Abraxane (+ Human albumin)

Uses

Shock: Albumin is used for the emergency treatment of shock and in other similar conditions where the restoration of blood volume is urgent. If there has been considerable loss of red blood cells, transfusion with packed red blood cells is used.

Burns: Albumin or Albumin in either normal saline or dextrose is used to prevent marked hemoconcentration and to maintain appropriate electrolyte balance.

Hypoproteinemia with or without edema: Albumin is used for those clinical situations usually associated with a low concentration of plasma protein and a resulting decreased circulating blood volume. Although diuresis may occur soon after albumin administration has been instituted, best results are obtained if albumin is continued until the normal serum protein level is regained.

Paclitaxel Injection is used for first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first- line therapy, paclitaxel is used for combination with cisplatin.

Paclitaxel Injection is used for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor negative tumors.

Paclitaxel Injection is used for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracyclineunless clinically contraused. Paclitaxel Injection, in combination with cisplatin, is used for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy. Paclitaxel Injection is used for the second-line treatment of AIDS-related Kaposi's sarcoma.

Abraxane (+ Human albumin) is also used to associated treatment for these conditions: Advanced Cervical Cancer, Advanced Head and Neck Cancer, Advanced Ovarian Cancer, Advanced Soft Tissue Sarcoma, Esophageal Cancers, Fallopian Tube Cancer, Kaposi’s sarcoma, Locally Advanced Non-Small Cell Lung Cancer, Malignant Neoplasm of Stomach, Malignant Peritoneal Neoplasm, Metastatic Bladder Cancer, Metastatic Breast Cancer, Metastatic Melanoma, Metastatic Non-Small Cell Lung Cancer, Non-Small Cell Lung Carcinoma (NSCLC), Ovarian Cancer, Pancreatic Adenocarcinoma Metastatic, Advanced Bladder cancer, Advanced Thymoma, Metastatic Penile cancer, Refractory Small cell lung cancer, Refractory Testicular germ cell cancer

How Abraxane (+ Human albumin) works

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.

Dosage

Abraxane (+ Human albumin) dosage

Albumin (Human) 25% may be given intravenously without dilution or it may be diluted with normal saline or 5% dextrose before administration. 200 mL per liter gives a solution which is approximately isotonic and iso-osmotic with citrated plasma.

When undiluted albumin solution is administered in patients with normal blood volume, the rate of infusion should be slow enough (1 mL per minute) to prevent too rapid expansion of plasma volume.

In the treatment of shock the amount of albumin and duration oftherapymust be based on the responsiveness of the patient as indicated byblood pressure, degree of pulmonary congestion, andhematocrit. The initial dose may be followed by additional albumin within 15-30 minutes if the response is deemed inadequate. If there is continued loss of protein, it may be desirable to give packed red blood cells.

In the treatment of burns an optimalregimeninvolving use of albumin, crystalloids, electrolytes and water has not been established. Suggested therapy during the first 24 hours includes administration of large volumes of crystalloid solution to maintain an adequate plasma volume. Continuation of therapy beyond 24 hours usually requires more albumin and less crystalloid solution to prevent marked hemoconcentration and maintain electrolyte balance. Duration of treatment varies depending upon the extent of protein loss through renal excretion, denuded areas of skin and decreased albumin synthesis. Attempts to raise the albumin level above 4.0 g/100 mL may only result in an increased rate ofcatabolism.

In the treatment of hypoproteinemia, 200 to 300 mL of 25% albumin may be required to reduce edema and to bring serum protein values to normal. Since such patients usually have approximately normal blood volume, doses of more than 100 mL of 25% albumin should not be given faster than 100 mL in 30 to 45 minutes to avoid circulatory embarrassment. If slower administration is desired, 200 mL of 25% albumin may be mixed with 300 mL of 10% dextrose solution and administered by continuous drip at a rate of 100 mL of this dextrose solution an hour.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Advanced non-small cell lung cancer: 135 mg/m2 over 24 hr or 175 mg/m2 over 3 hr, followed by cisplatin and repeated at 3 wk intervals.

Ovarian carcinoma: Primary treatment (in combination with cisplatin or carboplatin): 135 mg/m2 infused over 24 hr followed by cisplatin and repeated at 3 wk intervals. Secondary treatment (as a single agent): 135 or 175 mg/m2 infused over 3 hr once every 3 weeks.

Breast cancer: Adjuvant therapy; 2nd line monotherapy or 1st line treatment with trastuzumab: 175 mg/m2 infused over 3 hr once every 3 wk for 4 courses; when used with trastuzumab, the dose should be given the day after the 1st dose of trastuzumab or immediately after subsequent doses if well-tolerated. 1st line with doxorubicin: 220 mg/m2over 3 hr every 3 wk, the dose to be administered 24 hr after doxorubicin.

AIDS-related Kaposi's sarcoma: 135 mg/m2 over 3 hr every 3 weeks. Alternatively, 100 mg/m2 over 3 hr every 2 wk especially in patients with poor performance status.

