Efecient

Efecient is indicated for the treatment of iron deficiency anemia in adult patients and in pediatric patients age 6 years and older with chronic kidney disease receiving hemodialysis who are receiving supplemental epoetin therapy.

The dosage of Efecient is expressed in terms of mg of elemental iron. Each 5 mL sterile, single-use vial contains 62.5 mg of elemental iron (12.5 mg/mL).

Do not mix Efecient with other medications, or add to parenteral nutrition solutions for intravenous infusion. The compatibility of Efecient with intravenous infusion vehicles other than 0.9% sodium chloride has not been evaluated. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever the solution and container permit. If diluted, use immediately.

Efecient treatment may be repeated if iron deficiency reoccurs.

Adult Dosage And Administration

The recommended dosage of Efecient for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of Efecient (125 mg of elemental iron). Efecient may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session. Efecient may also be administered undiluted as a slow intravenous injection (at a rate of up to 12.5 mg/min) per dialysis session. For repletion treatment most patients may require a cumulative dose of 1000 mg of elemental iron administered over 8 dialysis sessions. Efecient has been administered at sequential dialysis sessions by infusion or by slow intravenous injection during the dialysis session itself.

Data from Efecient postmarketing spontaneous reports indicate that individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events.

Pediatric Dosage And Administration

The recommended pediatric dosage of Efecient for the repletion treatment of iron deficiency in hemodialysis patients is 0.12 mL/kg Efecient (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session. The maximum dosage should not exceed 125 mg per dose.

• Known hypersensitivity to sodium ferric gluconate or any of its components.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Efecient in post marketing experience. Patients may present with shock, clinically significant hypotension, loss of consciousness, or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Efecient administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Efecient when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

In the single-dose, post-marketing, safety study one patient experienced a life-threatening hypersensitivity reaction (diaphoresis, nausea, vomiting, severe lower back pain, dyspnea, and wheezing for 20 minutes) following Efecient administration. Among 1,097 patients who received Efecient in this study, there were 9 patients (0.8%) who had an adverse reaction that, in the view of the investigator, precluded further Efecient administration. These included one life-threatening reaction, six allergic reactions (pruritus x2, facial flushing, chills, dyspnea/chest pain, and rash), and two other reactions (hypotension and nausea). Another 2 patients experienced (0.2%) allergic reactions not deemed to represent drug intolerance (nausea/malaise and nausea/dizziness) following Efecient administration.

Hypotension

Efecient may cause clinically significant hypotension. Hypotension associated with lightheadedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been reported. These hypotensive reactions may or may not be associated with signs and symptoms of hypersensitivity reactions and usually resolve within one to two hours. In the single dose safety study, post-administration hypotensive events were observed in 22/1,097 patients (2%) following Efecient administration. Transient hypotension may occur during dialysis. Administration of Efecient may augment hypotension caused by dialysis. Monitor patients for signs and symptoms of hypotension during and following Efecient administration.

Iron Overload

Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Efecient require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin, and transferrin saturation).

Benzyl Alcohol Toxicity

Efecient contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long term carcinogenicity studies of sodium ferric gluconate in animals were not performed.

Sodium ferric gluconate was not genotoxic in the Ames test or the rat micronucleus test. Sodium ferric gluconate produced a clastogenic effect in an In vitro chromosomal aberration assay in Chinese hamster ovary cells.

Studies to assess the effects of sodium ferric gluconate on fertility were not conducted.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies with Efecient in pregnant women. Reproduction studies have been performed in mice at doses up to 100 mg/kg/day (300 mg/m²/day) and in rats at up to 20 mg/kg/day (120 mg/m²/day). The doses in mice and rats are 4 and 1.5 times the human dose of 125 mg/day (77 mg/m²/day) on a body surface area basis and have revealed no evidence of harm to the fetus due to Efecient. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Efecient contains benzyl alcohol as a preservative. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants.

Nursing Mothers

It is not known whether Efecient is excreted in human milk. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Caution should be exercised when Efecient is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Efecient have been established in pediatric patients 6 to 15 years of age. Safety and effectiveness in pediatric patients younger than 6 years of age have not been established.

Benzyl Alcohol Toxicity and Pediatrics

The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all credits.

Geriatric Use

Clinical studies of Efecient did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Hypersensitivity
• Hypotension

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The most commonly reported adverse reactions ( ≥ 10%) in adult patients were nausea, vomiting and/or diarrhea, injection site reaction, hypotension, cramps, hypertension, dizziness, abnormal erythrocytes (e.g., changes in morphology, color, or number of red blood cells), dyspnea, chest pain, leg cramps and pain. In patients 6 to 15 years of age the most common adverse reactions ( ≥ 10%) were hypotension, headache, hypertension, tachycardia and vomiting.

Studies A And B

In multiple dose Studies A and B (total 126 adult patients), the most frequent treatment emergent adverse reactions following Efecient were:

Body as a Whole: injection site reaction (33%), chest pain (10%), pain (10%), asthenia (7%), headache (7%), fatigue (6%), fever (5%), malaise, infection, abscess, chills, rigors, carcinoma, flu-like syndrome, sepsis, lightheadedness, weakness.

Nervous System: cramps (25%), dizziness (13%), paresthesias (6%), agitation, somnolence, decreased level of consciousness.

Respiratory System: dyspnea (11%), coughing (6%), upper respiratory infections (6%), rhinitis, pneumonia.

Cardiovascular System: hypotension (29%), hypertension (13%), syncope (6%), tachycardia (5%), bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema.

Gastrointestinal System: nausea, vomiting and/or diarrhea (35%), anorexia, abdominal pain (6%), rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena.

Musculoskeletal System: leg cramps (10%), myalgia, arthralgia, back pain, arm pain.

