İHALE DÜNYASI
İHALE DÜNYASI
DigiFab (R) [Digoxin Immune Fab (Ovine)] is a sterile, lyophilized preparation of digoxin-immune ovine Fab (monovalent) immunoglobulin fragments. These fragments are obtained from the blood of healthy sheep immunized with a digoxin derivative, digoxin-dicarboxymethoxylamine (DDMA), a digoxin analogue which contains the functionally essential cyclopentaperhydrophenanthrene: lactone ring moiety coupled to keyhole limpet hemocyanin (KLH). The final product is prepared by isolating the immunoglobulin fraction of the ovine serum, digesting it with papain and isolating the digoxin-specific Fab fragments by affinity chromatography. These antibody fragments have a molecular weight of approximately 46,000 Da. Each vial of DigiFab (R) , which will bind approximately 0.5 mg digoxin, contains 40 mg of digoxin immune Fab, 75 mg (approx) of mannitol USP, and 2 mg (approx) sodium acetate USP as a buffering agent. The product contains no preservatives and is intended for intravenous administration after reconstitution with 4 mL of Sterile Water for Injection USP.
DigiFab (R) is indicated for the treatment of patients with life-threatening or potentially life-threatening digoxin toxicity or overdose, including: Known suicidal or accidental consumption of fatal doses of digoxin: 10 mg or more of digoxin in healthy adults, or 4 mg (or more than 0.1 mg/kg) in healthy children, or ingestion of an amount that can cause steady state serum concentrations of ?10 ng/mL; Chronic ingestions causing steady-state serum digoxin concentrations >6 ng/mL in adults or 4 ng/mL in children; Manifestations of life-threatening toxicity of digoxin overdose such as severe ventricular arrhythmias, progressive bradycardia, and second or third degree heart block not responsive to atropine, serum potassium levels exceeding 5.5 mEq/L in adults or 6 mEq/L in children with rapidly progressive signs and symptoms of digoxin toxicity. DigiFab (R) is a digoxin immune fab (ovine) and is indicated for treatment of life-threatening or potentially life-threatening digoxin toxicity or overdose.
For Intravenous Use Only For intravenous use only Clinical Conditions Dosage Acute ingestion of unknown amounts of digoxin and toxicity in the absence of a serum digitalis concentration or estimated ingestion amount Administer 20 vials of DigiFab (R) . Monitor for volume overload in small (< 20 Kg) children. Start with 10 vials followed by an additional 10 vials, if needed, to avoid a febrile reaction. Chronic digoxin toxicity in the absence of a serum digitalis concentration Administer 6 vials of DigiFab (R) in Adults and Children ? 20 Kg. Administer 1 vial of DigiFab (R) in Infants and Children < 20 Kg. Acute ingestion of known amounts of digoxin Dose (in vials) = Amount of digoxin ingested (in mg) 0.5 mg/vial Chronic digoxin toxicity and known serum digitalis concentration Dose (in vials) = (Serum digoxin ng/mL)(weight in kg) 100 2.1 Dosage General Guidelines: Adjust the dosage of DigiFab (R) according to the amount of digoxin to be neutralized. Summary of Dosing Guidelines Clinical Conditions Dosage Acute ingestion of unknown amounts of digoxin and toxicity in the absence of a serum digitalis concentration or estimated ingestion amount Administer 20 vials of DigiFab (R) . Monitor for volume overload in small (< 20 Kg) children. Start with 10 vials followed by an additional 10 vials, if needed, to avoid a febrile reaction. Chronic digoxin toxicity in the absence of a serum digitalis concentration Administer 6 vials of DigiFab (R) in Adults and Children ? 