Analysis of reports of human exposure to Micotil 300 (tilmicosin injection)

Melissa F. Veenhuizen Eli Lilly & Co, Lilly Corporate Center, Indianapolis, IN 46285.

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Theressa J. Wright Eli Lilly & Co, Lilly Corporate Center, Indianapolis, IN 46285.

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Robert F. McManus Elanco Animal Health, a Division of Eli Lilly & Co, PO Box 708, Greenfield, IN 46140.

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Jane G. Owens Elanco Animal Health, a Division of Eli Lilly & Co, PO Box 708, Greenfield, IN 46140.

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Abstract

Objective—To identify clinical signs associated with and outcome of human exposure to Micotil 300 (tilmicosin injection).

Design—Retrospective case series.

Study Population—Reports of 3,168 human exposures to Micotil 300.

Procedures—Reports of human exposure to Micotil 300 submitted to the Elanco Animal Health Pharmacovigilance Unit between March 1992 and March 2005 were reviewed.

Results—At least 1 clinical sign was described in 1,404 (44%) reports, whereas the remaining 1,764 (56%) exposures were presumably asymptomatic. Eighty percent of exposures involved males; mean age was 38 years. Sixty-one percent of exposures were a result of accidental injection, with injection site pain, bleeding, swelling, or inflammation being the most common signs, followed by nausea, tachycardia, dizziness, anxiety, an abnormal taste, headache, lightheadedness, limb pain, paresthesia, chest pain, and soreness. Only 156 (5%) reports involved serious adverse effects (ie, tachycardia, bradycardia, hypertension, hypotension, heart disorder, chest pain, tachypnea, or death). There were reports of 13 deaths following tilmicosin exposure, but only 2 of those deaths were related to accidental exposure. Time to onset of clinical signs was ≤ 60 minutes in 63 of the 156 (40%) reports involving serious adverse effects.

Conclusions and Clinical Relevance—Results suggest that the overall risk of accidental human exposure to tilmicosin resulting in serious adverse effects is low (approx 2 people for every 1 million doses administered). Nevertheless, safe handling and proper use should be emphasized.

Abstract

Objective—To identify clinical signs associated with and outcome of human exposure to Micotil 300 (tilmicosin injection).

Design—Retrospective case series.

Study Population—Reports of 3,168 human exposures to Micotil 300.

Procedures—Reports of human exposure to Micotil 300 submitted to the Elanco Animal Health Pharmacovigilance Unit between March 1992 and March 2005 were reviewed.

Results—At least 1 clinical sign was described in 1,404 (44%) reports, whereas the remaining 1,764 (56%) exposures were presumably asymptomatic. Eighty percent of exposures involved males; mean age was 38 years. Sixty-one percent of exposures were a result of accidental injection, with injection site pain, bleeding, swelling, or inflammation being the most common signs, followed by nausea, tachycardia, dizziness, anxiety, an abnormal taste, headache, lightheadedness, limb pain, paresthesia, chest pain, and soreness. Only 156 (5%) reports involved serious adverse effects (ie, tachycardia, bradycardia, hypertension, hypotension, heart disorder, chest pain, tachypnea, or death). There were reports of 13 deaths following tilmicosin exposure, but only 2 of those deaths were related to accidental exposure. Time to onset of clinical signs was ≤ 60 minutes in 63 of the 156 (40%) reports involving serious adverse effects.

Conclusions and Clinical Relevance—Results suggest that the overall risk of accidental human exposure to tilmicosin resulting in serious adverse effects is low (approx 2 people for every 1 million doses administered). Nevertheless, safe handling and proper use should be emphasized.

Micotil 300 Injectiona is an injectable formulation of tilmicosin phosphate that was approved by the US FDA in March 1992 for use in the treatment of bovine respiratory tract disease associated with Mannheimia (Pasteurella) haemolytica infection at a dose of 10 mg/kg (4.5 mg/lb), SC. It was also approved for use in the control of disease in cattle at high risk of developing respiratory tract disease associated with M haemolytica infection. In 1990, similar injectable formulations of tilmicosin were approved in Canada, Italy, and Ireland for use in the treatment of bovine respiratory tract disease, and injectable formulations of the drug are currently marketed in > 55 countries for use in the control of respiratory tract disease in cattle, sheep, and rabbits. Additional formulations of tilmicosin have been approved for use in the control of respiratory tract disease in poultry, swine, cattle, and rabbits.

