Omontys

Name: Omontys

Omontys Precautions

Using peginesatide or other erythropoiesis-stimulating agents (ESAs) can lead to serious side effects including death.

  • If you decide to take peginesatide, your healthcare provider should prescribe the smallest dose of peginesatide that is needed to reduce your chance of needing red blood cell transfusions.
  • You may get serious heart problems such as heart attack, stroke, heart failure, and may die sooner if you are treated with peginesatide to reach a normal or near-normal hemoglobin level.
  • You may get blood clots while receiving peginesatide. If you are receiving peginesatide and you are going to have surgery, talk to your healthcare provider about whether or not you need to take a blood thinner to lessen the chance of blood clots during or following surgery. Clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of a blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus).

Call your healthcare provider or get medical help right away if you have any of these symptoms of blood clots:

  • Chest pain
  • Trouble breathing or shortness of breath
  • Pain in the legs, with or without swelling
  • A cool or pale arm or leg
  • Sudden confusion, trouble speaking, or understanding others’ speech
  • Sudden numbness or weakness of the face, arm, or leg, especially on one side of your body
  • Sudden trouble seeing
  • Sudden trouble walking, dizziness, loss of balance or coordination
  • Loss of consciousness (fainting)
  • Hemodialysis vascular access stops working.

Peginesatide should not be used for the treatment of anemia:

  • if you have chronic kidney disease (CKD) and are NOT on dialysis,
  • if you are receiving treatment for cancer and your anemia is NOT caused by CKD,
  • in place of emergency treatment for anemia (red blood cell transfusions).

Peginesatide has not been proven to improve the quality of life, fatigue, or well-being.

It is not known if peginesatide is safe and effective in children.

Do not use peginesatide if you:

  • have high blood pressure that is not controlled (uncontrolled hypertension).
  • have had a serious allergic reaction to peginesatide.

Omontys and Pregnancy

Tell your healthcare provider if you are pregnant or plan to become pregnant. It is not known if peginesatide will harm your unborn baby.

 

Omontys Dosage and Administration

Evaluation of Iron Stores and Nutritional Factors

Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Omontys [see Warnings and Precautions (5.7)].

Patients with Chronic Kidney Disease

Individualize dosing and use the lowest dose of Omontys sufficient to reduce the need for RBC transfusions [see Warnings and Precautions (5.1)]. In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events [see Boxed Warning and Clinical Studies (14)].

Initiation of Treatment and Starting Dose

Initiate Omontys treatment when the hemoglobin level is less than 10 g/dL.

The recommended starting dose for the treatment of anemia in patients who are not currently treated with an ESA is 0.04 mg/kg body weight administered as a single intravenous or subcutaneous injection once monthly.

Conversion from Epoetin Alfa or Darbepoetin Alfa to Omontys in Patients with CKD on Dialysis

Omontys is administered once monthly, either subcutaneously or intravenously.

In patients previously receiving epoetin alfa or darbepoetin alfa, estimate the starting monthly dose of Omontys for patients on the basis of the weekly dose of epoetin alfa or darbepoetin alfa at the time of substitution (see Table 1). Maintain the route of administration (intravenous or subcutaneous injection).

  • For patients previously receiving epoetin alfa, the first dose of Omontys should be administered one week after the last epoetin alfa dose was administered.
  • For patients previously receiving darbepoetin alfa, the first dose of Omontys should be administered at the next scheduled dose in place of darbepoetin alfa.
Table 1 Estimated Omontys Starting Doses for Patients Based on Previous Weekly ESA Dose
Previous Total Weekly Epoetin Alfa Dose (U/week) Previous Weekly Darbepoetin Alfa Dose (mcg/week) Omontys Dose Once Monthly (mg/month)
Less than 2,500 Less than 12 2
2,500 to less than 4,300 12 to less than 18 3
4,300 to less than 6,500 18 to less than 25 4
6,500 to less than 8,900 25 to less than 35 5
8,900 to less than 13,000 35 to less than 45 6
13,000 to less than 19,000 45 to less than 60 8
19,000 to less than 33,000 60 to less than 95 10
33,000 to less than 68,000 95 to less than 175 15
greater than or equal to 68,000 greater than or equal to 175 20

General Guidance including Dose Adjustments

Monitor hemoglobin levels at least every 2 weeks until stable, then monitor at least monthly. When adjusting therapy, consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.

