The Poison Control Center

Succimer (DMSA), An Oral Lead Chelator

Introduction
Approved indications
Clinical studies
Dosage and administration
Adverse effects
Recommended monitoring parameters
Conclusion
References

Introduction

Succimer (Chemet®), marketed by McNeil Consumer Products Company, Division of McNeil-PPC, Inc.) is an orally active chelating agent indicated for the treatment of lead poisoning in children with blood level concentrations >45 mcg./dL. Succimer is the first oral lead chelator for the treatment of lead poisoning in children. The selectivity, efficacy and safety characteristics of succimer offer many advantages over currently available agents.1 As an oral agent, it offers ease of administration and offers physicians the option of treating children as outpatients.2,3 The specificity of succimer substantially reduces the risk of essential mineral depletion associated with conventional chelating agents.

Chemet® (succimer) contains the stable meso isomer of dimercaptosuccinic acid which has also been known as DMSA. Succimer is a heavy metal chelating agent that, in vitro, forms stable water soluble complexes with lead4 and consequently increases the urinary excretion of lead.2-9 Succimer has also been found to chelate other toxic heavy metals such as arsenic10 and mercury.11

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Approved Indications

Chemet® is indicated for the treatment of lead poisoning in children with blood lead levels above 45 mcg./dL. Chemet® is not indicated for the prophylaxis of lead poisoning in a lead-containing environment; the use of Chemet® should always be accompanied by identification and removal of the source of the lead exposure. Identification of the source of lead in the child's environment and its abatement are critical to a successful therapy outcome. Chelation therapy is not a substitute for prevention of further exposure to lead and should not be used to permit continued exposure to lead.

Clinical Studies

Clinical studies8,9,12 indicate that succimer is a relatively selective and highly effective medication that lowers blood lead concentrations. Succimer reverses the adverse metabolic effects of lead on heme synthesis while increasing urinary lead output without adversely affecting essential mineral excretion at the recommended dosage regimen. The primary indicators of drug efficacy in the controlled trials of oral succimer were a lowering of blood lead concentrations and an increase in urinary lead excretion. Secondary indicators of efficacy included restoration of red cell ALA-D activity, an enzyme necessary for heme synthesis, and a reduction in urinary ALA and coproporphyrin. Measurement of coproporphyrin and ALA-D provide clinical investigators with an indication of lead effects on heme biosynthetic pathways and reversal of these effects during chelation therapy. ALA-D activity and urinary excretion of ALA are sensitive indicators of exposure to lead.

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Dosage and administration

The recommended initial dosage in children is 10 mg./kg. or 350 mg./m2 every eight hours for five days. Initiation of therapy at higher doses is not recommended. After the initial five days of therapy is complete, the dosage is reduced to 10 mg./kg. or 350 mg./m2 every 12 hours (two-thirds of initial daily dosage) for an additional two weeks of therapy. A course of treatment lasts 19 days. Repeated courses may be necessary if indicated by weekly monitoring of blood lead concentrations. A minimum of two weeks between courses is recommended unless blood lead concentrations indicated the need for more prompt treatment. Clinical experience with repeated courses is limited. The safety of uninterrupted dosing longer than three weeks has not been established and is not recommended.

In young children who cannot swallow capsules, Chemet® can be given by separating the capsule and administering immediately by sprinkling the beads on soft food or putting them in a spoon and following with a fruit drink, which may help to mask the characteristic sulfur odor.

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Adverse Effects

The most common adverse effects reported in clinical trials in children and adults were primarily gastrointestinal in nature and included nausea, vomiting, diarrhea, appetite loss and loose stools. Rashes, some necessitating discontinuation of therapy, have been reported in about 4 percent of patients (adults and children). If rash occurs, other causes should be considered before ascribing the reaction to succimer. Rechallenge with succimer may be considered if blood lead levels are high enough to warrant retreatment.

Mild, transient elevations of serum transaminases have been observed in approximately 6-10 percent of the patients (adults and children) receiving succimer therapy. The significance of these increases is presently unknown.