Ever since the drug was approved for use in the United States, the Micotil label has contained a boxed warning indicating that the drug may be fatal to humans and describing what to do in case of human exposure. Emergency medical telephone numbers have also been provided, along with information for physicians treating exposed patients. Studies1–3 of the toxicology and pharmacology of tilmicosin in animals given the drug by oral and parenteral routes suggest that the heart is the organ most susceptible to tilmicosin's toxic effects. During preclinical evaluations in various species, it was found that IM injection of tilmicosin at a dose of 20 mg/kg (9 mg/lb) in pigs or 30 mg/kg (13.6 mg/lb) in monkeys was fatal.1

A 1993 review1 of tilmicosin toxicosis indicated that the response to tilmicosin varies not only with dose but also with species, but that, regardless of species, clinical signs of tilmicosin toxicosis were related to the drug's positive chronotropic and negative inotropic cardiovascular effects. In dogs, tilmicosin causes dose-dependent decreases in left ventricular contractility (ie, a decrease in the maximum change in pressure over time) and aortic pulse pressure and a dose-dependent increase in heart rate.3 Propranolol was found to exacerbate the negative inotropic effects of tilmicosin and the decrease in left ventricular systolic pressure but did not alter the tachycardia. Dobutamine attenuates the change in ventricular contractility and restores left ventricular systolic pressure, thus reversing some, but not all, of the tilmicosininduced cardiovascular effects in dogs.

More recent testing involving human atrial myocytes and canine Purkinje fiber cells demonstrated that tilmicosin has substantial calcium channel antagonist activity.a A studyb involving dogs given tilmicosin IV followed by calcium chloride as an IV infusion demonstrated rapid reversal of the tilmicosin-induced decrease in left ventricular contractility and arterial pulse pressure and the increase in heart rate. These findings suggest that the cardiotoxicosis associated with tilmicosin exposure is a result of antagonism of L-type calcium channels and confirm that infusion of free calcium reverses the toxic effects of tilmicosin in dogs.

In December 2005, revisions to the Micotil label indicating that cardiotoxicosis may be attributable to calcium-channel blockade and that, in dogs, IV calcium administration offsets the tilmicosin-induced tachycardia and negative inotropy were approved. Additional information was included as a client information sheet or product insert for producers, emphasizing possible clinical effects of accidental human injection, proper methods for administering the product, and steps to take in case of accidental injection.

A previous study4 analyzed reports of 36 cases of accidental human exposure to tilmicosin submitted to the Poison Information Center in Toronto, Ontario, between 1991 and 1993. In 27 of the 36 (75%) cases, the patient had been exposed to ≤ 1 mL of the product, and in 26 (72%), exposure was a result of needle puncture. All patients in which exposure was a result of injection reported having pain at the injection site. The authors suggested that patients exposed to < 1 mL of tilmicosin could be treated symptomatically and did not need to be evaluated in a hospital. Further, they suggested that accidental ocular exposure or exposure to intact skin was unlikely to result in serious systemic or local toxic effects and cautioned that use of epinephrine should be avoided until the mechanisms underlying the interaction between epinephrine and tilmicosin had been clarified.

A reportc of death resulting from intentional exposure to tilmicosin (estimated dose, 18 to 21 mg/kg [8.2 to 9.5 mg/lb]) speculated that propylene glycol contained in the formulation was the true cause of death. However, in a report5 describing cardiogenic shock in a 49-year-old man accidentally injected with 2 to 3 mL of tilmicosin, any potential role for propylene glycol was dismissed when plasma concentration of propylene glycol 24 hours after the incident was found to be only 17 mg/mL, which was much lower than the concentration (50 mg/mL) reported to cause myocardial depression and cardiac arrhythmia. The absence of metabolic acidosis in this and in another reportd also helps rule out any role for propylene glycol in the cardiogenic shock seen in patients exposed to tilmicosin. Two additional reports6,7 describe electrocardiographic abnormalities in people exposed to tilmicosin, providing further evidence of myocardial damage.

A previous reporte described a 46-year-old male patient who was intentionally exposed to 12 mL of tilmicosin and who survived after treatment. The patient presented 1.5 hours after exposure with nausea, diaphoresis, and sinus tachycardia. The cardiac silhouette was enlarged on radiographs obtained 16 hours after exposure, but had normalized by 24 hours later. Treatment consisted of IV fluid therapy and administration of norepinephrine and dobutamine for 1 and 3 days, respectively. Acidosis did not develop, and the patient was discharged 6 days later.

