Summary Of Exposure |
A) USES: Levamisole is used in the United States as an antihelminthic agent in veterinary medicine to control parasites in livestock. Levamisole has been used for the treatment of colorectal cancer, but it is no longer available in the United States for this indication. Levamisole was formerly used to treat patients with rheumatoid arthritis, metastatic cancer, immunodeficiency states, idiopathic renal parenchymal diseases (eg, nephrosis), systemic lupus erythematosus, scleroderma, and ascariasis (roundworm) or other worm infections. Levamisole is widely used as an adulterant in cocaine, and cocaine use is the primary source of levamisole exposure in the US.
B) PHARMACOLOGY: Levamisole, an imidazothiazole, is an immunomodulator. It is the active levo-isomer of tetramisole hydrochloride. ANTIPARASITIC AGENT: Levamisole is a ganglionic nicotinic acetylcholine agonist. It appears to act by paralyzing susceptible worms which are then eliminated through the intestines. Levamisole also binds to the nicotinic receptor and stimulates the parasympathetic and sympathetic ganglia of susceptible worms and mammals.
C) TOXICOLOGY: AGRANULOCYTOSIS: Evidence suggests that levamisole-induced agranulocytosis occurs via a hapten mechanism. Levamisole, a thioazole, can act as haptens and trigger immune or cytotoxic responses, mainly by opsonization and destruction of white blood cells, resulting in agranulocytosis. COCAINE ADULTERATION: Levamisole may augment euphoria and cocaine-associated toxicities by increasing peripheral sympathetic activity and central neurotransmission. Levamisole can bind and stimulate the nicotinic receptor, increasing the firing of postganglionic neurons and increasing the release of norepinephrine at sympathetic innervated synapses. Levamisole also binds and stimulates the nicotinic receptor, increasing glutamatergic activity on dopaminergic neurons. In the same system, cocaine prevents the reuptake of norepinephrine at the postganglionic synapse and increases sympathetic activity. It also prevents the reuptake of dopamine at the synaptic level.
D) EPIDEMIOLOGY: Levamisole is used in the United States as an antihelminthic agent in veterinary practice. Overdose is very rare. Several cases of levamisole toxicity have been reported in individuals using cocaine (crack, powder) adulterated with levamisole. In 2009, the Drug Enforcement Administration (DEA) in the United States reported that 69% of bulk shipments of cocaine entering the US were adulterated with levamisole.
E) WITH THERAPEUTIC USE
1) The following adverse effects have been reported in patients receiving levamisole: Skin rash, vasculitis, nausea, vomiting, diarrhea, abdominal pain, increased salivation, dysgeusia, frequent urination and defecation, lip licking, head shaking, increased salivation, arthralgia, myalgia, CNS depression, seizures, dizziness, dyspnea, tachypnea, leukopenia, neutropenia, anemia, thrombocytopenia, agranulocytosis (some fatal), and multifocal inflammatory leukoencephalopathy. Hepatotoxicity is a rare adverse effect of levamisole therapy.
F) WITH POISONING/EXPOSURE
1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Several cases of levamisole toxicity (eg, granulocytosis, neutropenia, retiform purpura) have been reported in individuals using cocaine (crack, powder) adulterated with levamisole. Hyponatremia has been reported in 3 patients using cocaine adulterated with levamisole. However, causality could not be established. A child developed ataxia (hyperkinesis, paresthesias, and instability of gait) after inadvertently receiving high doses of levamisole (100 mg twice daily) for 3 days.
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) HYPERTHERMIA: Temperature greater than 40.5 degrees C occurred in 1.9% of patients given levamisole as an adjunct to surgery in a series of 203 patients with cancer (Colizza et al, 1981).
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Heent |
3.4.2) HEAD
A) WITH THERAPEUTIC USE 1) Lip licking and head shaking may occur with therapy (Hsu, 1980).
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Blurred vision may occur rarely with levamisole therapy (Dubey et al, 2001).
3.4.6) THROAT
A) WITH THERAPEUTIC USE 1) Increased salivation has been reported with therapy (Hsu, 1980).
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Cardiovascular |
3.5.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) DYSRHYTHMIA a) DOG: A 3-year-old, 5-kg, male, mixed breed dog developed occasional premature ventricular contractions (PVCs) associated with a 10-day course of levamisole phosphate (11 mg/kg/day) for elimination of microfilariae. This dog had no previous history of cardiac disease. The ECG resolved without treatment within 2 weeks of levamisole discontinuation (Hoskins, 1983).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) Dyspnea may occur with therapy (Hsu, 1980).
B) HYPERVENTILATION 1) WITH THERAPEUTIC USE a) Tachypnea has been reported during therapy (Hsu, 1980).
C) PULMONARY HYPERTENSION 1) WITH POISONING/EXPOSURE a) In animal and human studies, it was found that levamisole is metabolized to aminorex (2-amino-5-phenyl-2-oxazoline). In 1960s, aminorex, an amphetamine derivative, was used as an appetite suppressive agent in several countries, including Switzerland, Austria, and Germany. In these countries, there was a 5-year epidemic (1967-1972) of idiopathic pulmonary hypertension (IPH) caused by aminorex ingestion. After the withdrawal of aminorex, the incidence of IPH reverted back to normal levels. Most patients developed symptoms of IPH after 6 to 9 months of aminorex use (average dose ranges: 10 to 40 mg/day) (Karch et al, 2012; Chang et al, 2010).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) CENTRAL NERVOUS SYSTEM DEFICIT 1) WITH THERAPEUTIC USE a) CNS depression has been reported infrequently during therapeutic use (Hsu, 1980; Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
b) Confusion, loss of consciousness, extreme fatigue, memory loss, muscle weakness, paresthesias, seizures, and speech disturbances have been reported in patients receiving levamisole (Kinzie, 2009).