  • Do not increase the dose more frequently than once every 4 weeks.
  • If the hemoglobin rises rapidly (e.g., more than 1 g/dL in the 2 weeks prior to the dose or more than 2 g/dL in 4 weeks), reduce the dose of Omontys by 25% or more as needed to reduce rapid responses.
  • If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Omontys. After a dose has been withheld and once the hemoglobin begins to decrease, Omontys may be restarted at a dose approximately 25% below the previously administered dose.
  • For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
  • For patients who do not respond adequately over a 12-week escalation period, increasing the Omontys dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Omontys if responsiveness does not improve [see Warnings and Precautions (5.5)].
  • If a dose of Omontys is missed, administer the missed dose as soon as possible and restart Omontys at the prescribed once monthly dosing frequency.

When treating dialysis patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.2).

Refer patients who self-administer Omontys to the Instructions for Use [see Patient Counseling Information (17)].

Preparation and Administration of Omontys

Omontys is packaged as single use vials, single use pre-filled syringes, and multiple use vials. Omontys packaged in single use vials and single use pre-filled syringes contains no preservatives. Omontys is administered either subcutaneously or intravenously.

  • Use the single use vial or single use pre-filled syringe only one time. Discard unused portion of Omontys in single use vials.
  • Store unused portions of Omontys in multiple use vials at 36 °F to 46 °F (2 °C to 8 °C). Discard 28 days after first use.
  • Protect Omontys from light. Store Omontys vials or pre-filled syringes in their cartons until time of use.
  • Do not use if tamper-evident seal on carton is broken or missing.
  • Do not dilute Omontys and do not administer in conjunction with other drug solutions.
  • Omontys should be inspected visually for particulate matter and coloration prior to administration. Do not use any vials or pre-filled syringes of Omontys exhibiting particulate matter or a coloration other than colorless to slightly yellow.

Dosage Forms and Strengths

Dosage Form Strengths
Single use vials (preservative-free) 2 mg/0.5 mL, 3 mg/0.5 mL, 4 mg/0.5 mL, 5 mg/0.5 mL, and 6 mg/0.5 mL
Single use pre-filled syringes (preservative-free) 1 mg/0.5 mL, 2 mg/0.5 mL, 3 mg/0.5 mL, 4 mg/0.5 mL, 5 mg/0.5 mL, and 6 mg/0.5 mL
Multiple use vials (with preservative) 10 mg/mL and 20 mg/2 mL

Warnings and Precautions

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

  • In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups.
  • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
  • In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke.
  • In controlled clinical trials, ESAs increased risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures.

The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).

Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD
NHS
(N = 1265)
CHOIR
(N = 1432)
TREAT
(N = 4038)
Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009
Population Patients with CKD on
hemodialysis with
coexisting CHF or CAD,
hematocrit 30 ± 3% on
epoetin alfa
Patients with CKD not on
dialysis with hemoglobin
< 11 g/dL not previously
administered epoetin alfa
Patients with CKD not on
dialysis with type II
diabetes, hemoglobin
≤ 11 g/dL
Hemoglobin Target;
Higher vs. Lower
(g/dL)
14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥ 9.0
Median (Q1, Q3)
Achieved Hemoglobin
level (g/dL)
12.6 (11.6, 13.3) vs.
10.3 (10.0, 10.7)
13.0 (12.2, 13.4) vs.
11.4 (11.1, 11.6)
12.5 (12.0, 12.8) vs.
10.6 (9.9, 11.3)
Primary Endpoint All-cause mortality or
non-fatal MI
All-cause mortality, MI,
hospitalization for CHF,
or stroke
All-cause mortality, MI,
myocardial ischemia,
heart failure, and stroke
Hazard Ratio or
Relative Risk
(95% CI)
1.28 (1.06 - 1.56) 1.34 (1.03 - 1.74) 1.05 (0.94 - 1.17)
Adverse Outcome
for Higher Target Group
All-cause mortality All-cause mortality Stroke
Hazard Ratio or
Relative Risk
(95% CI)
1.27 (1.04 - 1.54) 1.48 (0.97 - 2.27) 1.92 (1.38 - 2.68)

Patients with Chronic Kidney Disease Not on Dialysis

Omontys is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis.

A higher percentage of patients (22%) who received Omontys experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81).

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs

Omontys is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for Omontys in this setting have not been evaluated.

The safety and efficacy of Omontys have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy.

Hypertension

Omontys is contraindicated in patients with uncontrolled hypertension.