20 Kg. Administer 1 vial of DigiFab (R) in Infants and Children < 20 Kg. Acute ingestion of known amounts of digoxin Dose (in vials) = Amount of digoxin ingested (in mg) 0.5 mg/vial Chronic digoxin toxicity and known serum digitalis concentration Dose (in vials) = (Serum digoxin ng/mL)(weight in kg) 100 Failure of the patient to respond to DigiFab (R) should alert the physician to the possibility that the clinical problem may not be caused by digitalis toxicity. DOSAGE CALCULATION General Methods for calculating a neutralizing dose of DigiFab (R) , based on a known or estimated amount of digoxin or digitoxin in the body, are provided below. When using the dose calculation methods provided, the following guidelines should be considered: Inaccurate estimates of the amount of digitalis ingested or absorbed may occur due to non-steady state serum concentrations or due to digitalis assay limitations. Most serum digoxin assay kits are designed to measure concentrations less than 5 ng/mL; therefore, sample dilution is required to accurately measure serum concentrations > 5 ng/mL. Dosage calculations are based on a steady state volume of distribution of approximately 5 L/kg for digoxin, which is used to convert serum digoxin concentrations to total body burden of digoxin in milligrams. The volume of distribution is a population average and may vary among individuals. Many patients may require higher doses for complete neutralization and doses should usually be rounded up to the nearest whole vial. If toxicity has not adequately reversed after several hours, or appears to recur, re-administration of DigiFab (R) , at a dose guided by clinical judgment, may be necessary. If a patient is in need of re-administration of DigiFab (R) due to recurrent toxicity, or to a new toxic episode that occurs soon after the first episode, measurement of free (unbound) serum digitalis concentrations should be considered since Fab may still be present in the body. Failure of a patient to respond to DigiFab (R) treatment may indicate that the clinical problem is not caused by digitalis intoxication. If there is no response to an adequate dose of DigiFab (R) , the diagnosis of digitalis toxicity should be questioned. Calculation for Ingestion of Known Amount: Each vial of DigiFab (R) (40 mg of purified digoxin-specific Fab) binds approximately 0.5 mg of digoxin. The total number of vials required can be calculated by dividing the total body load of digoxin in milligrams (mg) by 0.5 mg per vial (see Formula 1 ). Following an acute ingestion, total body load will be approximately equal to the amount ingested in milligrams for either digoxin capsules or digitoxin. In case of digoxin tablet ingestion , the total body load will be approximately equal to the amount ingested (in mg) multiplied by the bioavailability of the tablet preparation, which is 0.8. Table 1 gives dosage estimates in number of vials for adults and children who have ingested a single large dose of digoxin and for whom the approximate number of tablets or capsules is known. The dose of DigiFab (R) (in number of vials) represented in Table 1 can be approximated using the following formula: Formula 1 Dose = total digitalis body load in mg (in # of vials) 0.5 mg of digitalis bound/vial Table 1 Approximate Dose of DigiFab (R) for Reversal of a Single Large Digoxin Overdose * 0.25 mg tablets with 80% bioavailability or 0.2 mg capsules with 100% bioavailability Number of Digoxin Tablets or Capsules Ingested* Dose of DigiFab (R) # of vials 25 10 50 20 75 30 100 40 150 60 200 80 If, after several hours, toxicity is not adequately reversed, or appears to recur, additional administration of DigiFab (R) at a dose guided by clinical judgment may be required. Calculations Based on Steady-State Serum Digoxin Concentrations: Adults Table 2 gives dosage estimates in number of vials for adult patients for whom a steady-state serum digoxin concentration is known. The dose of DigiFab(R) (in number of vials) represented in Table 2 can be approximated using the following formula: Formula 2 (see Table 2 ) Dose = (Serum digoxin concentration in ng/mL)(weight in kg) (in # of vials) 100 Table 2 Adult Dose Estimate of DigiFab (R) (in # of vials) from Steady-State Serum Digoxin Concentration v = vials Patient Weight (kg) Serum Digoxin Concentration (ng/mL) 1 2 4 8 12 16 20 40 0.5v 1v 2v 3v 5v 7v 8v 60 0.5v 1v 3v 5v 7v 10v 12v 70 1v 2v 3v 6v 9v 11v 14v 80 1v 2v 3v 7v 10v 13v 16v 100 1v 2v 4v 8v 12v 16v 20v Children: Table 3 gives dosage estimates in milligrams for infants and small (< 20 Kg) children based on the steady-state serum digoxin concentration. The dose of DigiFab (R) represented in Table 3 can be estimated by multiplying the dose (in number of vials) calculated from Formula 