A review8 of 46 cases of human exposure to tilmicosin reported that most incidents involved adult (84%) males (80%). Only 48% of the exposures were parenteral, and only 21% of the parenteral exposures resulted in moderate or major effects. The primary clinical effect reported for all exposures was irritation or pain (20%), with low incidences of erythema or flushing (8%), headache (8%), cardiovascular effects (8%), neurologic effects (8%), chest pain (4%), electrocardiographic changes (4%), and hypertension (4%). A separate reviewf concluded that although most exposures produced no or minor effects, fatalities had occurred with parenteral exposure and prolonged adverse effects had been reported even after exposure to amounts < 0.5 mL. These authors suggested that all patients with parenteral exposure be referred to a health care facility for evaluation.

Previous studies of human exposure to tilmicosin have involved only a single case or a relatively low number of cases. The purposes of the study reported here were to review pharmacovigilance data related to human exposure to Micotil, identify clinical signs associated with and outcome of human exposure, and evaluate potential occupational risks associated with human exposure.

Procedures

Reports of human exposure to Micotil are submitted to the Elanco Animal Health Pharmacovigilance Unit by human poison control centers and individuals accessing any of the emergency medical telephone numbers published on the product label. Although most such reports come from centers and individuals in the United States, reports of potential adverse events may also be received from locations outside the United States through these emergency medical telephone numbers or via fax.

For the present study, all reports of human exposure to Micotil received from March 1992, when Micotil was first approved for use in the United States, through March 2005 were reviewed. Because the study involved only a retrospective review of spontaneously submitted adverse event reports, review of the experimental protocol by an institutional review board was not required.

Results

Number of exposures—A total of 3,168 reports of human exposure to Micotil were submitted to Elanco Animal Health during the study period. At least 1 clinical sign was described in 1,404 of these 3,168 (44%) reports, whereas the remaining 1,764 (56%) exposures were presumably asymptomatic. Between 1992 and 1998, 1,101 asymptomatic exposures were reported, but individual data were not provided, so information on route or type of exposure and gender or age of the exposed individual was not available.

Annual number of reports of human exposure to tilmicosin ranged from a low of 127 in 1992 to a high of 343 in 1995 and remained around 200 from 1998 through 2005. Mean age of individuals exposed to tilmicosin was 38 years. Of the 1,950 cases for which gender information was provided, 1,561 (80%) involved males and 389 (20%) involved females.

Route of exposure—Information on route of exposure was available for 1,980 reports of human exposure to tilmicosin, with accidental injection reported most frequently (1,207 reports [61%]), followed by dermal (345 [17%]), oral (341 [17%]), ocular (51 [2.6%]), and inhalation (2 [0.1%]) exposure. In the remaining 34 (2%), the specific route of exposure was not indicated or was listed as other, including lacerations by broken bottles or needles. Most of the exposures resulting from injection were presumed to be a result of IM needle sticks, although only 8 (0.4%) of the reports describing accidental injection reported IM exposure, compared with 5 (0.25%) reports that indicated SC exposure and 3 (0.15%) that indicated IV exposure.

Clinical signs—Of the 1,980 reports in which route of exposure was indicated, 576 (29%) indicated that there were no clinical signs. For the remaining 1,404 reports, the most common clinical signs were abnormal taste (280 [20%]), injection site pain (275 [20%]), blood at the injection site (233 [17%]), injection site swelling (142 [10%]), nausea (88 [6%]), injection site inflammation (76 [5%]), headache (71 [5%]), dizziness (71 [5%]), tachycardia (68 [5%]), other injection site abnormalities (67 [5%]), chest pain (61 [4%]), anxiety (57 [4%]), paresthesia (53 [4%]), vomiting (46 [3%]), lightheadedness (42 [3%]), numbness (38 [3%]), fever (37 [3%]), limb pain (32 [2%]), weakness (31 [2%]), oral paresthesia (29 [2%]), malaise (25 [2%]), nervousness (25 [2%]), soreness (25 [2%]), sweating (24 [2%]), hypertension (23 [2%]), and eye irritation (22 [2%]). Other clinical signs described in ≤ 1% of reports included dyspnea, ecchymoses, diarrhea, application site erythema, application site pain, abdominal pain, feeling cold, irritation, lethargy, shaking, skin irritation, exhaustion, injection site stiffness, swelling of limb, erythema, eye pain, death (intentional and, potentially, accidental exposure), breathing difficulty, fainting, joint pain, arrhythmias, heart disorder, hematoma, pain in digit, sleepiness, stiff hands, and tongue abnormalities.

