Succimer is an oral chelating agent approved for the treatment of lead toxicity or poisoning in pediatric patients with blood lead concentrations greater than 45 mcg/dL. Treatment must always be used in conjunction with identification and removal of the source of the lead exposure. The drug is not intended to be used as a prophylaxis of lead poisoning in a lead-containing environment. Succimer works by forming water-soluble chelates with lead, which are excreted in the urine. Succimer may have efficacy for lead encephalopathy and for other heavy metal poisoning such as mercury or arsenic poisoning; data are limited.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Capsules may be opened and the beads sprinkled on a small amount of soft food or put on a spoon and followed with a fruit drink.
Clinical experience with succimer is limited. Consequently, the full spectrum and incidence of adverse reactions including the possibility of hypersensitivity or idiosyncratic reactions have not been determined.
Gastrointestinal side effects (12% to 21%) occurred frequently during administration of succimer to adult and pediatric patients. Commonly reported GI side effects from clinical trials include nausea, vomiting, diarrhea, loose stools, and metallic taste in the mouth. Anorexia and hemorrhoids have also been reported. Symptoms are usually self-limiting and most do not require cessation of therapy.
Nervous system effects of succimer include drowsiness, dizziness, sleepiness, sensorimotor peripheral neuropathy, and paresthesias. These CNS effects were noted in 1% to 12.7% of patients who received succimer. Mild to moderate drowsiness is the most common side effect noted in both adults and children. Symptoms are usually mild, self-limiting and most do not require cessation of therapy. Irritability and changes in sleep behavior have also been reported in children in clinical trials.
Mild to moderate neutropenia has been rarely (roughly 0.8%) observed in patients receiving treatment with succimer; a causal relationship of neutropenia to succimer has not been definitely established, but neutropenia has been reported with other drugs in the same chemical class. Obtain a complete blood count with white blood cell differential before succimer initiation and weekly during succimer receipt. Withhold or discontinue succimer treatment if the absolute neutrophil count decreases to less than 1,200/microliter. Closely monitor the neutrophil count to document recovery of the ANC to above 1,500/microliter or to the patient's baseline neutrophil count. Limited experience exists for reexposure to succimer after neutropenia development. Rechallenge patients with succimer only if the benefit of succimer clearly outweighs the potential risk of another neutropenia episode. If succimer is used again, carefully monitor the patient. Instruct patients to promptly report any signs of infection. If infection is suspected, immediately obtain a complete blood count (CBC) with white blood cell differential.
During treatment with succimer, transient, mild elevated hepatic enzymes have been observed in 6% to 10% of patients. Elevated SGPT, SGOT, alkaline phosphatase, or serum cholesterol (hypercholesterolemia) was noted in 4.2% of 191 pediatric patients and in 10.4% of 134 adult patients. Monitor serum transaminases prior to starting initiating succimer and at least weekly during therapy. Patients with pre-existing hepatic disease should be monitored closely, as no data are available regarding the metabolism of succimer in patients with hepatic disease.
Consider the possibility of allergic or other mucocutaneous reactions to succimer with initial and subsequent exposure. Carefully monitor patients with each drug exposure. Rash has occurred in approximately 4% of patients during treatment with succimer. Some rashes required succimer discontinuation. Maculopapular rash, herpetic or vesicular rash, mucocutaneous eruptions including oral ulceration, and pruritus have been reported in 2.6% to 11.2% of patients. If a rash develops, exclude other causes before ascribing the reaction to succimer. Consider rechallenge if lead concentrations are high enough to warrant retreatment with succimer; there is limited experience with repeat courses. Allergic reactions, including angioedema and urticaria, have been reported upon succimer rechallenge. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity that affected the oral mucosa, the external urethral meatus, and the perianal area on the third, fourth, and fifth courses of succimer treatment. The reaction resolved in between courses and upon succimer discontinuation.
Genitourinary toxicities have been reported during succimer treatment. Among 134 adults, 3.7% had decreased urination or dysuria, difficulty voiding or urinary retention, or increased proteinuria. These effects were noted in 0% of pediatric patients. Patients should remain adequately hydrated during treatment with succimer. Cautious use of succimer is advised for patients with compromised renal function; most of the absorbed drug is excreted by the kidneys.