2 by the amount of DigiFab (R) contained in a vial (40 mg/vial) (see Formula 3 ). Administer smaller doses in children < 20 Kg requiring doses < 1mL with a tuberculin syringe after reconstituting 40 mg. For very small doses, a reconstituted vial can be diluted with 36 mL of sterile isotonic saline to achieve a concentration of 1 mg/mL. Formula 3 (see Table 3 ) Dose (in mg) = (Dose in # of vials) (40 mg/vial) Table 3 Infants and Small (< 20 Kg) Children Dose Estimates of DigiFab (R) (in mg) from Steady State Serum Digoxin Concentration * dilution of reconstituted vial to 1 mg/mL may be desirable Patient Weight (kg) Serum Digoxin Concentration (ng/mL) 1 2 4 8 12 16 20 1 0.4 mg * 1 mg * 1.5 mg * 3 mg * 5 mg 6.5 mg 8 mg 3 1 mg * 2.5 mg * 5 mg 10mg 14 mg 19 mg 24 mg 5 2 mg * 4 mg 8 mg 16 mg 24 mg 32 mg 40 mg 10 4 mg 8 mg 16 mg 32 mg 48 mg 64 mg 80 mg 20 8 mg 16 mg 32 mg 64 mg 96 mg 128 mg 160 mg Calculation Based on Steady-State Digitoxin Concentrations: The dose of DigiFab (R) for digitoxin toxicity can be approximated by using the following formula (which differs from Formula 2 in the denominator due to a 10-fold decrease in the volume of distribution of digitoxin as compared to digoxin). Formula 4 Dose = (Serum digitoxin concentration in ng/mL) (weight in kg) (in # of vials) 1000 If in any case, the dose estimated based on ingested amount (Formula 1) differs substantially from that calculated based on the serum digoxin or digitoxin concentration (Formulas 2 and 4), it may be preferable to use the higher dose estimate. 2.2 Preparation and Administration Each vial contains 40 mg of digoxin immune Fab protein and is intended for one time use only as it contains no preservatives Reconstitute each vial of DigiFab (R) with 4 mL of Sterile Water for Injection USP and gently mix to provide a solution containing approximately 10 mg/mL of digoxin immune Fab protein. Use the reconstituted product promptly. If not used immediately, store under refrigeration at 2° to 8°C (36° to 46°F) for up to 4 hours. Add the reconstituted product to an appropriate volume of 0.9% sodium chloride for injection. Visually inspect reconstituted vials for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, turbid or if it contains particulates. Administer DigiFab (R) slowly as an intravenous infusion over at least 30 minutes. Stop the infusion if infusion rate-related anaphylactoid-type reactions occur, such as hypotension, wheezing, or urticaria. The infusion can be re-started at a slower rate. Give DigiFab (R) by bolus injection, if cardiac arrest is imminent. An increased incidence of infusion-related reactions may be expected with bolus injection. For infants and small children who may require very small doses, reconstitute the 40 mg vial as directed and administer undiluted using a tuberculin syringe. For very small doses, a reconstituted vial can be diluted with an additional 36 mL of isotonic saline to achieve a concentration of 1 mg/mL.
There are no known contraindications to the use of DigiFab (R) . There are no known contraindications.
The most common adverse reactions (> 7%) related to DigiFab (R) administration are worsening congestive heart failure (13%), hypokalemia (13%) and worsening atrial fibrillation (7%). The most common adverse reactions (>7%) are worsening congestive heart failure (13%), hypokalemia (13%) and worsening atrial fibrillation (7%). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BTG 1-877-377-3784, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the clinical trials of DigiFab (R) , 6 of 15 patients in the digoxin overdose study had a total of 17 adverse events. Three events occurred in one patient and consisted of the following: pulmonary edema, bilateral pleural effusion and renal failure. The events were determined to be likely due to the loss of digoxin inotropic support in combination with the patient's underlying medical condition. Of 8 healthy volunteers who received DigiFab (R) , two experienced an adverse reaction that was considered to be related to DigiFab (R) . The reactions were; one episode of phlebitis of the infusion-site vein and one episode of transient postural hypotension.
