Omontys

Name: 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.

Clinical Studies

The efficacy and safety of OMONTYS in patients with CKD on dialysis were demonstrated in two randomized, active-controlled, open-label, multi-center clinical studies that evaluated OMONTYS in the maintenance of hemoglobin concentrations in patients who were being treated with another ESA (epoetin alfa or epoetin beta) at the time of study entry. The primary efficacy endpoint for each study was the change in hemoglobin from Baseline to the Evaluation Period (Weeks 29 to 36) using a non-inferiority comparison with epoetin. In Study 1, patients received epoetin via the intravenous route of administration and continued to use this route after randomization to either OMONTYS or epoetin. The average patient exposure year [PEY] per patient was 1.14 years for OMONTYS and the average PEY per patient was 1.25 years for epoetin. In Study 2, the route of administration previously used for epoetin (intravenous or subcutaneous) was used. The average PEY per patient was 1.17 years for OMONTYS and the average PEY per patient was 1.16 years for epoetin. The median dose of OMONTYS was 0.07 mg/kg administered once monthly and the median dose of epoetin was 113 units/kg administered weekly (in 1 to 3 doses).

Patients were randomized (2 to 1) to receive OMONTYS once monthly, or to continue on their current ESA treatment 1 to 3 times per week. The OMONTYS starting dose was based on the patient's total weekly ESA dose during the last week of the screening period. As shown in Table 4, treatment with OMONTYS once monthly and treatment with epoetin 1-3 times per week maintained hemoglobin concentrations within the study pre-specified hemoglobin range (10 to 12 g/dL). In both studies, the proportion of patients receiving transfusions was similar in each treatment group.

Table 4: Clinical Studies in Dialysis Patients

Group (N) Mean baseline Hemoglobin Change from Baseline to Weeks 29-36 Between group difference, Least Squares Mean g/dL (95% CI)
Study 1
OMONTYS (524) 11.3 g/dL -0.24 g/dL -0.15 g/dL
(-0.30, -0.01)
Epoetin (269) 11.3 g/dL -0.09 g/dL
Study 2
OMONTYS (542) 11.2 g/dL -0.07 g/dL 0.10 g/dL
(-0.05, 0.26)
Epoetin (273) 11.2 g/dL -0.17 g/dL

Studies 1 and 2 had a pre-specified, prospective, pooled analysis of a composite cardiovascular safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia. In patients receiving OMONTYS, 22.8% experienced one of these events compared to 24.4% receiving epoetin (hazard ratio 0.95, 95% CI 0.77, 1.17).

Omontys FDA Warning

WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

Chronic Kidney Disease:

  • 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.
  • Use the lowest peginesatide dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Peginesatide was not carcinogenic in a 2-year study in rats at doses up to 0.25 mg/kg administered every 3 weeks by intravenous injection. This dose is approximately 14% the human exposure (AUC) at a dose of 0.35 mg/kg in patients on dialysis. Peginesatide was not carcinogenic in a 26-week study in rasH2 transgenic mice when administered by intravenous injection at doses of 0.1, 0.25, or 0.5 mg/kg/dose every 3 weeks.

Peginesatide was not mutagenic or clastogenic in the in vitro Ames assay, in vitro mammalian chromosome aberration assay, and an in vivo mouse erythrocyte micronucleus assay.

When peginesatide was administered intravenously to male and female rats at weekly intervals prior to and during mating, and treated rats mated, fertility was reduced at ≥ 0.1 mg/kg (approximately 5% of the dose of 0.35 mg/kg in patients) and was most evident at doses ≥ 1.0 mg/kg of peginesatide. Adverse effects in males included reduced weight of seminal vesicles and prostate. Decreased viable fetuses at ≥ 0.1 mg/kg in females appeared to be due to pre- and post-implantation losses. There was no apparent drug-related effect on estrous cycles or number of corpora lutea.

Important information

You should not use Omontys if you are allergic to peginesatide, or if you have untreated or uncontrolled high blood pressure.