B) ATAXIA 1) WITH THERAPEUTIC USE a) Ataxia has been reported rarely during therapeutic use (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Hsu, 1980).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 3.5-year-old girl (13 kg) developed ataxia (hyperkinesis, paresthesias, and instability of gait) after inadvertently receiving high doses of levamisole (100 mg twice daily) for 3 days. She recovered following supportive care (Dubey et al, 2001).
C) ANXIETY 1) WITH THERAPEUTIC USE a) Anxiety with irritability has developed infrequently during therapy (Hsu, 1980; Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
D) HYPERESTHESIA 1) WITH THERAPEUTIC USE a) Hyperesthesia is considered a rare effect of levamisole therapy (Hsu, 1980; Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
E) SEIZURE 1) WITH THERAPEUTIC USE a) Generalized seizure and coma have been reported following the use of levamisole (Kinzie, 2009; Prieur et al, 1978).
b) Muscle tremors and clonic seizures have been reported with therapeutic use (Hsu, 1980).
c) Central nervous system stimulation which has included seizures and resulted in death in some cases has been more frequently reported following parenteral administration of levamisole (Hsu, 1980).
2) WITH POISONING/EXPOSURE a) Patients using cocaine adulterated with levamisole may present with seizures (Kinzie, 2009).
F) DIZZINESS 1) WITH THERAPEUTIC USE a) Dizziness may occur with therapeutic use (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Hsu, 1980).
G) TREMOR 1) WITH THERAPEUTIC USE a) Muscle tremors are rarely reported following therapeutic administration (Dubey et al, 2001; Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Hsu, 1980).
H) HEADACHE 1) WITH THERAPEUTIC USE a) Headache is an infrequently reported adverse effect of therapy (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Hsu, 1980).
I) FLACCID PARALYSIS 1) WITH THERAPEUTIC USE a) NEUROMUSCULAR BLOCKADE: May develop and result in flaccid paralysis (Eyre, 1969).
J) LEUKOENCEPHALOPATHY 1) WITH THERAPEUTIC USE a) SUMMARY: Cases of an encephalopathy-like syndrome associated with demyelination and multifocal inflammatory leukoencephalopathy have been reported in patients undergoing combination therapy with 5-fluorouracil (5-FU) and levamisole, and in patients receiving only levamisole. Onset of symptoms (confusion, memory loss, muscle weakness) and clinical presentation are quite variable (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998). b) Causality and risk factors for levamisole-associated encephalopathy have not been established. The case reports outlining this toxicity differ in patient history and the type of encephalopathy reported (El Kallab et al, 2003; Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Lucia et al, 1996; Chastel & Mabin, 1996; Kimmel et al, 1995; Fassas et al, 1994). c) CLINICAL MANIFESTATIONS 1) In a study of 16 patients with levamisole-induced leukoencephalopathy, the following symptoms were reported: Motor weakness (n=12; 75%), hemiparesis or quadriplegia (n=6; 37.5%), gait ataxia (n=5; 31.3%), hypertonia (n=4; 25%); dysphasia or aphasia (n=8; 50%), cognitive disorder (including apathy and memory and calculation impairment) (n=8; 50%), facial palsy (n=7; 43.8%), blurred vision (n=6; 37.5%), hyperreflexia (n=3; 18.8%), urinary incontinence (n=3; 18.8%), paraesthesia (n=3; 18.8%), conscious disturbance (n=2; 12.5%), seizures (n=2; 12.5%), and diplopia (n=1; 6.3%). Brain biopsy of one patient revealed multifocal demyelinating lesions without perivascular cuffing by lymphocytes. Following supportive care which included steroids and hyperbaric oxygen therapy, all patients recovered completely (Xu et al, 2009).
2) In one case series of 31 patients with levamisole-induced leukoencephalopathy, ataxia developed in 20 patients (64.5%); 13 of these patients experienced hemiparesis or quadriplegia. Confusion (n=15; 48.4%), dysphasia or aphasia (n=16; 51.6%), seizure, hyporeflexia, tremors, urinary incontinence, and paresthesia were also reported (Wu et al, 2006)
d) ONSET/DURATION 1) CASE SERIES: Nine patients developed leukoencephalopathy, 37 days to 144 days (mean, 76 days) after receiving levamisole (total doses, 700 to 2250 mg) for recurrent aphthous ulcers. Following the discontinuation of levamisole therapy and supportive care, all patients recovered within 12 months (Liu et al, 2006).