In reviewing reports (n = 1,207) involving accidental injection, localized clinical signs were most common, including injection site pain (270 [22%]), bleeding (231 [19%]), swelling (151 [12.5%]), inflammation (75 [6%]), and other injection site abnormalities (64 [5%]). Other clinical signs associated with exposure by injection that occurred less frequently but were indicative of potentially serious systemic effects included nausea (40 [3%]), tachycardia (38 [3%]), dizziness (35 [3%]), anxiety (28 [2%]), abnormal taste (27 [2%]), headache (26 [2%]), lightheadedness (26 [2%]), paresthesia (25 [2%]), chest pain (24 [2%]), numbness (19 [2%]), hypertension (18 [1%]), weakness (17 [1%]), vomiting (15 [1%]), and nervousness (12 [1%]).

In reports (n = 345) involving oral exposure, the most common clinical signs were taste abnormality (152 [44%]), headache (18 [5%]), paresthesia of the mouth or lips (18 [5%]), vomiting (18 [5%]), nausea (16 [5%]), chest pain (14 [4%]), dizziness (12 [4%]), tachycardia (12 [4%]), anxiety (8 [2%]), numbness (8 [2%]), malaise (6 [2%]), nervousness (6 [2%]), diarrhea (5 [2%]), fever or a feeling of being hot (5 [2%]), lightheadedness (5 [2%]), and muscle pain (5 [2%]).

In reports (n = 341) involving dermal exposure, the most common clinical signs were taste abnormality (90 [26%]), nausea (31 [9%]), headache (25 [7%]), chest pain (22 [6%]), paresthesia (22 [7%]), anxiety (19 [5%]), dizziness (19 [5%]), fever (14 [4%]), tachycardia (13 [4%]), vomiting (12 [3%]), weakness (12 [3%]), application site erythema (11 [3%]), application site pain (11 [3%]), numbness (11 [3%]), diarrhea (10 [3%]), dyspnea (10 [3%]), lightheadedness (10 [3%]), sweating (10 [3%]), paresthesia of the mouth or lips (10 [3%]), malaise (9 [3%]), abdominal pain (7 [2%]), and nervousness (7 [2%]).

For all routes of exposure, similar clinical signs, including potentially serious systemic signs, were reported; however, injection was the only route of exposure associated with death.

Volume of exposure—In most reports, regardless of route of exposure, the volume of drug to which individuals were exposed was ≤ 0.5 mL. In the 1,207 reports involving injection, 810 (67%) involved exposure to ≤ 0.5 mL, 33 (3%) involved exposure to > 0.5 but ≤ 1 mL, 12 (1%) involved exposure to > 1 but ≤ 2.5 mL, 7 (0.6%) involved exposure to 3 mL, and 11 (1%) involved exposure to 4 to 12 mL. In 334 (28%) reports, volume of exposure was not specified. Of the 8 reports that involved exposure by IM injection, 2 indicated that exposure volume was not known, 2 indicated exposure to 2 mL, and 1 each indicated exposure to 0.5, 4, 4.5, and 11 mL. Of the 5 reports that involved exposure by SC injection, 3 involved exposure to ≤ 0.5 mL, whereas 2 did not indicate volume of exposure. In all 4 reports that involved exposure by IV injection, the volume was estimated or unknown.

Volume of exposure was reported in only 91 of the 345 (26%) reports involving dermal exposure. Of these 91 reports, 65 (71%) involved exposure to ≤ 0.5 mL, 14 (15%) involved exposure to 1 to 2 mL, and 12 (13%) involved exposure to ≥ 3 mL. One report estimated total exposure at ≥ 2,000 mL (dermal exposure was implied). Volume of exposure was reported in 341 reports involving oral exposure. Of these 341 reports, 178 (52%) involved exposure to ≤ 0.5 mL, 11 (3%) involved exposure to > 0.5 but ≤ 1 mL, 12 (3.5%) involved exposure to > 1 but ≤ 5 mL, 2 (0.6%) involved exposure to 6 mL, and 1 (0.3%) involved exposure to approximately 10 mL. Fifty of the 51 reports involving ocular exposure, for which exposure volume was reported, involved exposure to ≤ 0.5 mL; 1 involved exposure to approximately 2 mL.

