomitant use of a cyp3a4 inducer is necessary or if a cyp3a4 inhibitor is discontinued, consider increasing the trezix™ dosage until stable drug effects are achieved. monitor for signs of opioid withdrawal [see 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. 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 precautions ; drug interactions ]. 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. 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 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. 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. 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. 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 ].

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.

nter-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 ].

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.

er 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.

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 ].

dolescents 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 ].

nadal hormone levels have not been adequately controlled for in studies conducted to date [see adverse reactions ].