2) CASE REPORT: Multifocal leukoencephalopathy was reported in a 37-year-old man following adjuvant therapy for adenocarcinoma of the colon with 5-FU, leucovorin, and levamisole for approximately 14 weeks. Effects included confusion, restlessness, ataxia, and slurred speech and a brain biopsy indicated demyelination in the cerebral white matter. Most symptoms had resolved by two and a half weeks after discontinuation of therapy. The authors speculated that a possible immune host reaction against the myelin may occur when the agents are given in combination resulting in neurological toxicity (Fassas et al, 1994).
e) CASE REPORTS 1) In one case report, a 57-year-old woman receiving adjuvant levamisole therapy (total dose, 1500 mg) for cutaneous malignant melanoma developed a cerebral demyelinating disease resembling multifocal inflammatory leukoencephalopathy (Kimmel et al, 1995). In another case report, a 59-year-old woman receiving levamisole developed neurological symptoms which resembled a demyelinating disorder. In both cases, withdrawal from therapy and treatment with steroids resolved the condition (Lucia et al, 1996). In another case, a 13-year-old girl developed acute fatal encephalitis 8 days after starting levamisole and aspirin therapy (Chastel & Mabin, 1996).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 29-year-old woman with AIDS (no current antiretroviral therapy) and a chronic crack cocaine abuser, presented with fever, malaise, and focal spinal pain. She had multiple excoriated, hyperpigmented lesions consistent with delusional parasitosis and focal spinal tenderness (neck to upper back) and left shoulder pain. A urine drug screen was positive for cocaine and opiates. Magnetic resonance imaging (MRI) guided needle aspiration revealed a MRSA infection of the perispinal musculature. Lesions consistent with multifocal inflammatory leukoencephalopathy (MIL) were observed in a brain MRI. Following supportive care, her condition gradually improved and a repeat brain MRI at 4 weeks revealed no significant worsening or improvement in the white matter abnormalities. Although no levamisole testing could be performed, it was suggested that MIL was caused by cocaine adulterated with levamisole (Blanc et al, 2012).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea, vomiting, abdominal pain, and increased salivation have been reported with therapeutic use (Hsu, 1980).
B) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea is a relatively frequent adverse effect of oral levamisole therapy (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Moertel et al, 1990; Laurie et al, 1989; Clemens et al, 1983; Anon, 1982; Anon, 1989).
b) In one large series of colon cancer patients receiving adjunctive oral levamisole therapy alone, the incidence of diarrhea was 13%. Maintenance combination therapy with 5-fluorouracil in these patients was associated with a significantly higher incidence of diarrhea (47%). These effects are similar to toxicity observed with fluorouracil alone (Moertel et al, 1990).
C) TASTE SENSE ALTERED 1) WITH THERAPEUTIC USE a) Abnormal taste (metallic or bitter) in the mouth has been associated with prolonged use of levamisole (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Hepatotoxicity may be a rare adverse effect of levamisole therapy. Elevations in aminotransferases and bilirubin have been described occasionally during levamisole therapy (Bulugahapitiya, 1997; Papageorgiou et al, 1982; Moertel et al, 1990).
b) One study reported that 2 of 11 patients administered levamisole for recurrent pyoderma developed elevated aspartate aminotransferase (Papageorgiou, 1982).
3.9.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) ENZYME INDUCTION: Levamisole appears to induce certain hepatic microsomal mixed function oxidases in mice following intraperitoneal administration of 20 mg/kg/day for 5 days (Dalvi, 1989).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) INCREASED FREQUENCY OF URINATION 1) WITH THERAPEUTIC USE a) Frequent urination and defecation have been reported (Hsu, 1980).
B) TOXIC NEPHROPATHY 1) WITH THERAPEUTIC USE a) CASE REPORT: A man with rheumatoid arthritis receiving levamisole 150 mg daily for 10 months developed mesangial proliferative glomerulonephritis (Hanson et al, 1978).
2) WITH POISONING/EXPOSURE a) COCAINE ADULTERATED WITH LEVAMISOLE: A 42-year-old woman who persistently denied substance abuse, presented with severe arthralgias, myalgias, intermittent abdominal pain, violaceous ulcerating skin lesions (mainly on the upper legs), and an episcleritis of the left eye. She later developed ileal-ileal intussusception, requiring an emergency ileocecal resection. All laboratory tests were negative; however, human neutrophil elastase antibodies (HNE-ANCA) were detected. Physical examination revealed perforation of the nasal septum, indicating cocaine abuse. Although several urine tests for cocaine were negative, hair testing with high-performance liquid chromatography with mass spectrometry was positive for cocaine and levamisole (concentrations: levamisole 18.3 ng/mg and cocaine 11.8 ng/mg). Following the discontinuation of cocaine, she recovered completely, but she presented again with recurrent arthralgias. Laboratory results revealed decreased renal function with erythrocyturia and proteinuria, and positive results for myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) and proteinase 3-ANCA (PR3-ANCA). A kidney biopsy revealed necrotizing crescentic glomerulonephritis and a diagnosis of levamisole-adulterated cocaine-induced ANCA-associated vasculitis was made. Following supportive care, including high-dose corticosteroids and cyclophosphamide for a few days and a maintenance therapy with azathioprine and prednisolone, she gradually recovered (van der Veer et al, 2015).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) AGRANULOCYTOSIS 1) WITH THERAPEUTIC USE a) Agranulocytosis is the most severe adverse reaction associated with levamisole therapy, and has been reported in 0.4% to as high as 20% of patients treated in various studies (Futrakul, 1995; Anon, 1989; Halberg et al, 1984; Amery & Butterworth, 1983; Hodinka et al, 1981; Heyns et al, 1979; Ruuskanen et al, 1976).
b) In postmarketing experience, fatal cases of agranulocytosis have occurred (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
c) It is suggested that levamisole causes agranulocytosis by inducing autoimmunity to antigens on neutrophil cell walls (Buchanan et al, 2010). Agranulocytosis appears to occur more frequently in patients with rheumatoid arthritis and in patients with HLA type B27 who are on levamisole therapy (Buchanan et al, 2010; Wiens et al, 2010; Hodinka et al, 1981; Heyns et al, 1979; Mielants & Veys, 1978).