Cases with serious adverse effects—A review of specific cases was conducted to better understand exposures that resulted in serious adverse effects. Cases were selected for review if 1 or more of the following clinical signs were reported: tachycardia, bradycardia, hypertension, hypotension, heart disorder, chest pain, tachypnea, or death. Of the 3,168 reports of human exposure, 156 (5%) met this criterion.

In the 156 reports involving serious adverse effects, the most common clinical signs were tachycardia (69 [44%]), chest pain (61 [39%]), hypertension (23 [15%]), dyspnea (23 [15%]), taste abnormality (19 [12%]), dizziness (18 [12%]), anxiety (16 [10%]), nausea (15 [10%]), heart disorder or failure (13 [8%]), fever or a feeling of being hot (11 [7%]), weakness (11 [7%]), lightheadedness (11 [7%]), headache (11 [7%]), arrhythmias (10 [6%]), and nervousness (8 [5%]). The frequency of these clinical signs was higher in reports involving serious adverse effects (ranging from 5% to 44% of such reports) than in reports of all exposures (ranging from < 1% to 3.5% of all reports; Figure 1).

For reports involving serious adverse effects, the time from exposure to onset of clinical signs ranged from < 15 minutes to > 24 hours; however, in 63 of the 116 (54%) reports in which time was known, the time from exposure to onset of clinical signs was ≤ 60 minutes. Time from exposure to onset of clinical signs was ≤ 60 minutes for 35 of the 62 (56%) reports involving exposure by injection, 16 of the 30 (53%) involving dermal exposure, and 11 of the 21 (52%) reports involving oral exposure. Duration of clinical signs could not be evaluated.

Of the 156 reports involving serious adverse effects, 119 (76%) involved males and 37 (24%) involved females. Exposure by injection was more common in males (73 [86%]) than in females (12 [14%]). Similarly, dermal exposure was more common in males (29 [78%]) than in females (8 [22%]). However, oral exposure was as common in females (13 [50%]) as in males (13 [50%]). Four of the reports in which route of exposure was unknown involved males and 3 involved females. The single report involving ocular exposure involved a female.

For 30 of the 85 (35%) reports involving serious adverse effects in which the route of exposure was injection, the volume of exposure was ≤ 0.5 mL; for 5 (6%), the volume was 1 mL; for 2 (2%), the volume was 12 mL (in 1 case, the patient recovered, and in the other, the patient died); and for 1 (1%) each, the volume was 1.5, 2, 3, 4, 4.5 (IM exposure; the patient died), 5, 6, and 11 (IM exposure; the patient died) mL. For the remaining reports (23 [27%]), including 5 reports in which the patient died, the volume of exposure was unknown. Of the 37 reports involving serious adverse effects in which the route of exposure was dermal, 3 (8%) involved volumes of ≤ 0.5 mL, 1 (3%) involved a volume of 5 mL, and 1 (3%) involved cumulative exposure of > 2,000 mL; for the remaining reports, volume of exposure was not known. Twelve of the 25 (48%) reports involving serious adverse effects in which route of exposure was oral involved volumes of ≤ 0.5 mL, 1 (4%) involved a volume of 1.0 mL, 2 (8%) involved volumes of 1.5 mL, and 11 (44%) were unknown. In the 1 report involving ocular exposure, volume of exposure was not reported. No deaths were reported following dermal, ocular, or inhalation exposure.

Figure 1—
Figure 1—

Frequency of clinical signs following human exposure to Micotil 300 (tilmicosin injection) by injection (black bars) and following exposure by any route among individuals who developed serious adverse effects (white bars).

Citation: Journal of the American Veterinary Medical Association 229, 11; 10.2460/javma.229.11.1737

Deaths—Only 13 reports of human exposure to tilmicosin involved death (Table 1). In 2 cases (both males), death was reportedly a result of accidental injection; whereas in 11 (5 males and 6 females), death was reportedly a result of known or presumed intentional exposure (suicide). In all 13 cases, route of exposure was IV or IM or presumed to be injection, although in 1 case, ingestion could not be ruled out. Approximate dose that resulted in death following IM injection was estimated from approximate volume administered and estimated patient weight and ranged from 20 to 82 mg/kg (9 to 37 mg/lb). dose that resulted in death following IV injection ranged from 14.7 to 250 mg/kg (6.7 to 114 mg/lb).

