Oprelvekin
Encyclopedia
Oprelvekin is recombinant
interleukin eleven (IL-11), a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production. It is marketed under the trade name Neumega.
Oprelvekin is produced in Escherichia coli (E. coli) by recombinant DNA technology. The protein has a molecular mass of approximately 19,000 daltons, and is non-glycosylated. The polypeptide is 177 amino acids in length (the natural IL-11 has 178). This alteration has not resulted in measurable differences in bioactivity either in vitro or in vivo.
The primary hematopoietic activity of Neumega is stimulation of megakaryocytopoiesis and thrombopoiesis. In mice and nonhuman primate studies Neumega has shown potent thrombopoietic activity in compromised hematopoiesis, including moderately to severely myelosuppressed animals. In these studies, Neumega improved platelet nadir
s and accelerated platelet recoveries compared to controls.
In animal studies Oprelvekin also has non-hematopoetic activities. This includes the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis (e.g., fibrinogen), and inhibition of macrophageal released pro-inflammatory cytokines. However, pathologic changes, some also seen in humans, have been noticed:
In preclinical human trials mature megakaryocytes which develop during in vivo treatment with Neumega were ultrastructurally, morphologically, and functionally normal. They also showed a normal life span.
In a study in which a single 50 µg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 ± 5.4 ng/mL was reached at 3.2 ± 2.4 h (Tmax) following dosing. The terminal half-life was 6.9 ± 1.7 h. In a second study in which single 75 µg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Neumega was >80%. In a study in which multiple, subcutaneous doses of both 25 and 50 µg/kg were administered to cancer patients receiving chemotherapy, Neumega did not accumulate and clearance of Neumega was not altered following multiple doses. Pediatric cancer patients treated with aggressive chemotherapy showed similar pharmakinetic characteristics.
In humans treated with Oprelvekin on a daily base a twofold increase in fibrinogen levels occurred. Healthy volunteers displayed an increase in von-Willebrand-factor (vWf) activity. Isolated molecules formed under Oprelvekin were found to have exact the same multimere structure as the 'normal' factor and were therefore fully functioning. These increases in coagulation factors may contribute to the development of stroke (see under side-effects), but a precise association cannot be made at this stage.
In a variety of clinical studies upon which FDA approval is based, Neumega showed effectivity in reducing thrombocytopenia
in oncologic patients treated with myelosuppressant chemotherapeutic drugs as measured by significantly decreased need of platelet transfusion
s.
Neumega is manufactured and sold by Wyeth
. The drug is formulated in single-use vials containing 5 mg of oprelvekin (specific activity approximately 8 x 106 Units/mg) as a sterile, lyophilized powder. The FDA approved the drug in 1997.
in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficiacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle.
s and reduction of number of fetus
, fetal malformations etc.). There is no sufficient human data available. Pregnant women should only be treated, if the benefit to the mother outweighs the potential risk to the unborn.
of the face and tongue, or larynx
; shortness of breath; wheezing; chest pain; hypotension
(including shock); dysarthria; loss of consciousness, rash
, urticaria
, flushing
, and fever
. These reaction can occur after the first dose or after any later application. Neumega should be permanently discontinued in patients with any sign of allergy. Treatment is largely symptomatic.
Oprelvekin also has caused quite often fluid retention, ranging from peripheral edema
(approximately 40% of patients) to dyspnea
and full developed lung edema with or without cardiac decompensation (see contraindications and precautions). These symptoms have led to some deaths. Fluid retention my also lead to dilutional anemia (in 10 to 15% of patients). Hypokalemia my also result. Symptoms of fluid retention have been observed more often in patients following myeloablative chemotherapy (see contraindications). Severe arrhythmias (atrial flutter
and atrial fibrillation
) as well as fatal cardiac arrest
have also been seen which may or may be not attributed to fluid retention/increased volume. Isolated cases of stroke
have been noted, those patients with previous transient ischemic attacks or partial/minor strokes may be at particular risk.
Papilledema
of the eyes has been observed (2%) and may lead to disturbed visual acuity
and even temporary or permanent blindness
. Patients with preexisting papilledema or with involvement of the central nervous system may be at higher risk.
In postmarketing studies isolated cases of severe ventricular arrhythmias and renal failure
have been seen.