2) WITH POISONING/EXPOSURE a) COCAINE ADULTERATED WITH LEVAMISOLE 1) Severe agranulocytosis has been reported in multiple patients using cocaine adulterated with levamisole. Urine toxicology testing detected the presence of cocaine (or its metabolite) and levamisole. All patients recovered following G-CSF and antibiotic therapy (Buchanan et al, 2010; Zhu et al, 2009).
2) In another study, 20 patients with agranulocytosis were described; 14 of these patients were exposed to levamisole-tainted cocaine. The following morphological features of agranulocytosis were more frequent in cocaine-exposed than in non-cocaine-exposed patients: Microcytosis; toxic neutrophilic granulation; peripheral left shift; increased circulating large granular lymphocytes, activated lymphocytes, plasmacytoid lymphocytes, and immunoblasts; thrombocytosis; mild megaloblastic change in erythroid precursors; prominent primary granules in myeloid precursors; bone marrow plasmacytosis; and increased megakaryocytes. Three of 5 patients tested were HLA-B27 positive. One cocaine-exposed patient died of infectious complications (Czuchlewski et al, 2010).
3) In one case series of patients (n=5) with levamisole-induced agranulocytosis, lupus anticoagulant were detected in all patients (Zhu et al, 2009). Several patients with levamisole-induced agranulocytosis were positive for isoantibodies, such as antineutrophil cytoplasmic antibody (ANCA; cytoplasmic ANCA (c-ANCA); perinuclear ANCA (p-ANCA)), antiphospholipid, and IgM anticardiolipin antibodies (Han et al, 2011; Buchanan et al, 2010; Knowles et al, 2009).
B) NEUTROPENIA 1) WITH THERAPEUTIC USE a) Neutropenia has occurred after several days to several months of levamisole treatment and is generally reversible upon withdrawal of the drug (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998; Futrakul, 1995).
b) One study described autoimmune and complement-dependent granulocytotoxic antibodies in several patients with severe neutropenia during levamisole therapy for bladder carcinoma (Drew et al, 1980).
2) WITH POISONING/EXPOSURE a) Severe neutropenia has been reported in multiple patients using cocaine adulterated with levamisole (Gaertner & Switlyk, 2014; Freyer & Peters, 2012; Han et al, 2011; Wiens et al, 2010; Waller et al, 2010). One patient developed mild neutropenia with necrosis of ears after using cocaine-adulterated with levamisole (de la Hera et al, 2011).
b) Neutropenia and retiform purpura, characterized by purpuric macules, papules, and plaques on the pinna, earlobes, cheeks, trunk, and extremities, have been reported in two patients with histories of cocaine use. Urine toxicology screens of both patients confirmed the presence of cocaine. Although the presence of levamisole was unconfirmed, the authors speculate that levamisole contamination may be the causative agent (Waller et al, 2010).
c) CASE REPORT: A 50-year-old cocaine user presented with neutropenia and a 6-month history of recurrent purpuric patches on her trunk and extremities. A skin biopsy revealed severe leukocytoclastic vasculitis with extensive intravascular fibrin thrombi and erythrocyte extravasation. Laboratory tests showed positive anticardiolipin IgM antibody and a weakly positive p-ANCA. The presence of levamisole could not be confirmed because it has a short half-life (Geller et al, 2011).
C) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) Thrombocytopenia has occurred during levamisole therapy. This complication occurs less frequently than leukopenia, and was reported in 2% to 3% of patients receiving levamisole alone as adjunctive therapy for colon carcinoma (Winquist & Lassam, 1995; Futrakul, 1995; Moertel et al, 1990; Halberg et al, 1984; Veys et al, 1987; Mielants & Veys, 1978).
b) In colon cancer patients receiving combined oral levamisole and weekly intravenous fluorouracil, thrombocytopenia (50,000 to 130,000/mcL) occurred in 18% to 24% of those treated; severe thrombocytopenia (less than 50,000/mcL) was observed in 4% of patients (Laurie et al, 1989; Moertel et al, 1990).
2) WITH POISONING/EXPOSURE a) Thrombocytopenia has been reported in patients using cocaine adulterated with levamisole (Gaertner & Switlyk, 2014; Freyer & Peters, 2012).
b) CASE REPORT: A 48-year-old woman with a history of levamisole-tainted cocaine use, developed diffuse palpable purpura complicated by streptococcal toxic shock syndrome (STSS), acute renal failure (serum creatinine 5 mg/dL), thrombocytopenia (platelet count 34 x 10(9)/L), severe anemia (hemoglobin nadir of 6.9 x 10(9)/L with no identified source of active bleeding), and lactic acidosis (serum lactate level 3.3 mmol/L). Following supportive care, her condition gradually improved; however, she developed limb necrosis and widespread gangrene requiring amputation of multiple appendages (Freyer & Peters, 2012).