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Recommended Monitoring Parameters

In addition to a diagnostic blood level concentration determined prior to therapy initiation, patients should be monitored for rebound in blood lead concentrations after therapy, because, as with all chelating agents, elevated blood lead concentrations and associated symptoms may return rapidly after discontinuation of succimer due to redistribution of lead from bone stores to soft tissues. Severity of the toxicity (as measured by the pretreatment blood lead concentration and the exposure history) should be used as a guide to the frequency of blood lead monitoring, but it should be performed at least once weekly until stable.

Reinstitution of therapy should be considered when blood lead concentrations rebound secondary to lead redistribution from bone stores. It is recommended that two weeks elapse between courses of chelation therapy unless blood concentrations indicate that a more rapid retreatment is necessary.

Succimer heavy metal chelates are excreted in the urine; therefore, all patients undergoing treatment should be adequately hydrated. Caution should be exercised in considering succimer therapy in patients with compromised renal function. Limited data suggest that succimer is dialyzable but that lead chelates are not.

Because transient elevations of serum transaminase levels have been observed during the course of succimer therapy, serum transaminases should be monitored prior to the initiation of therapy and at least weekly during therapy, particularly in patients with a history of liver disease.

Conclusion

Clinical studies indicate that succimer is a relatively selective and highly effective drug which lowers blood lead concentrations. Succimer reverses the adverse metabolic effects of lead on heme synthesis while increasing urinary lead output without adversely affecting essential mineral excretion. The benefit of an oral lead chelator may offer advantages over currently available agents.

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References

  1. Graziano JH. Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal poisoning. Med Toxicol. 1986 May-Jun;1(3):155-62.
  2. Kuntzelman DR, England KE, Angle CR. Urine lead (UPb) in outpatient treatment of lead poisoning with dimercaptosuccinic acid (DMSA). Vet Hum Toxicol 1990;4:346.
  3. Montalvan J, Okose P, Marcus S. Outpatient chelation therapy of 24 patients with lead intoxication by dimercaptosuccinic acid. Vet Hum Toxicol 1990;4:343.
  4. Rivera M, Zheng W, Aposhian HV, Fernando HQ. Determination and metabolism of dithiol chelating agents. VIII. Metal complexes of meso-dimercaptosuccinic acid. Toxicol Appl Pharmacol 1989 Aug;100(1):96-106.
  5. Bentur Y, Brook JG, Behar R, Taitelman U. Meso-2,3-dimercaptosuccinic acid in the diagnosis and treatment of lead poisoning. J Toxicol Clin Toxicol 1987;25(1-2):39-51.
  6. Fournier L, Thomas G, Garnier R, Buisine A, Houze P, Pradier F, Dally S. 2,3-dimercaptosuccinic acid treatment of heavy metal poisoning in humans. Med Toxicol Adverse Drug Exp 1988 Nov-Dec;3(6):499-504.
  7. Friedheim E, Graziano JH, Popovac D, Dragovic D, Kaul B. Treatment of lead poisoning by 2,3-dimercaptosuccinic acid. Lancet 1978 Dec;2(8102):1234-6.
  8. Graziano JH, LoIacono NJ, Meyer P. Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations. J Pediatr 1988 Oct;113(4):751-757.
  9. Graziano JR, Siris ES, LoIacono N, Silverberg SJ, Turgeon L. 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985 Apr;37(4):431-8.
  10. Lenz K, Hruby K, Druml W, Eder A, Gaszner A, Kleinberger G, Pichler M, Weiser M. 2,3-Dimercaptosuccinic acid in human arsenic poisoning. Arch Toxicol 1981 Jun;47(3):241-3.
  11. Mortensen ME, Valenzuela PM. 2,3-dimercaptosuccinic acid (DMSA) chelation in mercury (Hg) vapor poisoning. Vet Hum Toxicol 1990;4:362.
  12. Data on file. McNeil Consumer Products Company.

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