Rapid drop in serum potassium concentration after treatment with DigiFab (R) . Monitor frequently, especially after the first several hours of DigiFab administration. ( 5.1 ) Anaphylaxis and hypersensitivity reactions are possible. Patients with allergies to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may be at risk for an allergic reaction to DigiFab (R) . ( 5.2 ) Clinically misleading reading of standard serum digoxin concentration may occur after administration of DigiFab (R) due to interference with digitalis immunoassay measurements. ( 5.4 ) 5.1 General Suicidal ingestion may result from more than one drug. Toxic effects of other drugs or poisons should not be overlooked, especially in cases where signs and symptoms of digitalis toxicity are not relieved by administration of DigiFab (R) . Rapid drop in serum potassium concentration may occur after treatment with DigiFab (R) . Monitor frequently, especially after the first several hours of DigiFab (R) administration (see 5.4 Laboratory Tests ). Patients with poor cardiac function may deteriorate secondary to the withdrawal of the inotropic action of digoxin by DigiFab (R) . If needed, provide additional support by using other intravenous inotropes such as dopamine, dobutamine or vasodilators. However, take additional care not to aggravate the digitalis induced rhythm disturbances. Postpone re-digitalization, if possible, until the Fab fragments have been eliminated from the body, which may require several days, and patients with impaired renal function may require a week or longer. 5.2 Hypersensitivity Reactions Anaphylaxis and hypersensitivity reactions are possible. Carefully monitor all patients treated with DigiFab (R) for signs and symptoms of an acute allergic reaction (e.g., urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia) and treat immediately with appropriate emergency medical care (e.g., oxygen, diphenhydramine, corticosteroids, volume expansion and airway management), if one occurs. If an anaphylactic reaction occurs during the infusion, terminate DigiFab (R) administration at once and administer appropriate treatment. Balance the need for epinephrine against its potential risk in the setting of digitalis toxicity. Patients with known allergies to sheep protein are particularly at risk for an anaphylactic reaction, as are individuals who have previously received intact ovine antibodies or ovine Fab. Do not administer DigiFab (R) to patients with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available.Prior treatment with digoxin-specific ovine immune Fab carries a theoretical risk of sensitization to ovine serum protein and possible diminution of the efficacy of the drug due to the presence of human antibodies against ovine Fab. To date, there have been no clinical reports of human anti-ovine immunoglobulin antibodies causing a reduction in binding of ovine digoxin immune Fab or neutralization response to ovine digoxin immune Fab. 5.3 Use of DigiFab (R) in Renal Failure The elimination half-life of DigiFab (R) in renal failure has not been clearly defined. Monitor patients with severe renal failure who receive DigiFab (R) for digitalis toxicity for a prolonged period for possible recurrence of toxicity. Monitoring of free (unbound) digoxin concentrations after the administration may be appropriate in order to establish recrudescent toxicity in renal failure patients. 5 5.4 Laboratory Tests DigiFab (R) may interfere with digitalis immunoassay measurements. Thus, standard serum digoxin concentration measurements may be clinically misleading until the Fab fragments are eliminated from the body. This may take several days or a week or more in patients with markedly impaired renal function. Therefore, serum samples for digoxin concentration should be obtained before DigiFab (R) administration, if at all possible. Such measurements would establish the level of serum digoxin at the time of diagnosis of digitalis intoxication. At least 6 to 8 hours are required for equilibration of digoxin between serum and tissue, so absorption of the last dose may continue from the intestine. Therefore, serum measurements may be difficult to interpret if samples are drawn soon after the last digitalis dose. The total serum digoxin concentration may rise precipitously following administration of DigiFab (R) , but this will be almost entirely bound to the Fab fragment and therefore not able to react with receptors in the body. Patients should be closely monitored, including temperature, blood pressure, electrocardiogram, and potassium concentration, during and after administration of DigiFab (R) . Digoxin causes a shift of potassium from inside to outside the cell, such that severe intoxication can cause a life-threatening elevation of serum potassium. This may lead to increased urinary excretion of potassium so that a patient may have hyperkalemia but a whole body deficit of potassium. When the toxic effects of digoxin are reversed by DigiFab (R) , potassium shifts back into the cell with a resulting decline in serum potassium concentration. This hypokalemia may develop rapidly. For these reasons, serum potassium concentration should be followed closely, especially during the first several hours after DigiFab (R) administration. Cautious potassium supplementation should then be given when necessary.