D) ANEMIA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 48-year-old woman with a history of levamisole-tainted cocaine use, developed diffuse palpable purpura complicated by streptococcal toxic shock syndrome (STSS), acute renal failure (serum creatinine 5 mg/dL), thrombocytopenia (platelet count 34 x 10(9)/L), severe anemia (hemoglobin nadir of 6.9 x 10(9)/L with no source of active bleeding identified), and lactic acidosis (serum lactate level 3.3 mmol/L). Following supportive care, her condition gradually improved; however, she developed limb necrosis and widespread gangrene requiring amputation of multiple appendages (Freyer & Peters, 2012).
E) LEUKOPENIA 1) WITH THERAPEUTIC USE a) Leukopenia has been observed in 3% to 8% of patients during levamisole therapy, particularly in patients with cancer and rheumatoid arthritis who receive the drug for prolonged periods. Leukopenia is mild and reversible in most patients (Moertel et al, 1990; Laurie et al, 1989; Anon, 1989; Loutfi et al, 1987; Anon, 1982; Feldmann et al, 1981; Mielants & Veys, 1978).
b) In one large series of colon carcinoma patients receiving oral levamisole alone, the incidence of leukopenia (2000 to 4000/mcL) was 8%. Leukopenia of less than 2000/mcL was observed in 1% of patients treated. During maintenance combination therapy with oral levamisole and weekly IV fluorouracil, leukopenia (2000 to 4000/mcL) was the dose-limited toxic effect of treatment. However, leukopenia of less than 2000/mcL occurred in only 2% of patients (Moertel et al, 1990).
2) WITH POISONING/EXPOSURE a) Leukopenia has been reported in patients using cocaine adulterated with levamisole (Gaertner & Switlyk, 2014; Buchanan et al, 2010a).
b) CASE REPORT: Leukopenia (WBC 1900 cells/(mm(3)) and occlusive necrotizing vasculitis of the ears developed in a man 9 hours after using nasal cocaine adulterated with levamisole. Despite treatment with 10 mg of subcutaneous phentolamine to both ears, his symptoms did not improve. He was discharged following supportive care (Buchanan et al, 2010a).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) Skin rash has occurred with relative frequency during levamisole therapy (Gupta & Gupta, 2005; Moertel et al, 1990; Anon, 1989; Halberg et al, 1984; Feldmann et al, 1981; Veys et al, 1987; Anon, 1982; Laurie et al, 1989).
2) WITH POISONING/EXPOSURE a) In one study, 16 cases (4 new and 12 previously reported; average age, 43 years; range, 22 to 59 years; 81% female) of cutaneous vasculitis syndrome caused by levamisole-contaminated cocaine were reviewed. Rash on extremities was observed in 15 (94%) patients. Rash of the earlobes was observed in more than half of the patients (10/16, 63%); 8 patients had purpuric plaques and were reported in a retiform, reticular, or stellate pattern. Bullae, necrotic lesions, or ulcers were also noted. Leukopenia or neutropenia developed in 10 patients (56%). Four patients had hypocomplementemia. Positive anti-nuclear cytoplasmic antibody (ANCA), antiphospholipid antibodies, anti-cardiolipin IgM, and lupus anti-coagulant were observed in 15 (94%), 10 (63%), 7 (44%), and 5 (31%) patients, respectively. Biopsy results revealed vasculitis with thrombosis in 7 patients, thrombotic vasculopathy in 6 patients, and pure small vessel vasculitis in 2 patients (Gross et al, 2011).
B) PYODERMA GANGRENOSUM 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 51-year-old woman with a history of cocaine abuse, developed pyoderma gangrenosum a week after smoking crack cocaine, adulterated with levamisole. Physical examination showed 14 skin lesions, including large ulcerated plaques with indurated undermined borders, including some necrotic erosive nodules throughout her body. Laboratory results were positive for perinuclear antineutrophil cytoplasmic antibodies, antinuclear antibodies, lupus anticoagulant, anticardiolipin (IgM and IgA), and trace cryoglobulins. Her symptoms resolved gradually with cocaine abstinence and prednisone therapy for 5 months; however, she developed a new eruption a week after using cocaine again (Keith et al, 2015).
C) VASCULITIS 1) WITH THERAPEUTIC USE a) Several cases of vasculitis have been reported in patients receiving levamisole for relapsing nephrotic syndrome, rheumatoid arthritis, or cancer (Powell et al, 2002; Bagga & Hari, 2000; Rongioletti et al, 1999; Laux-end et al, 1996; Menni et al, 1997; Futrakul, 1995; Macfarlane & Bacon, 1978; Scheinberg et al, 1978). 1) CASE SERIES: Vasculopathic purpura of the ears was described in one girl and four boys (average age, 10 years) receiving long-term oral levamisole (dose range, 1.7 to 2.5 mg/kg daily) monotherapy for management of pediatric nephrotic syndrome. Presenting symptoms were sudden in onset, and included rapidly enlarging purpuric and erythematous macules, with necrotic areas and hemorrhagic bullae. These lesions occurred on the ears in all five patients, and also appeared on the cheeks, thighs and/or lower leg in three of the children. Mean onset latency from initial dose to symptom onset was 24 months. Four of the children were seropositive for circulating autoimmune antibodies. Histological examination of the ear lesions revealed a leukocytoclastic and thrombotic hypersensitivity vasculitis and a vascular occlusive disorder without signs of true vasculitis. Complete resolution of vasculopathic symptoms occurred within three weeks of levamisole withdrawal (Rongioletti et al, 1999).