Injection site reaction like have also been observed (dermatitis, pain, and discoloration), but are usually mild.
or Sargramostim
showed no potential interactions. Additionally, no other interactions are known. Interactions with drugs undergoing P450 enzyme metabolism are not likely to occur.
and pericardial effusions should be monitored closely for signs of worsening.
, or hip. Most patients will be able to self-administer the drug after appropriate training.
Patients with severe renal impairment should receive only 25 µg/kg daily.
The first dose should be given 6 to 24 hours after completion of chemotherapy. Dosing should be continued until platelet counts reach at least 50,000 cells. Usually, one course of Neumega encompasses 10 to 21 days.
The drug should be discontinued at least 2 days before starting the next chemotherapy cycle.
You have been diagnosed having a cancer disease. This cancer is in your case treated with chemotherapy. The chemotherapy has caused or can cause severe depression of platelets. You need a normal level of platelets to maintain coagulation and prevent severe bleeding episodes. Neumega is used to increase depressed platelet counts to a higher level to promote protection against bleeding episodes. The drug is injected once a day subcutaneously e.g., in your hip or thigh. Your clinician will show you the correct technique, so you can complete further courses of Neumega-therapy at home. One course of Neumega usually starts 6 to 24 hours after completion of chemotherapy and is continued for 10 to 21 days at the discretion of the physician. Your doctors will ask you to undergo frequent blood cell counts to determine effects of therapy and the further course of treatment. Please adhere to his/her advices for reasons of your own safety.
Neumega is a potent drug and can have certain, sometimes dangerous, side-effects. Most important are severe allergic reactions, which can occur at any time of Neumega-therapy. Inform you doctor immediately if you experience swollen face, tongue or larynx, shortness of breath, hypotension, shock, fever or skin reactions (urticaria, rash). Additionally, Neumega can cause fluid retention in a high rate of patients. If you notice an unexplainable massive gain of weight, peripheral edemas (e.g. swollen ankles, arms or legs) that are more than mild to moderate, or if you experience shortness of breath without signs of allergy contact your doctor immediately or dial 911. You maybe suffer from lung edema and/or decompensated heart failure which must be treated immediately. The same is true, if you have an irregular heartbeat together with dizziness and vertigo, or sudden loss of consciousness.
If you should notice a decrease in visual acuity or even blindness call you doctor at once or dial 911, because you are in a situation of absolute emergency.
Reactions at the injection site are usually mild and consist of skin-reaction (dermatitis), pain or discoloration. They do not require termination of therapy. To prevent these side-effects you will be asked to change injection-sites regularly.
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
interleukin eleven (IL-11), a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production. It is marketed under the trade name Neumega.
Chemical, pharmacological and marketing data
IL-11 is a member of a family of human growth factors and is being produced in the bone marrow of healthy adults. Synonyms are:- AGIF
- Adipogenesis inhibitory factor
- Interleukin-11 precursor.
Oprelvekin is produced in Escherichia coli (E. coli) by recombinant DNA technology. The protein has a molecular mass of approximately 19,000 daltons, and is non-glycosylated. The polypeptide is 177 amino acids in length (the natural IL-11 has 178). This alteration has not resulted in measurable differences in bioactivity either in vitro or in vivo.
The primary hematopoietic activity of Neumega is stimulation of megakaryocytopoiesis and thrombopoiesis. In mice and nonhuman primate studies Neumega has shown potent thrombopoietic activity in compromised hematopoiesis, including moderately to severely myelosuppressed animals. In these studies, Neumega improved platelet nadir
Nadir
The nadir is the direction pointing directly below a particular location; that is, it is one of two vertical directions at a specified location, orthogonal to a horizontal flat surface there. Since the concept of being below is itself somewhat vague, scientists define the nadir in more rigorous...
s and accelerated platelet recoveries compared to controls.
In animal studies Oprelvekin also has non-hematopoetic activities. This includes the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis (e.g., fibrinogen), and inhibition of macrophageal released pro-inflammatory cytokines. However, pathologic changes, some also seen in humans, have been noticed:
- papilledema
- fibrosis of tendons and joint capsules
- periostal thickening and
- embryotoxicity (see under pregnancy).
In preclinical human trials mature megakaryocytes which develop during in vivo treatment with Neumega were ultrastructurally, morphologically, and functionally normal. They also showed a normal life span.
