Document 3 Summary of Data and Guidance for Medical Professionals Anvirzel Anvirzel is a novel antitumor compound extracted from the plant Nerium oleander, which belongs to the family Apocynaceae. Anvirzel consists of several compounds, including complex polysaccharides, proteins and individual sugars. It contains non-water soluble compounds, and two of these have been specifically identified by molecular weight and fragmentation characterization as Oleandrin and Oleandrigenin. These two compounds of Anvirzel are cytotoxic. 1.1 Indications and Usage Potential indications include the treatment of cancer and Hepatitis C. Anvirzel has completed a Phase I Clinical Trial at the Cleveland Clinic, Cleveland, Ohio. 1.2 Contraindications Patients should not receive Anvirzel if they: Have a history of digitalis toxicity of any kind; Are receiving concurrent digoxin or digitoxin; Have acute myocardial infarction or severe pulmonary disease; Patients should not co-administer the following drugs with digoxin / Anvirzel. Verapamil, aminodarone, propafenone, indomethacin, itraconazole, alprazolam, sotalol, quinidine or Furosemide Increase the risk of digitalis toxicity. Flecainide Increases serum digoxin concentration, mechanism not known. Clarithromycin Decreases the conversion of digoxin to dihydrodigoxin by the gut flora.
1.3 Warnings Even though there have been no reports from the Clinical Trials of material adverse side effects other than the effects described under Precautions, the following information is included for the benefit of medical professionals. This Guidance has been written to include and address the possible side effects that could be associated with the administration of a cardiac glycoside. 1.4 Precautions 1.4.1 General The drug Anvirzel has been shown to be safe in animals and patients. The Phase I Clinical Trials Conclusion is Anvirzel can be safely administered at doses up to 1.2 ml/m2/d. No dose limiting toxicities were found. When therapeutic doses of oleander extract are administered to patients, the following side effects may occur and the attending physician should take the necessary steps to reduce these side effects. 1.4.2 Allergic Reactions It may be possible to have itching and exfoliation of the epidermis. These symptoms can be alleviated if adjuvant therapies such as antihistamines or cortisones are provided. If adjuvant therapy provided no benefit, then the treatment with Anvirzel should be abandoned. 1.4.3 Cardiac Toxicity Anvirzel contains very small sub-therapeutic amount of cardiac glycosides such as oleandrin. These glycosides exert similar actions like digoxin, an approved drug to treat cardiac problems. 1 ml of Anvirzel contains approximately between 20 and 100 ug/ml of oleandrin. Anvirzel has a cross reactivity to digoxin immunoassays and has a false-positive digoxin concentration between 10 and 40 ug/ml. The concentration of oleandrin and the cross-reactive concentration of digoxin is very low as compared to the recommended adult therapeutic dose of digoxin, 250-400 ug/day. Even though the cardiac glycosides are present at a very low concentration in Anvirzel as compared to the recommended doses of digoxin, it is important to monitor the patients for possible cardiac toxicity. Cardiac glycosides toxicity develops more frequently and lasts longer in patients with renal impairment because of the decreased excretion of cardiac glycosides. Therefore, the patients with renal impairment have to be monitored for possible cardiac glycosides toxicity more frequently by measuring the serum oleandrin and false positive digoxin levels than in patients with normal renal function.
In patients with hypokalemia, toxicity may occur because potassium depletion sensitizes the myocardium to cardiac glycosides. Therefore, it is desirable to maintain normal serum potassium levels in patients being treated with Anvirzel. Hypokalemia may result from diuretic, amphotericin B or corticosteroid therapy and from dialysis or mechanical suction of gastrointestinal secretions. It may also accompany malnutrition, diarrhea, prolonged vomiting, old age and long-standing heart failure. In general, rapid changes in serum potassium or other electrolytes should be avoided. Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmia in patients taking Anvirzel. Hypercalcemia from any cause predisposes the patient to digitalis toxicity. These interactions are related to the fact that calcium affects contractility and excitability of the heart in a manner similar to cardiac glycosides. Hypomagnesemia may predispose to digitalis toxicity. If low magnesium levels are detected in a patient on Anvirzel, replacement therapy should be instituted. Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, and alprazolam cause a rise in serum digoxin and oleandrin concentration, with the implication that digitalis intoxication may result. This rise appears to be proportional to the dose. The effect is mediated by a reduction in the cardiac glycosides clearance and, in the case of quinidine, decreased volume of distribution as well. Patients with acute myocardial infarction or severe pulmonary disease may be unusually sensitive to cardiac glycosides-induced disturbances of rhythm. These patients may not be suitable for Anvirzel therapy. In patients with Wolff-Parkinson-White Syndrome and atrial fibrillation, cardiac glycosides can enhance transmission of impulses through the accessory pathway. This effect may result in extremely rapid ventricular rates and even ventricular fibrillation. Anvirzel may produce false positive S-T changes in the electrocardiogram during exercise testing. 1.4.4 Miscellaneous Effects In most cases, pain in the breast glands, similar to that occurring during adolescence has been noted, along with an increase in sexual activity. During the regular treatment period, the leukocyte count has been observed to rise above normal values, sometimes up to 12,000-24,000. 1.5 Drug Interactions Concomitant use of Anvirzel and sympathomimetics may increase the risk of cardiac arrhythmia, because both enhance ectopic pacemaker activity. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmia in patients on Anvirzel. Patients who are on beta-adrenergic blockers or calcium channel blockers may be susceptible to complete heart block if they take Anvirzel.