Table 1—

Summary of reports of human exposure to Micotil 300 (tilmicosin injection) that resulted in death.

Case No.RouteVolume (mL)Body weight (kg)Dose (mg/kg)Type of exposureConcomitant drugs
1IM25 (approx)9182IntentionalNone known
2IM3–690 (estimated)20 (estimated)IntentionalNone known
3IVUnknownUnknownUnknownIntentionalNone known
4UnknownUnknownUnknownUnknownIntentionalAlcohol, hydrocodone, acetaminophen
5IV4–581.614.7–18.4IntentionalAlcohol
6IVUnknownUnknownUnknownIntentionalEpinephrine
7IM (presumed)1290 (estimated)40 (estimated)IntentionalNone known
8UnknownUnknownUnknownUnknownIntentionalAlcohol
9Unknown20–3060100–150IntentionalNone known
10Unknown*UnknownUnknownUnknownIntentionalNone known
11IV50–6060250IntentionalParacetemal, alcohol, temazepam
12IM10–1210030–36AccidentalNone
13IM10 (estimated)90 (estimated)33AccidentalNone

Possible ingestion and injection.

Clinical signs in fatal cases were often not described, as patients were found collapsed (1 with pupils fixed and dilated), unconscious, or dead. In 2 cases, collapse and cardiac arrest were the only clinical signs reported, and in 2 other cases, vomiting, chest pain, arrhythmias, tachycardia, cyanosis, and collapse with agonal heart rhythm and cardiac and respiratory arrest were reported. However, it was unclear whether all clinical signs were associated with tilmicosin administration because concomitant medications were present in at least 6 cases and treatments were administered in at least 2 cases. Time to onset of clinical signs was not reported in most cases. In 2 reports, clinical signs developed immediately, but in 1 report, time to onset of clinical signs was > 1 hour.

Intentional exposure—In at least 18 reports of human exposure to tilmicosin, exposure was identified as intentional. Eleven of these patients died and 7 survived. The volume of exposure in these cases was often not provided, but was estimated to be between 5 and 30 mL. In many cases, other agents such as alcohol, valium, epinephrine, and other unidentified substances were also administered.

Pharmacologic intervention—Information on pharmacologic intervention in cases with serious adverse effects was minimal. Nine reports indicated that patients received dobutamine, dopamine, epinephrine, or atropine. Four of these 9 patients died, including 3 that received epinephrine and 1 that received dopamine (this patient had fixed and dilated pupils at the time of examination). Of the 5 patients who survived, 4 received dobutamine and 1 received atropine.

A single report received after the end of the study period described treatment with IV administration of calcium chloride. This was a case of intentional exposure to an unknown volume of tilmicosin IM. The patient was treated with calcium chloride, dopamine, norepinephrine, and milrinone and survived.

Estimated risk of accidental human exposure—A rigorous evaluation of the risk of accidental human exposure to Micotil was not possible. However, given the number of reports of human exposure during the study period and the estimated total number of cattle treated with tilmicosin during this period, it was estimated that the risk of human exposure (symptomatic and asymptomatic) was 38.6 people for every 1 million doses administered (assuming use of a label dose of 1.5 mL/100 lb to treat 550-lb calves [ie, average dose of 8.25 mL]), and it was estimated that the risk of human exposure resulting in clinical signs was 17.1 people for every 1 million doses administered. The risk of human exposure resulting in serious adverse effects was estimated to be 2 people for every 1 million doses administered, and the risk of death following accidental injection was estimated to be 1 person for every 41 million doses administered .

Discussion

Results of the present study suggest that the overall risk of accidental human exposure to tilmicosin resulting in serious adverse effects was low (approx 2 people for every 1 million doses administered). The higher proportion of males versus females accidentally exposed to tilmicosin likely reflected the higher proportion of male versus female agricultural workers, rather than any difference in susceptibility between genders. In a recent national survey9 of agricultural workers, 80% were reported to be male, with a mean age of 31 years.