2) CASE REPORT: In a case report, an 11-year-old girl developed cutaneous vasculitis after treatment with levamisole and prednisone for 5 years. Withdrawal of levamisole led to the resolution of the vasculitis. Circulating autoantibodies were detected seven months after levamisole withdrawal (Laux-End et al, 1996).
3) CASE REPORT: A 10-year-old child with relapsing nephrotic syndrome, developed bullous hemorrhagic lesions on both ear lobes after receiving levamisole (2 mg/kg/day) for 1.5 years. Histology ruled out leukocytoclastic allergic vasculitis due to immune complexes and revealed thrombotic occlusion of large vessels of the deep plexus, possibly induced by levamisole. The lesions healed completely within 25 days of stopping levamisole treatment and administering prednisone (Menni et al, 1997).
4) CASE REPORT: An 11-year-old boy with factor V Leiden developed cutaneous necrosis after levamisole for several years for relapsing nephrotic syndrome. He presented with purpuric patches which rapidly progressed to large, painful, deep, necrotic ulcers on his ear lobes and hands, forearms and lower legs. He was found to be heterozygous for factor V Leiden mutation, and his direct antiglobulin (Coombs' test) and the auto-antibody p-ANCA (perinuclear antineutrophilic cytoplasmic antibody) were positive. Skin histology revealed vascular occlusion with fibrin thrombi in the absence of fibrinoid necrosis or neutrophilic infiltration of the vessel walls. It is hypothesized that an interaction of levamisole-induced lupus anticoagulant and p-ANCA in the presence of a heritable thrombophilic defect, may have been the cause of the skin necrosis in this patient. Following the discontinuation of levamisole, the lesions healed over the next few weeks (Powell et al, 2002).
2) WITH POISONING/EXPOSURE a) COCAINE ADULTERATED WITH LEVAMISOLE: A 42-year-old woman who persistently denied substance abuse, presented with severe arthralgias, myalgias, intermittent abdominal pain, violaceous ulcerating skin lesions (mainly on the upper legs), and an episcleritis of the left eye. She later developed ileal-ileal intussusception, requiring an emergency ileocecal resection. All laboratory tests were negative; however, human neutrophil elastase antibodies (HNE-ANCA) were detected. Physical examination revealed perforation of the nasal septum, indicating cocaine abuse. Although several urine tests for cocaine were negative, hair testing with high-performance liquid chromatography with mass spectrometry was positive for cocaine and levamisole (concentrations: levamisole 18.3 ng/mg and cocaine 11.8 ng/mg). Following the discontinuation of cocaine, she recovered completely, but she presented again with recurrent arthralgias. Laboratory results revealed decreased renal function with erythrocyturia and proteinuria, and positive results for myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) and proteinase 3-ANCA (PR3-ANCA). A kidney biopsy revealed necrotizing crescentic glomerulonephritis and a diagnosis of levamisole-adulterated cocaine-induced ANCA-associated vasculitis was made. Following supportive care, including high-dose corticosteroids and cyclophosphamide for a few days and a maintenance therapy with azathioprine and prednisolone, she gradually recovered (van der Veer et al, 2015).
b) In one study, 5 of 6 cocaine users who developed levamisole-induced vasculopathy with purpuric skin lesions, were initially misdiagnosed with granulomatosis with polyangiitis, lupus, or necrosis of unknown origin. All 5 patients had positive ANCA and were treated for autoimmune conditions. Retiform, nonpalpable purpura to necrotic papules and plaques with ear purpura were observed in all patients. Finger involvement with hand edema were observed in 3 patients. A vasculopathic process, with or without vasculitis, was observed in skin biopsy specimens. Additional abnormalities in autoimmune markers were observed in 4 patients. Some patients also had agranulocytosis, arthralgias, or proteinuria. Following the discontinuation of cocaine use and systemic corticosteroid therapy, most patients improved quickly (Strazzula et al, 2013).
c) In one study, 16 cases (4 new and 12 previously reported; average age, 43 years; range, 22 to 59 years; 81% female) of cutaneous vasculitis syndrome caused by levamisole-contaminated cocaine were reviewed. Rash on extremities was observed in 15 (94%) patients. Rash of the earlobes was observed in more than half of the patients (10/16, 63%); 8 patients had purpuric plaques and were reported in a retiform, reticular, or stellate pattern. Bullae, necrotic lesions, or ulcers were also noted. Leukopenia or neutropenia developed in 10 patients (56%). Four patients had hypocomplementemia. Positive anti-nuclear cytoplasmic antibody (ANCA), antiphospholipid antibodies, anti-cardiolipin IgM, and lupus anti-coagulant were observed in 15 (94%), 10 (63%), 7 (44%), and 5 (31%) patients, respectively. Biopsy results revealed vasculitis with thrombosis in 7 patients, thrombotic vasculopathy in 6 patients, and pure small vessel vasculitis in 2 patients (Gross et al, 2011).