In a study in which a single 50 µg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 ± 5.4 ng/mL was reached at 3.2 ± 2.4 h (Tmax) following dosing. The terminal half-life was 6.9 ± 1.7 h. In a second study in which single 75 µg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Neumega was >80%. In a study in which multiple, subcutaneous doses of both 25 and 50 µg/kg were administered to cancer patients receiving chemotherapy, Neumega did not accumulate and clearance of Neumega was not altered following multiple doses. Pediatric cancer patients treated with aggressive chemotherapy showed similar pharmakinetic characteristics.
In humans treated with Oprelvekin on a daily base a twofold increase in fibrinogen levels occurred. Healthy volunteers displayed an increase in von-Willebrand-factor (vWf) activity. Isolated molecules formed under Oprelvekin were found to have exact the same multimere structure as the 'normal' factor and were therefore fully functioning. These increases in coagulation factors may contribute to the development of stroke (see under side-effects), but a precise association cannot be made at this stage.
In a variety of clinical studies upon which FDA approval is based, Neumega showed effectivity in reducing thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
in oncologic patients treated with myelosuppressant chemotherapeutic drugs as measured by significantly decreased need of platelet transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s.
Neumega is manufactured and sold by Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
. The drug is formulated in single-use vials containing 5 mg of oprelvekin (specific activity approximately 8 x 106 Units/mg) as a sterile, lyophilized powder. The FDA approved the drug in 1997.
Indications
Neumega is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficiacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle.
Contraindications and precautions
- Patients with known hypersensitivity to Oprelvekin itself or any other ingredient.
- Patients with severe or decompensated heart failure should not be treated, because Oprelvekin may cause excessive fluid retention with edema and cardiac decompensation. Patients with compensated heart disease should be treated with caution and under permanent clinical supervisionClinical supervisionSupervision is used in counselling, psychotherapy, and other mental health disciplines as well as many other professions engaged in working with people. It consists of the practitioner meeting regularly with another professional, not necessarily more senior, but normally with training in the skills...
.
- Neumega is not indicated following myeloablative chemotherapy (increased likelihood of severe side-effects) and in pediatric patients.
- Renal impairment : Neumega is excreted renally. No differences of pharmakinetic parameterParameterParameter from Ancient Greek παρά also “para” meaning “beside, subsidiary” and μέτρον also “metron” meaning “measure”, can be interpreted in mathematics, logic, linguistics, environmental science and other disciplines....
s and clinical differences have been seen in mild to moderate impairment. Severe impairment has led to an increased number of patients with reduced hemoglobinHemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
due to dilutional anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Patients with severely disturbed renal function should be monitored very closely.
- The efficacy of Oprelvekin has not been systematically studied in patients receiving chemotherapy regimes of more than 5 days duration/each cycle or in those regimes containing agents that induce delayed thrombocytopenia (e.g. nitrosoureas, mitomycin C. Neumega should not be given in these cases.
Pregnancy
In studies with rats and rabbits treated chronically, Oprelvekin showed embryo- and fetotoxicity (early death of embryoEmbryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
s and reduction of number of fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
, fetal malformations etc.). There is no sufficient human data available. Pregnant women should only be treated, if the benefit to the mother outweighs the potential risk to the unborn.
Lactation
No human data is available if the drug is distributed into human milk. Nursing women should either discontinue breast-feeding or Neumega, the decision should take into account the importance of the drug to the mother.Side effects
Neumega has caused allergic reaction which at times have been very serious. Symptoms have been edemaEdema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
of the face and tongue, or larynx
Larynx
The larynx , commonly called the voice box, is an organ in the neck of amphibians, reptiles and mammals involved in breathing, sound production, and protecting the trachea against food aspiration. It manipulates pitch and volume...
; shortness of breath; wheezing; chest pain; hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(including shock); dysarthria; loss of consciousness, rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
, urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
, and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
. These reaction can occur after the first dose or after any later application. Neumega should be permanently discontinued in patients with any sign of allergy. Treatment is largely symptomatic.
Oprelvekin also has caused quite often fluid retention, ranging from peripheral edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
(approximately 40% of patients) to dyspnea
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
and full developed lung edema with or without cardiac decompensation (see contraindications and precautions). These symptoms have led to some deaths. Fluid retention my also lead to dilutional anemia (in 10 to 15% of patients). Hypokalemia my also result. Symptoms of fluid retention have been observed more often in patients following myeloablative chemotherapy (see contraindications). Severe arrhythmias (atrial flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...
and atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
) as well as fatal cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
have also been seen which may or may be not attributed to fluid retention/increased volume. Isolated cases of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
have been noted, those patients with previous transient ischemic attacks or partial/minor strokes may be at particular risk.
