ks should not, however, prevent the proper management of pain in any given patient. patients at increased risk may be prescribed opioids such as acetaminophen and codeine phosphate tablets but use in such patients necessitates intensive counseling about the risks 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 acetaminophen and codeine phosphate tablets. 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 (co 2 ) 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 acetaminophen and codeine phosphate tablets 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 to 72 hours of initiating therapy with and following dosage increases of acetaminophen and codeine phosphate tablets. to reduce the risk of respiratory depression, proper dosing and titration of acetaminophen and codeine phosphate tablets are essential [see dosage and administration ]. overestimating the acetaminophen and codeine phosphate tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. accidental ingestion of acetaminophen and codeine phosphate tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine. neonatal opioid withdrawal syndrome prolonged use ofacetaminophen and codeine phosphate tabletsduring 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. observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see precautions , information for patients/caregivers , pregnancy]. codeine phosphate death related to ultra-rapid metabolism of codeine to morphine codeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see contraindications ] . respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome p450 isoenzyme 2d6 [cyp2d6] or high morphine concentrations). deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see precautions, nursing mothers]. some individuals may be ultra-rapid metabolizers because of a specific cyp2d6 genotype (gene duplications denoted as *1/*1xn or *1/*2xn). the prevalence of this cyp2d6 phenotype varies widely and has been estimated at 0.5 to 1% in chinese and japanese, 0.5 to 1% in hispanics, 1 to 10% in caucasians, 3% in african americans, and 16 to 28% in north africans, ethiopians, and arabs. data are not available for other ethnic groups. these individuals convert 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 ]. children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. risks of interactions with drugs affecting cytochrome p450 isoenzymes the effects of concomitant use or discontinuation of cytochrome p450 3a4 inducers, 3a4 inhibitors, or 2d6 inhibitors with codeine are complex. use of cytochrome p450 3a4 inducers, 3a4 inhibitors, or 2d6 inhibitors with acetaminophen and codeine phosphate tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. cytochrome p450 3a4 interaction the concomitant use of acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets and any cyp3a4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen and codeine phosphate tablets are used in conjunction with inhibitors and inducers of cyp3a4 [see warnings, precautions, drug interactions]. risks of concomitant use or discontinuation of cytochrome p450 2d6 inhibitors the concomitant use of acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets and any cyp2d6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when acetaminophen and codeine phosphate tablets are used in conjunction with inhibitors of cyp2d6 [see precautions , drug interactions]. risks from concomitant use with benzodiazepines or other cns depressants profound sedation, respiratory depression, coma, and death may result from the concomitant use of acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets are 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 , information for patients, drug interactions]. life-threatening respiratory depression in patients with chronic pulmonary disease or elderly, cachectic, or debilitated patients the use of acetaminophen and codeine phosphate tablets 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: acetaminophen and codeine phosphate tablets-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 acetaminophen and codeine phosphate tablets [see warnings; life-threatening respiratory depression]. elderly, cachectic, or debilitated patients: life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, including clearance, compared to younger, healthier patients [see warnings; respiratory depression]. monitor such patients closely, particularly when initiating and titrating acetaminophen and codeine phosphate tablets and when acetaminophen and codeine phosphate tablets is given concomitantly with other drugs that depress respiration [see warnings ; life threatening-respiratory depression]. alternatively, consider the use of non-opioid analgesics in these patients. interaction with monoamine oxidase inhibitors monoamine oxidase inhibitors (maois) may potentiate the effects of morphine, codeine’s active metabolite including respiratory depression, coma, and confusion. acetaminophen and codeine phosphate tablets should not be used in patients taking maois or within 14 days of stopping such treatment. 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. severe hypotension acetaminophen and codeine phosphate tablets may cause severe hypotension including hypotension and syncope in ambulatory patients. there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain cns depressant drugs (e.g., phenothiazines or general anesthetics) [see precautions; drug interactions]. monitor these patients for signs of hypotension after initiating or titrating the dosage of acetaminophen and codeine phosphate tablets. in patients with circulatory shock acetaminophen and codeine phosphate tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. avoid the use of acetaminophen and codeine phosphate tablets with circulatory shock. hepatotoxicity acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. 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 4,000 milligrams of acetaminophen per day, even if they feel well. serious skin reactions rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (agep), stevens-johnson syndrome (sjs), and toxic epidermal necrolysis (ten), which can be fatal. patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. hypersensitivity/anaphylaxis there have been postmarketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. clinical signs include 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 acetaminophen and codeine phosphate tablets immediately and seek medical care if they experience these symptoms. do not prescribe acetaminophen and codeine phosphate tablets for patients with acetaminophen allergy. risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness in patients who may be susceptible to the intracranial effects of co2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), acetaminophen and codeine phosphate tablets may reduce respiratory drive, and the resultant co2 retention can further increase intracranial pressure. monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with acetaminophen and codeine phosphate tablets. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of acetaminophen and codeine phosphate tablets in patients with impaired consciousness or coma. risks of use in patients with gastrointestinal conditions acetaminophen and codeine phosphate tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. the administration of acetaminophen and codeine phosphate tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. acetaminophen and codeine phosphate tablets may cause spasm of the sphincter of oddi. opioids may cause increases in serum amylase. monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. sulfite sensitivity acetaminophen and codeine phosphate tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. the overall prevalence of sulfite sensitivity in the general population is unknown and probably low. sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. increased risk of seizures in patients with seizure disorders the codeine in acetaminophen and codeine phosphate tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. monitor patients with a history of seizure disorders for worsened seizure control during acetaminophen and codeine phosphate tablets therapy. withdrawal avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including acetaminophen and codeine phosphate tablets. in these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. when discontinuing acetaminophen and codeine phosphate tablets, gradually taper the dosage [see dosage and administration]. do not abruptly discontinue acetaminophen and codeine phosphate tablets [see drug abuse and dependence ].