Although results of the present study suggest that the risk of serious adverse effects associated with accidental exposure to tilmicosin is low, they also suggest that all such exposures should be taken seriously and that the exposed individual should consult with a local health care professional or poison control center. In the present study, 5% of the reports of human exposure to tilmicosin involved serious adverse effects. In particular, signs of systemic effects, such as changes in heart rate or blood pressure (eg, flushing or feeling hot) or chest pain, should prompt immediate medical attention. Other signs of potentially serious systemic effects included nausea, dizziness, anxiety, lightheadedness, headache, numbness, weakness, and vomiting. These findings underscore the fact that exposure to tilmicosin that results in signs of tachycardia, dizziness, chest pain, nausea, anxiety, lightheadedness, headache, hypertension (sometimes reported as feeling hot or flushed), weakness, vomiting, or nervousness should be considered potentially life-threatening and that exposed individuals should seek medical attention immediately. Data for time of onset of clinical signs in the present study demonstrate that in most cases with serious adverse effects, clinical signs develop within 1 hour of exposure, indicating that it is important to seek medical attention immediately if the exposed individual is experiencing tachycardia, bradycardia, hypertension, hypotension, heart disorders, chest pain, or tachypnea.

Results of the present and previous preclinical studies1,3,4,b suggest that β-adrenoceptor antagonists and epinephrine should probably not be used in the medical management of patients exposed to tilmicosin. Patients treated with dobutamine or dopamine may have benefited from these drugs.

The most common route of exposure in the present study was accidental injection. Frequently, this resulted in no symptoms or in local injection site reactions, such as pain, bleeding, swelling, and inflammation. For all routes of exposure combined, an unusual or bitter taste was the most frequently reported sign.

Even though the risk of serious adverse effects associated with accidental exposure to tilmicosin appears to be low, measures should be taken to reduce the potential for accidental exposure when handling this product. Various hose adaptor kits can be used to reduce the number of times a needle has to be inserted into multiuse vials, reducing the risk of an accidental needle stick. Use of new trigger-lock syringes can reduce the risk of accidentally dispensing medications while carrying loaded syringes, and simple measures such as removing the needle from the syringe during transport can also be helpful. All needles should be kept guarded when not in use, and used needles should be disposed of in a dedicated container and not recapped following use. Limiting the dose volume per trigger pull with multiuse syringes to ≤ 2 mL can reduce the risk of accidental exposures to large volumes of drug. Properly restraining animals in such a way that they are unable to move in an unpredictable manner during drug administration is important, as is having a work area where syringes, needles, and medications can be safely placed while working. Proper training on safe handling and use should be provided for all those who administer products, and emergency numbers should be posted or preprogrammed into telephones in case of an emergency. If an accidental injection does occur, seek medical attention immediately; apply ice to the injection site while avoiding direct contact with the skin; and call 1-800-722-0987 or 1-317-276-2000 for additional emergency information

Micotil is a safe and effective product when administered as directed on the label. It is important to read and follow label instructions with this product, as with any product on the market today, because the label is an important source of the most current and pertinent product information.

a.

Micotil 300 (tilmicosin injection), Elanco Animal Health, Indianapolis, Ind.

b.

Main BW, Clark JO, Tucker TJ, et al. Attenuation of tilmicosin cardiotoxicity with calcium chloride infusion in conscious Beagle dogs (abstr), in Proceedings. 2005 North Am Cong Clin Toxicol. J Toxicol 2005;43:695.

c.

Kuffner E, Dart R. Death following intravenous injection of Micotil 300 (abstr), in Proceedings. 1996 North Am Cong Clin Toxicol. J Toxicol 1996;34:574.

d.

Mueller C, Bottei E. Suicide from tilmicosin injection: case report and blood levels (abstr), in Proceedings. 2003 North Am Cong Clin Toxicol. J Toxicol 2003;41:649–650.

e.

DeWitt CR, Inhabar N, Bronstein AC, et al. Survival after intramuscular self-injection of Micotil (abstr), in Proceedings. 2005 North Am Cong Clin Toxicol. J Toxicol 2005;43:736.

f.

Seifert SA, Jacobitz K. TESS-based characterization of human tilmicosin exposure and the parenteral dose-response relationship (abstr), in Proceedings. 2005 North Am Cong Clin Toxicol. J Toxicol 2005;43:735–736.

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