Generalized symptoms, such as back pain, abdominal pain, abdominal cramps, head pain, rib pain, flank pain, chills, fever, flu-like symptoms, fatigue, head cold, headache, and monoliasis (candidiasis) occurred in 5.2% to 15.7% of patients who received succimer. Kneecap pain or leg pain occurred in 3% of adults. If infection is suspected, immediately obtain a complete blood count with white blood cell differential.
Sore throat or throat irritation, rhinorrhea, nasal congestion, and cough were respiratory effects reported in 0.7% to 3.7% of patients who received succimer. Side effects affecting special senses included a cloudy film in eye or conjunctivitis, ears plugged, otitis media, and lacrimation (watery eyes) were reported in 1% to 3.7% of patients. Some effects have not been conclusively attributed to succimer therapy.
Among 191 pediatric patients who received succimer, 0.5% had an increased platelet count (thrombocytosis) or intermittent eosinophilia. The adverse events were noted in 1.5% of 134 adults who received the drug. Obtain a direct platelet count before succimer initiation and weekly during succimer receipt.
Among 134 adults who received succimer, 1.8% had an arrhythmia (unspecified). This side effect was not reported in children. Arrhythmia exacerbation may be caused by succimer. Clinical experience with succimer is limited. Consequently, the full spectrum and incidence of adverse reactions have not been determined.
Carefully observe patients during succimer therapy. After succimer discontinuation, elevated blood lead concentrations and associated symptoms may return rapidly because of lead redistribution from bone stores to soft tissues and blood; monitor blood lead concentrations at least once weekly until the concentration is stable. More frequent monitoring may be needed; consider the initial blood lead concentration and the rate and degree of rebound of blood lead. Clinical experience with repeated courses is limited. Further, the safety of uninterrupted dosing longer than 3 weeks has not been established and is not recommended.
Although a causal relationship has not been established, mild to moderate neutropenia has been observed in some patients receiving succimer. If a patient develops an absolute neutrophil count (ANC) below 1,200/microliter during treatment, succimer should be withheld or discontinued. Continue to monitor the patient closely until the ANC recovers to above 1,500/microliter or the patient's baseline neutrophil count. There is limited experience with re-exposure to succimer in patients who have developed neutropenia during therapy. Re-exposure should be avoided unless the benefit of therapy clearly outweighs the potential risk of another episode of neutropenia and then only with careful patient monitoring. Patients should be counseled to promptly report any signs or symptoms of infection, which may indicate a lowered WBC count; if patients report infection, a CBC should be assessed.
Use caution when administering succimer to a patient with renal impairment or renal failure, hypovolemia, or dehydration. Most of a succimer dose is excreted renally, including the water-soluble lead chelates. All patients undergoing treatment with succimer should remain adequately hydrated during therapy. Limited data suggests succimer is dialyzable, but the lead chelates are not; use caution in the patient on dialysis.
Patients with a history of hepatic disease should be monitored closely if treatment with succimer is indicated. Transient mild elevations in serum transaminases have occurred during treatment with succimer. Monitor serum transaminases before starting therapy with succimer and at least weekly during treatment. No data are available regarding the metabolism of succimer in patients with hepatic disease.
Succimer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women; however, the drug has been found to be teratogenic and fetotoxic in pregnant mice. Exposure to lead can be a concern for maternal and fetal harm. Per CDC current guidelines, the essential actions for managing pregnant women with blood lead levels of 5 mcg/dL or more are removal of the lead source, disruption of the route of exposure, and avoidance of the lead-containing substance or activity. In circumstances where the maternal blood lead concentration is 45 mcg/dL or more, chelation therapy may be warranted after consultation with an expert in lead poisoning and perinatologists; for lower lead concentrations, data are insufficient to advise the use of chelation during pregnancy. Avoid chelation during the first trimester in all pregnant women, unless the lead intoxication is severe (maternal lead encephalopathy), due to the general concerns of drug use during organogenesis. Although no chelation-attributable toxicities have been reported in the existing published case reports of the treatment of pregnant women, very limited information is available to understand any potential short- or long-term effects for the fetus.