Skin and Appendages: pruritus (6%), rash, increased sweating.

Genitourinary System: urinary tract infection, and menorrahagia.

Special Senses: conjunctivitis, rolling of the eyes, watery eyes, puffy eye lids, arcus senilis, redness of the eye, diplopia, and deafness.

Metabolic and Nutritional Disorders: hyperkalemia (6%), generalized edema (5%), leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia.

Hematologic System: abnormal erythrocytes (11%) (changes in morphology, color, or number of red blood cells), anemia, leukocytosis, lymphadenopathy.

Study C – Pediatric

Pediatric Patients: In a clinical trial of 66 iron-deficient pediatric hemodialysis patients, 6 to 15 years of age, inclusive, who were receiving a stable erythropoietin dosing regimen, the most common adverse reactions, occurring in ≥ 5%, regardless of treatment dosage, were: hypotension (35%), headache (24%), hypertension (23%), tachycardia (17%), vomiting (11%), fever (9%), nausea (9%), abdominal pain (9%), pharyngitis (9%), diarrhea (8%), infection (8%), rhinitis (6%), and thrombosis (6%). More patients in the higher dose group (3.0 mg/kg) than in the lower dose group (1.5 mg/kg) experienced the following adverse events: hypotension (41% vs. 28%), tachycardia (21% vs. 13%), fever (15% vs. 3%), headache (29% vs. 19%), abdominal pain (15% vs. 3%), nausea (12% vs. 6%), vomiting (12% vs. 9%), pharyngitis (12% vs. 6%), and rhinitis (9% vs. 3%).

Post Marketing Experience

In the single-dose, postmarketing safety study, 11% of patients who received Efecient and 9.4% of patients who received placebo reported adverse reactions. The most frequent adverse reactions following Efecient were: hypotension (2%), nausea, vomiting and/or diarrhea (2%), pain (0.7%), hypertension (0.6%), allergic reaction (0.5%), chest pain (0.5%), pruritus (0.5%), and back pain (0.4%). The following additional events were reported in two or more patients: hypertonia, nervousness, dry mouth, and hemorrhage.

In the multiple-dose, open-label surveillance study, 28% of the patients received concomitant angiotensin converting enzyme inhibitor (ACEi) therapy. The incidences of both drug intolerance or suspected allergic events following first dose Efecient administration were 1.6% in patients with concomitant ACEi use compared to 0.7% in patients without concomitant ACEi use. The patient with a life-threatening event was not on ACEi therapy. One patient had facial flushing immediately on Efecient exposure. No hypotension occurred and the event resolved rapidly and spontaneously without intervention other than drug withdrawal.

The following additional adverse reactions have been identified with the use of Efecient from postmarketing spontaneous reports: anaphylactictype reactions, shock, loss of consciousness, convulsion, skin discoloration, pallor, phlebitis, dysgeusia, and hypoesthesia.

Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events based on information from postmarketing spontaneous reports. These adverse events included hypotension, nausea, vomiting, abdominal pain, diarrhea, dizziness, dyspnea, urticaria, chest pain, paresthesia, and peripheral swelling.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The Efecient iron complex is not dialyzable.

No data is available regarding overdose of Efecient in humans. Excessive dosages of Efecient may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Efecient to patients with iron overload.

Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events.

Efecient at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg caused deaths in mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions.

Multiple sequential single dose intravenous pharmacokinetic studies were performed on 14 healthy iron-deficient volunteers. Entry criteria included hemoglobin ≥ 10.5 gm/dL and transferrin saturation ≤ 15% (TSAT) or serum ferritin value ≤ 20 ng/mL. In the first stage, each subject was randomized 1:1 to undiluted Efecient injection of either 125 mg/hr or 62.5 mg/0.5 hr (2.1 mg/min). Five days after the first stage, each subject was rerandomized 1:1 to undiluted Efecient injection of either 125 mg/7 min or 62.5 mg/4 min ( > 15.5 mg/min).

Peak drug levels (Cmax ) varied significantly by dosage and by rate of administration with the highest Cmax observed in the regimen in which 125 mg was administered in 7 minutes (19.0 mg/L). The terminal elimination half-life for drug bound iron was approximately 1 hour. Half-life varied by dose but not by rate of administration. Half-life values were 0.85 and 1.45 hours for the 62.5 mg/4 min and 125 mg/7 min regimens, respectively. Total clearance of Efecient was 3.02 to 5.35 L/h. The AUC for Efecient bound iron varied by dose from 17.5 mg-h/L (62.5 mg) to 35.6 mg-h/L (125 mg). Approximately 80% of drug bound iron was delivered to transferrin as a mononuclear ionic iron species within 24 hours of administration in each dosage regimen. Direct movement of iron from Efecient to transferrin was not observed. Mean peak transferrin saturation returned to near baseline by 40 hours after administration of each dosage regimen.

Pediatrics

Single dose intravenous pharmacokinetic analyses were performed on 48 iron-deficient pediatric hemodialysis patients. Twenty-two patients received 1.5 mg/kg Efecient and 26 patients received 3.0 mg/kg Efecient (maximum dose 125 mg). The mean Cmax, AUC0-∞ , and terminal elimination half-life values following a 1.5 mg/kg dose were 12.9 mg/L, 95.0 mg·hr/L, and 2.0 hours, respectively. The mean Cmax, AUC0-∞, and terminal elimination half-life values following a 3.0 mg/kg dose were 22.8 mg/L, 170.9 mg·hr/L, and 2.5 hours, respectively.

In vitro experiments have shown that less than 1% of the iron species within Efecient can be dialyzed through membranes with pore sizes corresponding to 12,000 to 14,000 daltons over a period of up to 270 minutes. Human studies in renally competent patients suggest the clinical insignificance of urinary excretion.