Before using Omontys, tell your doctor if you have heart disease, congestive heart failure, high blood pressure, cancer, a seizure disorder, a blood cell or clotting disorder (such as sickle cell anemia or hemophilia), or a history of stroke, heart attack, or blood clot.

Your other medication doses may need to be changed after you start using Omontys. Tell your doctor about all medications you use.

To be sure Omontys is helping your condition, your iron and blood cells will need to be checked with frequent blood tests. Your blood pressure will also need to be checked often. Visit your doctor regularly.

Contact your doctor if you feel weak, lightheaded, or short of breath, or if your skin looks pale. These may be signs that your body has stopped responding to this medication.

Omontys can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. This risk will increase the longer you use Omontys. Seek emergency medical help if you have symptoms of heart or circulation problems, such as: chest pain, sudden numbness or weakness, severe headache, problems with vision or speech, sudden cough, coughing up blood, pain or warmth in your leg, cold or tingly feeling, feeling short of breath, rapid weight gain, or problems with your hemodialysis vein access.

Omontys side effects

Get emergency medical help if you have any of these signs of an allergic reaction to Omontys: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Contact your doctor if you feel weak, lightheaded, or short of breath, or if your skin looks pale. These may be signs that your body has stopped responding to this medication.

Omontys can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. This risk will increase the longer you use Omontys.

Seek emergency medical help if you have symptoms of heart or circulation problems, such as:

  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  • sudden numbness or weakness, especially on one side of the body;

  • sudden severe headache, confusion, problems with vision, speech, or balance;

  • chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

  • pain, swelling, warmth, or redness in one or both legs;

  • numbness, tingling, cold feeling, or pale appearance in your arms or legs;

  • feeling short of breath, even with mild exertion;

  • swelling, rapid weight gain;

  • feeling light-headed, fainting; or

  • if your hemodialysis vein access stops working.

Call your doctor at once if you have any other serious side effect such as:

  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

  • feeling light-headed, fainting;

  • pale skin, feeling short of breath, rapid heart rate, trouble concentrating;

  • high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling);

  • fever;

  • seizure (convulsions); or

  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

Less serious Omontys side effects may include:

  • nausea, vomiting, diarrhea;

  • cough;

  • headache;

  • back pain, muscle spasm, pain in your arms or legs;

  • joint pain; or

  • cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Omontys?

There may be other drugs that can interact with Omontys. Your other medication doses may need to be changed after you start using Omontys.

Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

For the Consumer

Applies to peginesatide: injection solution

Along with its needed effects, peginesatide (the active ingredient contained in Omontys) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking peginesatide:

More common
  • Abdominal or stomach pain
  • blurred vision
  • body aches or pain
  • chills
  • confusion
  • cough
  • difficulty with breathing
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • ear congestion
  • fever
  • headache
  • irregular heartbeat
  • loss of voice
  • nasal congestion
  • nausea or vomiting
  • nervousness
  • numbness or tingling in the hands, feet, or lips
  • pounding in the ears
  • runny nose
  • shortness of breath
  • slow or fast heartbeat
  • sneezing
  • sore throat
  • sweating
  • unusual tiredness or weakness
  • weakness or heaviness of the legs
Incidence not known
  • Back pain
  • chest tightness
  • chills
  • difficulty with swallowing
  • flushing
  • hives
  • itching
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • seizures
  • skin rash
  • trouble breathing
  • weakness

Some side effects of peginesatide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Diarrhea
  • difficulty with moving
  • muscle pain or stiffness
  • muscle spasms
  • pain in the arms or legs
  • pain in the joints

Peginesatide Levels and Effects while Breastfeeding

Summary of Use during Lactation

No information is available on the clinical use of peginesatide during breastfeeding. Because of its large molecular weight of 4900 daltons, excretion into breastmilk should be minimal and it would not be expected to be absorbed from breastmilk by the infant. If peginesatide is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Epoetin Alfa

References

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