Oprelvekin

Basic Chemical, Pharmacological and Marketing Data
Interleukin eleven (IL-11) is 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. 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, the active ingredient in Neumega® is recombinant Interleukin eleven, which 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 nadirs 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 in oncologic patients treated with myelosuppressant chemotherapeutic drugs as measured by significantly decreased need of platelet transfusions. 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 has approved the drug very recently, in 2006.

Indications
Neumega® is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy 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 supervision.


 * 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 parameters and clinical differences have been seen in mild to moderate impairment. Severe impairment has led to an increased number of patients with reduced hemoglobin due to dilutional anemia. 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
Pregnanc Category C:

In studies with rats and rabbits treated chronically, Oprelvekin showed embryo- and fetotoxicity (early death of embryos 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.

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 edema 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). Hypokalema 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.

Interactions
The concomitant application of GM-CSFs such as filgrastim or Sargramostim 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 ascites 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 thigh, or hip. Most patients will be able to self-administer the drug after appropriate training.

Patients with severe renal impairment should receive only 25µg/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.