Appropriately control hypertension prior to initiation of and during treatment with Omontys. Reduce or withhold Omontys if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].

Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, hypotension, bronchospasm, angioedema and generalized pruritus, may occur in patients treated with Omontys. Immediately and permanently discontinue Omontys and administer appropriate therapy if a serious allergic reaction occurs.

Lack or Loss of Response to Omontys

For lack or loss of hemoglobin response to Omontys, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Omontys therapy [see Dosage and Administration (2.2)].

Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies.

Dialysis Management

Patients may require adjustments in their dialysis prescriptions after initiation of Omontys. Patients receiving Omontys may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Laboratory Monitoring

Evaluate transferrin saturation and serum ferritin prior to and during Omontys treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% [see Dosage and Administration (2.1)]. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable.

Omontys - Clinical Pharmacology

Mechanism of Action

Peginesatide binds to and activates the human erythropoietin receptor and stimulates erythropoiesis in human red cell precursors in vitro.

Pharmacodynamics

Peginesatide increases the reticulocyte count, followed by increases in hemoglobin. The rate of hemoglobin increase varies among patients and is dependent upon the dose of peginesatide administered.

Effect on Cardiac Repolarization

The effect of Omontys (0.1 mg/kg intravenously) on QTc interval was evaluated in a randomized, double-blind, double-dummy, three-period crossover thorough QT study in 65 healthy subjects. A dose of 0.1 mg/kg administered intravenously did not delay cardiac repolarization compared to placebo. The dose of 0.1 mg/kg is adequate to represent the median dose (0.07 mg/kg) in the phase 3 trials, however is not sufficient to represent doses higher than 0.1 mg/kg in the intended patients.

Pharmacokinetics

Following single intravenous and subcutaneous injections at doses ranging from 0.03 to 0.1 mg/kg to dialysis patients, maximal plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) increase with dose. Following subcutaneous administration, the maximum concentrations of peginesatide are reached in approximately 48 hours. The bioavailability of peginesatide following subcutaneous administration is approximately 46%.

No mass balance study has been conducted in humans. Preclinical radiolabeled peginesatide study indicated that peginesatide is not metabolized and that urinary excretion was the predominant route of elimination following either intravenous or subcutaneous dosing.

The mean half-life is 25.0 ± 7.6 hours following intravenous administration and 53.0 ± 17.7 hours following subcutaneous administration in healthy subjects. The mean half-life in dialysis patients is 47.9 ± 16.5 hours following intravenous administration. Mean systemic clearance is 0.5 ± 0.2 mL/hr•kg and mean volume of distribution is 34.9 ± 13.8 mL/kg following intravenous administration in dialysis patients. No accumulation is observed following administration every 4 weeks following intravenous or subcutaneous administration. The pharmacokinetics of peginesatide in patients with CKD on dialysis are not altered by age, gender or race based on population pharmacokinetic analyses.

For Healthcare Professionals

Applies to peginesatide: injectable solution

Cardiovascular

Cardiovascular side effects have included hypotension (14.2%), hypertension (13.2%), and procedural hypotension (10.9%).[Ref]

Gastrointestinal

Gastrointestinal side effects have included diarrhea (18.4%), nausea (17.4%), and vomiting (15.3%).[Ref]

General

General side effects have included pyrexia (12.2%).[Ref]

Immunologic

Immunologic side effects have included the development of peginesatide (the active ingredient contained in Omontys) specific antibodies (1.2%).[Ref]

Metabolic

Metabolic side effects have included hyperkalemia (11.4%).[Ref]

Musculoskeletal

Musculoskeletal side effects have included muscle spasms (15.3%), pain in extremity (10.9%), back pain (10.9%), and arthralgia (10.7%).[Ref]

Nervous system

Nervous system side effects have included headache (15.4%).[Ref]

Other

Other side effects have included arteriovenous fistula site complication (16.1%).[Ref]

Respiratory

Respiratory side effects have included dyspnea (18.4%), cough (15.9%), and upper respiratory infection (11.0%).[Ref]

Hypersensitivity

Hypersensitivity side effects have included postmarketing reports of serious allergic reactions including fatal reactions (0.02%).

Some side effects of Omontys may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Peginesatide Pregnancy Warnings

Peginesatide has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of teratogenicity and embryofetal lethality at doses and/or exposures that resulted in polycythemia. There are no adequate and well controlled studies in pregnant women. The manufacturer recommends that peginesatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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