d) In one study, 55 cases (23 published case reports/series and 4 cases observed by the author) of levamisole-induced vasculopathy were evaluated. In many cases, the time of last cocaine use was within 24 hours of hospital presentation. The involved sites included lower extremities (46/55 patients), ears (40/55), upper extremities (34/55), face (26/55), trunk (22/55), nose (21/55), and oral region (4/55). Neutropenia was reported in 31 (60%) patients and arthralgia in 27 patients. The following laboratory results were elevated: perinuclear ANCA (p-ANCA; 42 of 48 patients [88%]), cytoplasmic ANCA (c-ANCA; 10 of 48 patients [21%]), anti-myeloperoxidase (anti-MPO; 25 of 41 patients), and anti-proteinase-3 (anti-PR3; 26 of 42 patients); ANA (24 of 47 patients [51%]) and human neutrophil elastase antibodies (11 of 11 patients). Biopsy results of 50 patients showed 24 (48%) patients with thrombosis, 8 (16%) patients with vasculitis and thrombosis, 18 (36%) patients with both thrombosis and vasculitis (Pearson et al, 2012).
e) CASE REPORT: Occlusive necrotizing vasculitis of the ears developed in a man 9 hours after using nasal cocaine adulterated with levamisole. He also had left upper arm and right second toe discoloration. Despite treatment with 10 mg of subcutaneous phentolamine to both ears, his symptoms did not improve. He was discharged following supportive care (Buchanan et al, 2010a).
f) CASE REPORT: A 50-year-old cocaine user presented with neutropenia and a 6-month history of recurrent purpuric patches on her trunk and extremities. A skin biopsy revealed severe leukocytoclastic vasculitis with extensive intravascular fibrin thrombi and erythrocyte extravasation. Laboratory tests showed positive anticardiolipin IgM antibody and a weakly positive p-ANCA. The presence of levamisole could not be confirmed because it has a short half-life (Geller et al, 2011).
g) CASE REPORT: Necrotizing vasculitis and thrombotic vasculopathy developed in a 47-year-old man after snorting cocaine. He presented with retiform purpura lesions on the lower extremities, ears, cheeks, tongue, trunk, and genitalia. These lesions had necrotic centers and bright erythematous, irregular or stellate borders. Laboratory analysis revealed a positive p-ANCA, weak positive myeloperoxidase antibody, and negative proteinase-3 antibody. Urinalysis was positive for cocaine and levamisole (Jenkins et al, 2011).
h) CASE REPORT: A 40-year-old man presented with bilateral necrotic lesions in his ears 3 days after using cocaine adulterated with levamisole. Physical examination showed bilateral confluent erythematous and purpuric patches with hemorrhagic phlyctena and necrosis of the ears. Laboratory results revealed mild neutropenia, prolonged activated partial thromboplastin time (58 s, normal 28 to 38 s), positive antineutrophil cytoplasmic antibodies (ANCA) with perinuclear pattern (p-ANCA; titer 1:160), positive anticardiolipin IgM antibodies, and lupus anticoagulant. A biopsy of a necrotic papule revealed hyaline thrombosis of small blood vessels and infarction of the dermis and epidermis, indicating thrombotic vasculopathy. Following supportive care, his lesions resolved gradually. He developed similar lesions 10 days later, 3 days after using cocaine again (de la Hera et al, 2011).
D) PURPURA 1) WITH POISONING/EXPOSURE a) RETIFORM PURPURA WITHOUT VASCULITIS 1) CASE REPORT: A 52-year-old woman with a history of inhalational cocaine use presented with a 4-month history of intermittent painful bruises (retiform purpura) involving her arms and legs, with ulceration of nasal tip, ears, and cheeks. Laboratory analysis revealed neutropenia with positive atypical perinuclear antineutrophil cytoplasmic antibody, elevated proteinase 3 level, and positive anticardiolipin antibodies for immunoglobulin M. Extensive thrombotic vasculopathy without vasculitis was observed during skin biopsy. In a previous admission, she presented with cutaneous vascular necrosis and abnormal anticardiolipin serology. Following supportive care, her symptoms improved gradually. Although the presence of levamisole was unconfirmed, the authors speculate that levamisole contamination may be the causative agent (Han et al, 2011).
2) CASE REPORTS: Neutropenia and retiform purpura, characterized by purpuric macules, papules, and plaques on the pinna, earlobes, cheeks, trunk, and extremities, have been reported in two patients with histories of cocaine use. Urine toxicology screens of both patients confirmed the presence of cocaine. Although the presence of levamisole was unconfirmed, the authors speculate that levamisole contamination may be the causative agent (Waller et al, 2010).
3) CASE REPORT: A 48-year-old woman with a history of levamisole-tainted cocaine use, presented with a right elbow wound caused by a fall. She was discharged after her wound was sutured. She presented again with nausea, vomiting, and right elbow pain 2 days later. An abscess of the wound was noted and drained. Despite treatment with intravenous vancomycin and piperacillin-tazobactam, she developed sepsis and fluid collected from the lesion revealed Streptococcus pyogenes (group A Streptococcus). Laboratory results showed acute renal failure (serum creatinine 5 mg/dL), thrombocytopenia (platelet count 34 x 10(9)/L), and lactic acidosis (serum lactate level 3.3 mmol/L). Physical examination showed bullae of the right elbow and diffuse purpura with necrotic centers covering a large portion of her body, including her trunk, legs, arms, back, toes, fingers, and tip of nose. At this time, she received vancomycin and clindamycin and later ceftriaxone to treat streptococcal toxic shock syndrome (STSS). Skin biopsy showed purpura with dermal vessel fibrin thrombi formation. She also received intravenous immune globulin 48 g. Her condition deteriorated and she required mechanical ventilation for septic shock, lactic acidosis, and acute renal failure. Following supportive care, including 12 units of platelets for worsening thrombocytopenia, blood transfusion for severe anemia, and intravenous fluid resuscitation for acute renal failure, she gradually improved. A urine sample from the first day of admission revealed a levamisole concentration of 0.81 mcg/mL. She later required amputation of 4 fingers on each hand, 4 toes on her left foot, and right below-the-knee amputation, due to severe gangrene. On days 25 and 39, transient neutropenia (absolute neutrophil count less than 1.5 x 10(9) L) was observed, which was complicated by vancomycin-resistant Enterococcus faecium and Candida species noted on bone cultures. On day 40, she was discharged to a long-term rehabilitation facility (Freyer & Peters, 2012).