ated. adult doses of codeine higher than 60 mg are associated with an increased incidence of adverse reactions and are not associated with greater efficacy. the usual adult dosage is: acetaminophen and codeine phosphate tablets (codeine 15 mg and acetaminophen 300 mg): take 1 to 2 tablets every 4 hours as needed for pain. acetaminophen and codeine phosphate tablets (codeine 30 mg and acetaminophen 300 mg): take 1 to 2 tablets every 4 hours as needed for pain. acetaminophen and codeine phosphate tablets (codeine 60 mg and acetaminophen 300 mg): take one tablet every 4 hours as needed for pain. single doses (range) maximum 24-hour dose codeine phosphate 15 mg to 60 mg 360 mg acetaminophen 300 mg to 1000 mg 4000 mg the prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours, based upon the above dosage guidance. this information should be conveyed in the prescription. the usual dose of codeine phosphate in children is 0.5 mg/kg. doses may be repeated up to every 4 hours. conversion from other opioids to acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets. it is safer to underestimate a patient’s 24-hour acetaminophen and codeine phosphate tablets dosage than to overestimate the 24-hour acetaminophen and codeine phosphate tablets dosage and manage an adverse reaction due to overdose. initiating treatment with acetaminophen and codeine phosphate tablets the prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours based upon the above dosage guidance. this information should be conveyed in the prescription. it should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. equivalently high doses in children would have similar effects. titration and maintenance of therapy individually titrate acetaminophen and codeine phosphate tablets to a dose that provides adequate analgesia and minimizes adverse reactions. continually reevaluate patients receiving acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets when a patient who has been taking acetaminophen and codeine phosphate tablets regularly and may be physically dependent no longer requires therapy with acetaminophen and codeine phosphate tablets,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 acetaminophen and codeine phosphate tablets in a physically-dependent patient [see warnings , drug abuse and dependence ].

ed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis. cardiovascular system : faintness, flushing, hypotension, palpitations, syncope digestive system: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis nervous system: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness skin and appendages: rash, sweating, urticarial • 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 acetaminophen and codeine phosphate tablets. • androgen deficiency : cases of androgen deficiency have occurred with chronic use of opioids [see clinical pharmacology ].

d mydriasis rather than miosis may be seen due to hypoxia in overdose situations. effects on the gastrointestinal tract and other smooth muscle codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. digestion of food in the small intestine is delayed and propulsive contractions are decreased. propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of oddi, and transient elevations in serum amylase. effects on the cardiovascular system codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. effects on the endocrine system opioids inhibit the secretion of adrenocorticotropic hormone (acth), cortisol, and luteinizing hormone (lh) in humans [see adverse reactions]. they also stimulate prolactin, growth hormone (gh) secretion, and pancreatic secretion of insulin and glucagon. chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. the causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see adverse reactions]. effects on the immune system opioids have been shown to have a variety of effects on components of the immune system. the clinical significance of these findings is unknown. overall, the effects of opioids appear to be modestly immunosuppressive. concentration–efficacy relationships the minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. the minimum effective analgesic concentration of codeine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see dosage and administration]. concentration–adverse reaction relationships there is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, cns effects, and respiratory depression. in opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions see dosage and administration]. pharmacokinetics the behavior of the individual components is described below. codeine codeine is readily absorbed from the gastrointestinal tract. it is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. the plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is about 7-25% bound to plasma proteins and does not accumulate in body tissues. about 70 to 80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (c6g) and via o-demethylation to morphine (about 5 to 10%) and n-demethylation to norcodeine (about 10%) respectively. udp-glucuronosyltransferase (ugt) 2b7 and 2b4 are the major enzymes mediating glucurodination of codeine to c6g. cytochrome p450 2d6 is the major enzyme responsible for conversion of codeine to morphine and p450 3a4 is the major enzyme mediating conversion of codeine to norcodeine. morphine and norcodeine are further metabolized by conjugation with glucuronic acid. the glucuronide metabolites of morphine are morphine-3-glucuronide (m3g) and morphine-6-glucuronide (m6g). morphine and m6g are known to have analgesic activity in humans. the analgesic activity of c6g in humans is unknown. norcodeine and m3g are generally not considered to possess analgesic properties. the plasma half-life is about 2.9 hours. the elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. the urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). the remainder of the dose is excreted in the feces. at therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. acetaminophen acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. a small fraction (10-25%) of acetaminophen is bound to plasma proteins.the plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, p450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. the principal cytochrome p450 isoenzyme involved appears to be cyp2e1, with cyp1a2 and cyp3a4 as additional pathways. approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. see overdosage for toxicity information.