Papilledema
Papilledema
Papilledema is optic disc swelling that is caused by increased intracranial pressure. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare....
of the eyes has been observed (2%) and may lead to disturbed visual acuity
Visual acuity
Visual acuity is acuteness or clearness of vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain....
and even temporary or permanent blindness
Blindness
Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...
. Patients with preexisting papilledema or with involvement of the central nervous system may be at higher risk.
In postmarketing studies isolated cases of severe ventricular arrhythmias and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
have been seen.
Injection site reaction like have also been observed (dermatitis, pain, and discoloration), but are usually mild.
Interactions
The concomitant application of GM-CSFs such as filgrastimFilgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
or Sargramostim
Sargramostim
Sargramostim is a recombinant granulocyte macrophage colony-stimulating factor that functions as an immunostimulator.It is produced in yeast.-Therapeutic uses:...
showed no potential interactions. Additionally, no other interactions are known. Interactions with drugs undergoing P450 enzyme metabolism are not likely to occur.
Necessary examinations during treatment
Complete blood counts should be obtained before starting chemotherapy and in short intervals afterwards. Platelet counts should be done at the time of expected nadir (lowest number of platelets) and at least until remission starts (platelet counts greater than 50,000). The patients should be watched for signs of allergy, fluid retention and anemia during and after therapy with Neumega. Preexisting ascitesAscites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
and pericardial effusions should be monitored closely for signs of worsening.
Dosage regime
The dosage in patients without severe renal impairment is 50 µg/kg subcutaneously once a day either abdominal, in thighThigh
In humans the thigh is the area between the pelvis and the knee. Anatomically, it is part of the lower limb.The single bone in the thigh is called the femur...
, or hip. Most patients will be able to self-administer the drug after appropriate training.
Patients with severe renal impairment should receive only 25 µg/kg daily.
The first dose should be given 6 to 24 hours after completion of chemotherapy. Dosing should be continued until platelet counts reach at least 50,000 cells. Usually, one course of Neumega encompasses 10 to 21 days.
The drug should be discontinued at least 2 days before starting the next chemotherapy cycle.
Additional information
Neumega vials must be stored in a refrigerator at 2 to 8 C (36 to 46 F). Protect from light. Do not freeze.Information for patients/'non-specialized' people
This section provides information for patients treated with Neumega or those people 'non-specialized' but interested in medicine/pharmacology:You have been diagnosed having a cancer disease. This cancer is in your case treated with chemotherapy. The chemotherapy has caused or can cause severe depression of platelets. You need a normal level of platelets to maintain coagulation and prevent severe bleeding episodes. Neumega is used to increase depressed platelet counts to a higher level to promote protection against bleeding episodes. The drug is injected once a day subcutaneously e.g., in your hip or thigh. Your clinician will show you the correct technique, so you can complete further courses of Neumega-therapy at home. One course of Neumega usually starts 6 to 24 hours after completion of chemotherapy and is continued for 10 to 21 days at the discretion of the physician. Your doctors will ask you to undergo frequent blood cell counts to determine effects of therapy and the further course of treatment. Please adhere to his/her advices for reasons of your own safety.
Neumega is a potent drug and can have certain, sometimes dangerous, side-effects. Most important are severe allergic reactions, which can occur at any time of Neumega-therapy. Inform you doctor immediately if you experience swollen face, tongue or larynx, shortness of breath, hypotension, shock, fever or skin reactions (urticaria, rash). Additionally, Neumega can cause fluid retention in a high rate of patients. If you notice an unexplainable massive gain of weight, peripheral edemas (e.g. swollen ankles, arms or legs) that are more than mild to moderate, or if you experience shortness of breath without signs of allergy contact your doctor immediately or dial 911. You maybe suffer from lung edema and/or decompensated heart failure which must be treated immediately. The same is true, if you have an irregular heartbeat together with dizziness and vertigo, or sudden loss of consciousness.
If you should notice a decrease in visual acuity or even blindness call you doctor at once or dial 911, because you are in a situation of absolute emergency.
Reactions at the injection site are usually mild and consist of skin-reaction (dermatitis), pain or discoloration. They do not require termination of therapy. To prevent these side-effects you will be asked to change injection-sites regularly.