b) VASCULOPATHY WITH PURPURIC SKIN LESIONS 1) In one study, 5 of 6 cocaine users who developed levamisole-induced vasculopathy with purpuric skin lesions, were initially misdiagnosed with granulomatosis with polyangiitis, lupus, or necrosis of unknown origin. All 5 patients had positive ANCA and were treated for autoimmune conditions. Retiform, nonpalpable purpura to necrotic papules and plaques with ear purpura were observed in all patients. Finger involvement with hand edema were observed in 3 patients. A vasculopathic process, with or without vasculitis, was observed in skin biopsy specimens. Additional abnormalities in autoimmune markers were observed in 4 patients. Some patients also had agranulocytosis, arthralgias, or proteinuria. Following the discontinuation of cocaine use and systemic corticosteroid therapy, most patients improved quickly (Strazzula et al, 2013).
2) CASE REPORT: A 54-year-old man who was using levamisole-contaminated cocaine, presented with a 2-week history of bilateral axillary adenopathy and fatigue. Despite treatment with broad-spectrum antibiotics (trimethoprim-sulfamethoxazole and cephalexin), his symptoms did not improve. He presented a few days later with ulcerated axillary lymph nodes, fever, fatigue, night sweats, oral ulcers, and dysphagia. Laboratory results revealed leukopenia with severe neutropenia. He was treated with granulocyte colony-stimulating factor and broad-spectrum antibiotics. A bone marrow biopsy showed reactive myeloid hyperplasia. At this time, he developed rapid onset progressive cutaneous violaceous ecchymosis, areas of purpura, and hemorrhagic bullae, mainly on the nasal tip, lips, and ears which were ischemic and blackened. His skin symptoms worsened several days later with the involvement of 40% of the skin surface, including the extremities, trunk, and face and second (30% of the skin surface area) and third degree (10% of the skin surface area) burn-like skin loss. A CBC showed thrombocytopenia. A skin biopsy showed numerous intravascular thrombi involving superficial and deep dermal vessels without vasculitis, consistent with vascular occlusive disease. Other laboratory findings included an increased prothrombin time and partial thromboplastin time, decreased fibrinogen, reduced antithrombin III antigen, reduced serum complement concentrations, a positive perinuclear antineutrophil cytoplasmic antibody (ANCA) and weakly positive IgM antiphospholipid autoantibody. Despite supportive care, his condition worsened and he developed respiratory distress, renal and hepatic failure, and transient coma. He continued to have cutaneous lesions, with complete necrosis of the nose, focal necrosis of lower extremity muscles and bone, extensive skin and soft tissue loss in the chest and extremities, necessitating skin grafts. He remained hospitalized at the time of this report (Gaertner & Switlyk, 2014).
E) LICHENOID DERMATITIS 1) WITH THERAPEUTIC USE a) LICHENOID ERUPTIONS were associated with levamisole therapy in 2 patients with rheumatoid arthritis. The eruptions subsided when the levamisole was discontinued (Kirby et al, 1980).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) MUSCULOSKELETAL FINDING 1) WITH THERAPEUTIC USE a) Arthralgia and/or myalgia has been reported during levamisole therapy . Studies have described arthralgia or myalgia in 7% of patients treated with oral levamisole alone as adjunctive therapy for colon cancer. During combination therapy with weekly intravenous fluorouracil, these complications were observed in 4% of patients treated (Moertel et al, 1990).
b) CASE REPORT: Severe acute polyarthropathy was described in a 17-year-old boy with Crohn's disease after receiving levamisole 100 mg daily for approximately 1 year (Benfield et al, 1984).
c) CASE REPORT: A 67-year-old woman developed diffuse arthralgia affecting mainly the knees and elbows after ingesting levamisole 150 mg/day for 3 days. Her symptoms resolved within 2 days of discontinuing levamisole. Levamisole therapy 10 days later resulted in recurrence of severe and generalized arthralgia (Siklos, 1977).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) WITH POISONING/EXPOSURE a) Allergic reactions (difficulty breathing, swelling of lips, tongue, or face, and hives) may occur, but have been reported infrequently in patients using levamisole (Kinzie, 2009; Futrakul, 1995).
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Reproductive |
3.20.1) SUMMARY
A) Levamisole is in pregnancy category C.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) ANIMAL DATA - In studies in rats and rabbits at oral doses up to 180 mg/kg fetal malformations were not observed (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) Pregnancy Category C (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998)
2) Levamisole should not be given to pregnant women unless the benefits outweigh the risks (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
3) ANIMAL DATA - Fetal malformations have been seen in rats at doses of 160 mg/kg and significant toxicity was observed in rabbits at doses of 180 mg/kg (Prod Info Ergamisol(R) Tablets, levamisole hydrochloride, 1998).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
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Carcinogenicity |
3.21.3) HUMAN STUDIES
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.
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