Gastromark

Gastromark is indicated for the treatment of iron deficiency anemia (IDA) in adult patients:

• who have intolerance to oral iron or have had unsatisfactory response to oral iron or
• who have chronic kidney disease (CKD).

The recommended dose of Gastromark is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer Gastromark as an intravenous infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes. Administer while the patient is in a reclined or semi-reclined position.

Gastromark does not contain antimicrobial preservatives. Discard unused portion. Gastromark, when added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 mg elemental iron per mL, should be used immediately but may be stored at controlled room temperature (25°C ± 2°C) for up to 4 hours or refrigerated (2-8° C) for up to 48 hours.

The dosage is expressed in terms of mg of elemental iron, with each mL of Gastromark containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second Gastromark infusion. The recommended Gastromark dose may be readministered to patients with persistent or recurrent iron deficiency anemia.

For patients receiving hemodialysis, administer Gastromark once the blood pressure is stable and the patient has completed at least one hour of hemodialysis. Monitor for signs and symptoms of hypotension following each Gastromark infusion.

Allow at least 30 minutes between administration of Gastromark and administration of other medications that could potentially cause serious hypersensitivity reactions and/or hypotension, such as chemotherapeutic agents or monoclonal antibodies.

Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration.

Gastromark is contraindicated in patients with:

• Known hypersensitivity to Gastromark or any of its components
• History of allergic reaction to any intravenous iron product

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Hypersensitivity Reactions

Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness have occurred in patients receiving Gastromark. Other adverse reactions potentially associated with hypersensitivity have occurred (pruritus, rash, urticaria, and wheezing). These reactions have occurred following the first dose or subsequent doses in patients in whom a previous Gastromark dose was tolerated.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Gastromark to these patients.

Only administer Gastromark when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after Gastromark administration for at least 30 minutes and until clinically stable following completion of each infusion.

In clinical studies predominantly in patients with CKD, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Gastromark. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. In other trials excluding patients with Stages 4 and 5 CKD, moderate to severe hypersensitivity reactions were reported in 2.6% (26/1014) of patients treated with Gastromark.

In the post-marketing experience, fatal and serious anaphylactic type reactions presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Gastromark may have more severe outcomes.

Hypotension

Severe adverse reactions of clinically significant hypotension have been reported. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Hypotension has also been reported in the post-marketing experience. Monitor patients for signs and symptoms of hypotension following each Gastromark administration.

Iron Overload

Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy. Do not administer Gastromark to patients with iron overload.

In the 24 hours following administration of Gastromark, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Gastromark complex.

Magnetic Resonance (MR) Imaging

Administration of Gastromark may transiently affect the diagnostic ability of MR imaging. Anticipated MR imaging studies should be conducted prior to the administration of Gastromark. Alteration of MR imaging studies may persist for up to 3 months following the last Gastromark dose. If MR imaging is required within 3 months after Gastromark administration, use T1-or proton density-weighted MR pulse sequences to minimize the Gastromark effects; MR imaging using T2-weighted pulse sequences should not be performed earlier than 4 weeks after the administration of Gastromark. Maximum alteration of vascular MR imaging is anticipated to be evident for 1 – 2 days following Gastromark administration.

Gastromark will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound or nuclear medicine imaging.

Patient Counseling Information

Refer patients to the FDA approved Patient Package Insert.

Prior to Gastromark administration:

• Question patients regarding a history of allergy to intravenous iron or any medications.
• Advise patients of the serious risks associated with Gastromark.
• Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Gastromark administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems. Advise patients to seek immediate medical attention if these occur.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ferumoxytol was not tested for carcinogenic effects. In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.

No adverse effects on fertility or general reproductive performance were noted in animal studies. Ferumoxytol had no effect on male or female fertility or general reproductive function in rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no studies of Gastromark in pregnant women. In animal studies, ferumoxytol caused fetal malformations and decreased fetal weights at maternally toxic doses of 6 times the estimated human daily dose. Use Gastromark during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and/or soft tissue fetal malformations and decreased fetal weights.

Nursing Mothers

It is not known whether Gastromark is present in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to avoid Gastromark, taking into account the importance of Gastromark to the mother and the known benefits of nursing.

Pediatric Use

The safety and effectiveness of Gastromark in pediatric patients (less than 18 years old) have not been established.

Geriatric Use

In controlled clinical trials, 330 patients ≥ 65 years of age were treated with Gastromark. No overall differences in safety and efficacy were observed between older and younger patients in these trials, but greater sensitivity of older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Gastromark may have more severe outcomes. The potential risks and benefits of Gastromark administration should be carefully considered in these patients.

The following serious adverse reactions are described elsewhere in the labeling:

• Serious Hypersensitivity Reactions
• Hypotension
• Iron Overload
• Magnetic Resonance (MR) Imaging Test Interference

Clinical Trial Experience

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

In clinical studies, 3,968 subjects were exposed to Gastromark. Of these subjects 31% were male and the median age was 54 years (range of 18 to 96 years).

The data described below reflect exposure to Gastromark in 997 patients exposed to a 1.02 g course of ferumoxytol administered as two 510 mg intravenous (IV) doses: 992 subjects (99.5%) received at least 1 complete dose of ferumoxytol and 946 subjects (94.9%) received 2 complete doses. The mean cumulative IV Iron exposure was 993.80 ±119.085 mg.