Furthermore, caution should be exercised when combining Anvirzel with any drug that may cause a significant deterioration in renal function, since this may impair the excretion of cardiac glycosides. 1.6 Pregnant Use Animal reproduction studies have not been conducted with Anvirzel. It is not known whether Anvirzel can cause fetal harm when administered to a pregnant woman or whether Anvirzel can affect reproductive capacity. 1.7 Pediatric Use Safety and effectiveness in children have not been studied. 1.8 Nursing Mothers Mothers should refrain from breast-feeding during the treatment to avoid potential injury to their children. 1.9 Overdosage 1.9.1 Symptoms The Phase I study demonstrated that dosages up to 3 times the recommended dosage didn t produce cardiologic alterations in the patient without cardiac lesions and who was not using digitalis. Unifocal or multiform ventricular premature contractions, especially in bigeminal or trigeminal patterns, are the most common arrhythmia associated with cardiac glycosides toxicity in adults with heart disease. Ventricular tachycardia may result from digitalis toxicity. Atrioventricular (AV) dissociation, accelerated junctional (nodal) rhythm and atria] tachycardia with block are also common arrhythmia caused by cardiac glycoside overdose. Excessive slowing of the pulse is a clinical sign of Anvirzel overdose. Note: The electrocardiogram is fundamental in determining the presence and nature of these cardiac disturbances. Cardiac glycosides may also induce other changes in the ECG, e.g., PR prolongation, ST depressions, which represent cardiac glycosides effect and may or may not be associated with digitalis toxicity. 1.9.1.1 Gastrointestinal Anorexia, nausea, vomiting and less commonly diarrhea are common early symptoms of overdose. However, uncontrolled heart failure may also produce such symptoms. Digitalis toxicity very rarely may cause abdominal pain and hemorrhagic necrosis of the intestines.
1.9.1.2 CNS Visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy and psychosis can occur. 1.9.1.3 Others Anvirzel has certain polysaccharides known to exert immune stimulating properties. Overdose of the drug may result in seizures, anaphylactic shocks, breathing difficulties and decreased urine volume. If any of these symptoms occur, the patient should call the attending physician. 1.9.2 Treatment of Arrhythmia Produced by Overdosage Anvirzel should be discontinued until all signs of toxicity are gone. Discontinuation may be all that is necessary if toxic manifestations are not severe. 1.10 Dosage and Administration The product should be reconstituted by aseptically adding 10 ml of distilled or purified water, into the vial and gently swirling the contents until all visible particles have dissolved. The freeze-dried Anvirzel powder should be stored at room temperature between 15 and 30 C. Any unused, reconstituted Anvirzel solution should be stored between 2 and 8 C and protected from light. Reconstituted product should be used within 20 days. 1.11 How Supplied Anvirzel is a sterile, freeze-dried powder to be reconstituted before using. Anvirzel is supplied in 10 ml butyl-rubber stoppered vials. Each vial contains 150 mg of Nerium oleander extract, 500 mg mannitol, 50 mg sodium ascorbate, 2 mg ascorbic acid, 10 mg methylparaben sodium, and 1 mg propylparaben sodium. Each vial with 150 mg of oleander extract contains approximately 200-900 ug oleandrin and 500-700 ug oleandrigenin; therefore, there is approximately 20-100 ug oleandrin and 50-70 ug oleandrigenin per ml of reconstituted solution.