It is not known if succimer is excreted in human breast milk. Because many drugs and heavy metals are excreted in human milk, lactating mothers requiring succimer therapy should be discouraged from nursing infants. According to CDC guidelines, the risk of adverse developmental effects in infants with blood lead concentrations of 5 mcg/dL or more is of greater concern than the risks associated with not breast-feeding. Thus, the CDC encourages mothers with blood lead concentrations of 40 mcg/dL or more to pump and discard their breast milk until their blood lead levels drop below 40 mcg/dL. These recommendations are made for the US population and may not be appropriate for other countries, where infant mortality from other causes is a greater concern.
Safety and efficacy of succimer in infants and neonates have not been established. Use of chelation agents may be considered in some cases, but an expert in management of lead toxicity should be consulted.
Serum and urine laboratory test interference may occur during treatment with succimer. In vitro studies of succimer have shown false positive results for ketones in urine using nitroprusside reagents (e.g., Ketostix) and falsely decreased measurement of serum uric acid and creatine phosphokinase (CPK).
General Dosing Information
-Identification of the lead source and its abatement are critical to a successful therapeutic outcome. Chelation therapy is not a substitute for preventing further exposure and should not be used to permit continued exposure to lead.
-Elevated blood lead concentrations and associated symptoms may return rapidly after succimer discontinuation because of redistribution of lead from bone stores to soft tissues and blood.
-In patients who have received edetate calcium disodium with or without dimercaprol, succimer can be used for subsequent treatment after an interval of 4 weeks.
For the treatment of lead toxicity secondary to serum lead concentrations above 45 mcg/dL:
Oral dosage:
Adults*: 30 mg/kg/day PO administered as 5-day treatment courses separated by rest periods of 7 to 10 days has been evaluated in adults. In a study of adults with occupational lead exposure resulting in blood lead concentrations of at least 40 mcg/dL and a positive edetate calcium disodium lead mobilization test, 1,050 mg/m2/day (approximately 30 mg/kg/day) was administered in 3 divided doses over two 5-day courses separated by a 10-day rest period. Another study administered 30 mg/kg/day as a series of 5-day courses separated by at least 1 week to adults with blood lead concentrations of 50 mcg/dL or higher. For pediatric patients, a maximum daily dose of 1,500 mg is recommended by the FDA for patients weighing more than 45 kg.
Children and Adolescents: 10 mg/kg/dose or 350 mg/m2/dose PO every 8 hours for the first 5 days, then reduce dosing frequency to every 12 hours for 14 days (total course = 19 days). Max: 1,500 mg/day. Adjust weight-based dose to available practical dose strength: weight 8 to 15 kg = 100 mg/dose; weight 16 to 23 kg = 200 mg/dose; weight 24 to 34 kg = 300 mg/dose; weight 35 to 44 kg = 400 mg/dose; weight more than 45 kg = 500 mg/dose. Repeat courses may be necessary based upon weekly monitoring of blood lead concentrations. Wait at least 2 weeks in between courses of therapy unless blood lead concentrations indicate the need for prompt treatment.
Maximum Dosage Limits:
-Adults
30 mg/kg/day PO has been evaluated for off label use.
-Geriatric
30 mg/kg/day PO has been evaluated for off label use.
-Adolescents
more than 45 kg: 500 mg/dose PO.
35 to 44 kg: 400 mg/dose PO.
24 to 34 kg: 300 mg/dose PO.
16 to 23 kg: 200 mg/dose PO.
8 to 15 kg: 100 mg/dose PO.
-Children
more than 45 kg: 500 mg/dose PO.
35 to 44 kg: 400 mg/dose PO.
24 to 34 kg: 300 mg/dose PO.
16 to 23 kg: 200 mg/dose PO.
8 to 15 kg: 100 mg/dose PO.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. No data are available regarding the metabolism of succimer in patients with hepatic impairment. Closely monitor patients with a history of hepatic disease, as transient mild elevations in serum transaminases have occurred during treatment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Use with caution in patients with renal impairment.
