Renocis

Renocis is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. Renocis is not indicated for prophylaxis of lead poisoning in a lead-containing environment; the use of Renocis should always be accompanied by identification and removal of the source of the lead exposure.

Start dosage at 10 mg/kg or 350 mg/m² every eight hours for five days. Initiation of therapy at higher doses is not recommended. (See Table II for Dosing chart and number of capsules.) Reduce frequency of administration 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 concentration. A minimum of two weeks between courses is recommended unless blood lead levels indicate the need for more prompt treatment.

TABLE II : Renocis (SUCCIMER) PEDIATRIC DOSING CHART

In young pediatric patients who cannot swallow capsules, Renocis can be administered by separating the capsule and sprinkling the medicated beads on a small amount of soft food or putting them in a spoon and following with fruit drink.

Identification of the source of lead in the pediatric patient's environment and its abatement are critical to a successful therapy outcome. Chelation therapy is not a substitute for preventing further exposure to lead and should not be used to permit continued exposure to lead.

Patients who have received CaNa2EDTA with or without BAL may use Renocis for subsequent treatment after an interval of four weeks. Data on the concomitant use of Renocis with CaNa2EDTA with or without BAL are not available, and such use is not recommended.

Renocis should not be administered to patients with a history of allergy to the drug.

WARNINGS

Keep out of reach of pediatric patients. Renocis (succimer) is not a substitute for effective abatement of lead exposure.

Mild to moderate neutropenia has been observed in some patients receiving succimer. While a causal relationship to succimer has not been definitely established, neutropenia has been reported with other drugs in the same chemical class. A complete blood count with white blood cell differential and direct platelet counts should be obtained prior to and weekly during treatment with succimer. Therapy should either be withheld or discontinued if the absolute neutrophil count (ANC) is below 1200/µL and the patient followed closely to document recovery of the ANC to above 1500/µL or to the patient's baseline neutrophil count. There is limited experience with reexposure in patients who have developed neutropenia. Therefore, such patients should be rechallenged only if the benefit of succimer therapy clearly outweighs the potential risk of another episode of neutropenia and then only with careful patient monitoring.

Patients treated with succimer should be instructed to promptly report any signs of infection. If infection is suspected, the above laboratory tests should be conducted immediately.

PRECAUTIONS

The extent of clinical experience with Renocis (succimer) is limited. Therefore, patients should be carefully observed during treatment.

General: Elevated blood lead levels and associated symptoms may return rapidly after discontinuation of Renocis (succimer) because of redistribution of lead from bone stores to soft tissues and blood. After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring.

All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using Renocis (succimer) therapy in patients with compromised renal function. Limited data suggests that Renocis (succimer) is dialyzable, but that the lead chelates are not.

Transient mild elevations of serum transaminases have been observed in 6-10% of patients during the course of succimer therapy. Serum transaminases should be monitored before the start of therapy and at least weekly during therapy. Patients with a history of liver disease should be monitored closely. No data are available regarding the metabolism of succimer in patients with liver disease.

Clinical experience with repeated courses is limited. The safety of uninterrupted dosing longer than three weeks has not been established and it is not recommended.

The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on readministration (as well as during initial courses). Patients requiring repeated courses of Renocis (succimer) should be monitored during each treatment course. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity affecting the oral mucosa, the external urethral meatus and the perianal area on the third, fourth and fifth courses of the drug. The reaction resolved between courses and upon discontinuation of therapy.

Carcinogenesis, Mutagenesis and Impairment of Fertility: Renocis (succimer) has not been tested for carcinogenic potential in long-term animal studies. Renocis (succimer) up to a dose of 510 mg/kg/day in males and 100 mg/kg/day in females did not show any adverse effect on fertility and reproductive performance. It was not mutagenic in the Ames bacterial assay and in the mammalian cell forward gene mutation assay.

Pregnancy: Teratogenic Effects - Pregnancy Category C. Renocis (succimer) has been shown to be teratogenic and fetotoxic in pregnant mice when given subcutaneously in a dose range of 410 to 1640 mg/kg/day during the period of organogenesis. In a developmental study in rats, Renocis (succimer) produced maternal toxicity and deaths at the dose of 720 mg/kg/day or more during organogenesis.

The dose of 510 mg/kg/day was the highest tolerable dose in pregnant rats. Impaired development of reflexes was noted in pups of 720 mg/kg/day group dam. There are no adequate and well controlled studies in pregnant women. Renocis (succimer) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs and heavy metals are excreted in human milk, nursing mothers requiring Renocis (succimer) therapy should be discouraged from nursing their infants.

Pediatric Use: Refer to the INDICATIONS and DOSAGE AND ADMINISTRATION sections. Safety and efficacy in pediatric patients less than 12 months of age have not been established.

Clinical experience with Renocis has been limited. Consequently, the full spectrum and incidence of adverse reactions including the possibility of hypersensitivity or idiosyncratic reactions have not been determined. The most common events attributable to succimer, i.e., gastrointestinal symptoms or increases in serum transaminases, have been observed in about 10% of patients (see PRECAUTIONS). Rashes, some necessitating discontinuation of therapy, have been reported in about 4% of patients. If rash occurs, other causes (e.g. measles) should be considered before ascribing the reaction to succimer. Rechallenge with succimer may be considered if lead levels are high enough to warrant retreatment. One allergic mucocutaneous reaction has been reported on repeated administration of the drug (see PRECAUTIONS). Mild to moderate neutropenia has been observed in some patients receiving succimer (see WARNINGS). Table I presents adverse events reported with the administration of succimer for the treatment of lead and other heavy metal intoxication.

TABLE I : INCIDENCE OF ADVERSE EVENTS IN DOMESTIC STUDIES REGARDLESS OF ATTRIBUTION OR SUCCIMER DOSAGE

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-755-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Doses of 2300 mg/kg in the rat and 2400 mg/kg in the mouse produced ataxia, convulsions, labored respiration and frequently death. No case of overdosage has been reported in humans. Limited data indicate that succimer is dialyzable. In case of acute overdosage, induction of vomiting or gastric lavage followed by administration of an activated charcoal slurry and appropriate supportive therapy are recommended.

In a study performed in healthy adult volunteers, after a single dose of ¹⁴C-succimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days.

In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.