Paclitaxel must be diluted before infusion. It can be diluted in 0.9% sodium chloride inj, 5% dextrose inj, 5% dextrose and 0.9% sodium chloride inj or 5% dextrose in lactated Ringer's inj to a concentration of 0.3-1.2 mg/ml.

Side Effects

Allergic or pyrogenic reactions are characterized primarily by fever and chills; rash, nausea, vomiting, tachycardia and hypotension have also been reported. Should an adverse reaction occur, slow or stop the infusion for a period of time which may result in the disappearance of the symptoms. If administration has been stopped and the patient requires additional Albumin (Human), material from a different lot should be used. Albumin (Human), particularly if administered rapidly, may result in vascular overload with resultant pulmonary edema.

Neutropenia, leukopenia, thrombocytopenia, anaemia, bleeding; hypersensitivity reactions (dyspnoea, flushing, chest pain, tachycardia, rash, hypotension, hypertension); bradycardia, abnormal ECG; neurotoxicity (mainly peripheral neuropathy), myalgia, arthralgia; nausea, vomiting, diarrhoea; severe mucositis, alopecia; rarely hepatic necrosis and encephalopathy, inj site reactions e.g. erythema, tenderness, skin discolouration, swelling; interstitial pneumonitis; infections (mainly UTIs and upper respiratory tract); mucosal inflammation, severe elevation in LFTs (aspartate aminotransferase and alkaline phosphatase).

Toxicity

Rat (ipr) LD₅₀=32530 µg/kg. Symptoms of overdose include bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity.

Precaution

Hypertension or low cardiac reserve; additional fluids for dehydrated patients. Monitor for signs of cardiac overload in injured or postoperative patients. May carry risk of viral transmission. Volume admin and rate of infusion must always be individualised according to situation and response. Pregnancy, lactation.

Bone marrow suppression during therapy. Monitor cardiac function if conduction abnormalities result. Premedicaton (with corticosteroid, antihistamine and histamine H2-receptor antagonist) may be required to reduce risk of hypersensitivity reaction. Discontinue, if severe reactions e.g. hypotension, dyspnoea, angioedema or urticaria occur. Caution in patients with moderate hepatic impairment. Monitor for reactions of admin. Safety and efficacy in paediatric patients have not been established. Administer before platinum derivatives (cisplatin, carboplatin) if used in combination. Hazardous agent; use appropriate precautions for handling and disposal.

Interaction

Albumin solution should not be mixed by protein hydrolysates or alcoholic solutions. Risk of atypical reactions to ACE inhibitors in patients undergoing therapeutic plasma exchange with albumin human replacement.

Myelosuppression was more profound when given after cisplatin than with the alternate sequence (e.g., paclitaxel before cisplatin). CYP2C8 inducers e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifapentine, and secobarbital may reduce levels or effects. CYP2C8 inhibitors e.g. gemfibrozil, ketoconazole, montelukast, and ritonavir may increase levels or effects. CYP3A4 inducers e.g. aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins may decrease the levels or effects. CYP3A4 inhibitors e.g. azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil may increase levels or effects. May increase anthracycline (eg doxorubicin, epirubicin) levels or toxicity; admin of anthracycline at least 24 hr prior to paclitaxel may reduce interaction. May decrease the absorption of cardiac glycosides (may only affect digoxin tablets); levels should be monitored.

Volume of Distribution

• 227 to 688 L/m^2 [apparent volume of distribution at steady-state, 24 hour infusion]

Elimination Route

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL.

Half Life

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours.

Clearance

• 21.7 L/h/m2 [Dose 135 mg/m2, infusion duration 24 h]
• 23.8 L/h/m2 [Dose 175 mg/m2, infusion duration 24 h]
• 7 L/h/m2 [Dose 135 mg/m2, infusion duration 3 h]
• 12.2 L/h/m2 [Dose 175 mg/m2, infusion duration 3 h]

Elimination Route

In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Albumin (Human) may be contraindicated in patients with severe anemia or cardiac failure and in patients with a history of allergic reactions to human albumin.

History of hypersensitivity (especially macrogol glycerol ricinolate). Patients with baseline neutropenia of <1500 cells/mm3 (<1000 cells/mm3 for kaposi's sarcoma). Pregnancy and lactation. In kaposi's sarcoma, contraindicated in patients with concurrent, serious, uncontrolled infections.

Special Warning

Pediatric Use: No clinical studies using Albumin (Human) 25%, have been conducted in pediatric patients. Safety and effectiveness in pediatric patients have not been established. However, extensive experience in patients suggests that children respond to Albumin (Human) 25%, in the same manner as adults.

Hepatic Impairment:

Advanced non-small cell lung cancer: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendation, consult local protocol.

Ovarian carcinoma: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendations, consult local protocol.

Breast cancer: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendation, consult local protocol.

AIDS-related Kaposi's sarcoma: Do not use in severe impairment, increased risk of hepatotoxicity. For detailed dosing recommendation, consult local protocol.

Acute Overdose

Complications: bone marrow suppression, peripheral neurotoxicity and mucositis. There is no known antidote. Treatment is symptom specific and supportive.

Storage Condition

Store below 30°C. Do not freeze.

Innovators Monograph

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