The safety of Gastromark was studied in a randomized, multicenter, double-blind clinical trial in patients with IDA (IDA Trial 3),. In this trial, patients were randomized to two intravenous infusions of 510 mg (1.02 g) of Gastromark (n=997), or two intravenous infusions of 750 mg (1.500 g) of ferric carboxymaltose (FCM) (n=1000). Both intravenous irons were infused over a period of at least 15 minutes. Most patients received their second infusion of Gastromark and FCM 7(+1) days after Dose 1.

The mean (SD) age of the study population (N=1997) was 55.2 (17.16) years. The majority of patients were female (76.1%), white (71.4%) and non-Hispanic (81.8%). The mean (SD) hemoglobin at baseline for all patients was 10.4 (1.5) g/dl.

Serious adverse events were reported in 3.6% (71/1997) of ferumoxytol-and FCM-treated patients. The most common (≥2 subjects) serious AEs reported in Gastromark-treated patients were syncope, gastroenteritis, seizure, pneumonia, hemorrhagic anemia, and acute kidney injury. In FCM-treated patients the most common (≥2 subjects) serious AEs were syncope, cardiac failure congestive, angina pectoris, and atrial fibrillation.

Adverse reactions related to Gastromark and reported by ≥ 1% of Gastromark-treated patients in IDA Trial 3 are listed in Table 1.

Table 1: Adverse Reactions to Gastromark Reported in ≥1% of IDA Patients in IDA Trial 3

In IDA Trial 3, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 Gastromark-treated patients included arthralgia (0.3%), dyspnea (0.3%), flushing (0.2%), chest discomfort (0.2%), chest pain (0.2%), nausea (0.2%), back pain (0.2%), dizziness (0.2%) and headache (0.2%).

Across two clinical trials in patients with IDA (IDA Trial 1 and 2), , patients were randomized to: two injections (rapid intravenous injection -prior method of administration no longer approved) of 510 mg of Gastromark (n=1,014), placebo (n=200), or five injections/infusions of 200 mg of iron sucrose (n=199). Most patients received their second Gastromark injection 3 to 8 days after the first injection. Adverse reactions related to Gastromark and reported by ≥ 1% of Gastromark-treated patients in these trials were similar to those seen in Trial 3.

In Trials 1 and 2, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 Gastromark-treated patients included hypersensitivity (0.6%), hypotension (0.3%), and rash (0.2%).

In addition, a total of 634 subjects enrolled in and completed participation in a Phase 3 open label extension study. Of these, 337 subjects met IDA treatment criteria and received Gastromark. Adverse reactions following this repeat Gastromark dosing were generally similar in type and frequency to those observed after the first two intravenous injections.

Across three randomized clinical trials in patients with IDA and CKD (CKD Trials 1, 2, and 3), , a total of 605 patients were exposed to two injections of 510 mg of Gastromark and a total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients received their second Gastromark injection 3 to 8 days after the first injection.

Adverse reactions related to Gastromark and reported by ≥ 1% of Gastromark-treated patients in the CKD randomized clinical trials are listed in Table 2. Diarrhea (4%), constipation (2.1%) and hypertension (1%) have also been reported in Gastromark-treated patients.

Table 2: Adverse Reactions to Gastromark Reported in ≥1% of Patients with IDA and CKD Trials 1, 2 and 3

In these clinical trials in patients with IDA and CKD, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 Gastromark-treated patients included hypotension (0.4%), chest pain (0.3%), and dizziness (0.3%).

Following completion of the controlled phase of the trials, 69 patients received two additional 510 mg intravenous injections of Gastromark (for a total cumulative dose of 2.04 g). Adverse reactions following this repeat Gastromark dosing were similar in character and frequency to those observed following the first two intravenous injections.

Postmarketing Experience

Because adverse 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 following serious adverse reactions have been reported from the post-marketing experience with Gastromark: fatal, life-threatening, and serious anaphylactic-type reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually occurred within 30 minutes after the administration of Gastromark. Reactions have occurred following the first dose or subsequent doses of Gastromark.

Limited data are available regarding overdosage of Gastromark in humans.

Excessive dosages of Gastromark may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Gastromark to patients with iron overload [WARNINGS AND PRECAUTIONS].

Cardiac Electrophysiology

In a randomized, positive-and placebo-controlled, parallel-group study, healthy subjects received a supratherapeutic regimen of Gastromark (1.02 g given as two 510 mg doses within 24 hours), placebo or a single dose of 400 mg moxifloxacin (positive control). Results demonstrated no effect of Gastromark on QT interval durations. No clinically meaningful effect of Gastromark on heart rate was observed.

The pharmacokinetic (PK) behavior of Gastromark has been examined in healthy subjects and in patients with CKD stage 5D on hemodialysis. Gastromark exhibited dose-dependent, capacity-limited elimination from plasma with a half-life of approximately 15 hours in humans. The clearance (CL) was decreased by increasing the dose of Gastromark. Volume of distribution (Vd) was consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t½) values increased with dose. The estimated values of CL and Vd following two 510 mg doses of Gastromark administered intravenously within 24 hours were 69.1 mL/hr and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence on Gastromark PK parameters. No gender differences in Gastromark PK parameters were observed. Gastromark is not removed by hemodialysis.