Intermittent hemodialysis
Limited data suggest that succimer is dialyzable, but lead chelates are not.
*non-FDA-approved indication
Edetate Calcium Disodium, Calcium EDTA: (Moderate) Concomitant use of succimer and other chelation therapy such as edetate calcium disodium, calcium EDTA (CaNa2EDTA) with or without dimercaprol (BAL) is not recommended, as data are not available. Patients who have received CaNa2EDTA with or without dimercaprol may use succimer for subsequent treatment after an interval of 4 weeks.
Sulfacetamide; Sulfur: (Moderate) Concomitant use of succimer and other chelation therapy such as edetate calcium disodium, calcium EDTA (CaNa2EDTA) with or without dimercaprol (BAL) is not recommended, as data are not available. Patients who have received CaNa2EDTA with or without dimercaprol may use succimer for subsequent treatment after an interval of 4 weeks.
Succimer is an orally administered lead chelator. The sulfhydryl, or thiol, groups of succimer bind with lead to form water-soluble chelates, which are excreted in the urine.
Succimer lowers blood lead concentrations. For example, among adults with blood lead concentrations of 44 to 96 mcg/dL who received oral succimer, the mean lead blood concentrations decreased 72.5% after 5 days of 10 mg/kg orally every 8 hours, 58.3% after 5 days of 6.7 mg/kg every 8 hours, and 35.5% after 5 days of 3.3 mg/kg every 8 hours. In the initial 24 hours after receipt of the 10 mg/kg dose, the mean urinary excretion of lead was 28.6-times the pretreatment 24-hour urinary lead excretion. As the chelatable pool was reduced during treatment, urinary lead output decreased. In addition to adults, succimer also lowers blood lead concentrations in children. Among children 2 to 7 years of age who received 350 mg/m2 every 8 hours for 5 days, the mean blood lead concentration decreased 78%. Unfortunately, both adults and pediatric patients experienced a rebound in blood lead concentrations after succimer discontinuation. For example, after receipt of 350 mg/m2 (10 mg/kg) every 8 hours for 5 days, the mean lead concentration rebounded and plateaued at 60% to 85% of pretreatment concentrations 2 weeks after therapy.
Succimer receipt beyond 5 days was studied to examine the effect of longer dosing on the rebound of blood lead concentrations. Children 1 to 7 years of age with blood lead concentrations of 42 to 67 mcg/dL who received 350 mg/m2 every 12 hours for 2 weeks after the initial 5 days of 350 mg/m2 every 8 hours did not experience rebound of blood lead concentrations after the initial 5-day treatment period. Further, less rebound was noted after succimer discontinuation. In another study, 10 children aged 21 to 72 months with blood lead concentrations of 30 to 57 mcg/dL received succimer 350 mg/m2 by mouth every 8 hours for 5 days, followed by 350 mg/m2 by mouth every 12 hours for an additional 19 to 22 days. Blood lead concentrations decreased and remained stable under 15 mcg/dL during the extended dosing period. Succimer is indicated for a total therapy duration of 19 days, and additional treatment courses may be needed.
Succimer is an effective chelator with minimal effect on the excretion of essential minerals when compared to edetate calcium disodium, calcium EDTA (another medication used for the treatment of lead toxicity). Treatment with succimer results in a doubling in zinc excretion but does not have a significant effect on the urinary elimination of iron, calcium, or magnesium.
Succimer is administered orally. After 10 mg/kg of succimer was administered orally to healthy adults, succimer was rapidly and extensively metabolized. Approximately 25% of the dose was excreted in the urine, with peak blood concentration and urinary excretion occurring between 2 and 4 hours. Only 10% of succimer excreted in the urine was excreted as unchanged drug. The majority of drug excreted in the urine occurred as mixed succimer-cysteine disulfides.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Oral Route
In a study of healthy volunteers, after the administration of a single dose of radiolabeled succimer, absorption was rapid but variable with peak blood radioactivity concentrations occurring within 1 to 2 hours after administration.
-Special Populations
Renal Impairment
Limited data suggest that succimer is dialyzable, but lead chelates are not.