a lipopeptide antifungal drug Caspofungin acetate CAS NO.162808-62-0

Caspofungin acetate

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Process

Caspofungin (brand name Cancidas worldwide) is a lipopeptide antifungal drugIt is a member of a new class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall. Caspofungin was the first inhibitor of fungal (1→3)-β-D-glucan synthesis to be approved by the United States Food and Drug Administration.Caspofungin is administered intravenously.Its currently approved therapeutic indications by both organisations include the empirical therapy of presumed fungal infections in febrile, neutropenic adult patients and the treatment of invasive aspergillosis in adult patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B and/or itraconazole). Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis, pleural cavity infections, and esophagitis) and the EMEA approval includes indication for the treatment of general invasive candidiasis in adult patients.

Clinical efficacy

About 36% of patients refractory to other therapies responded well to caspofungin therapy, while even 70% of patients intolerant to other therapies were classified as responders. Direct comparative studies to other drugs in the treatment of invasive aspergillosis have so far not been undertaken.

Contraindications

Known hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation contraindicate its use.

Resistance

Resistance in C. albicans has been described, but is currently still rare. The mechanism is probably a point mutation in the (1→3)-β-D-glucan synthase gene.

Drug interactions

• Cyclosporin: see under hepatic effects
• Tacrolimus: potential pharmacokinetic interactions
• Other systemic antimycotic agents: with amphotericin B, itraconazole and mycophenolate, no interactions have been seen
• Inducers of drug clearance (e.g. carbamazepine, phenytoin, rifampin, dexamethasone): consider 70 mg intravenous as maintenance dose instead of 50 mg

Duration of treatment

The mean duration of therapy in previous studies was 34 days. Some patients were even healed by a one-day treatment. However, a few patients were treated for as long as 162 days and tolerated the drug well, indicating that longtime use may be indicated and tolerated favourably in complicated cases of aspergillosis. Generally, the duration of treatment is dictated by the severity of the disease, the clinical response, and the improvement of immunocompetence in immunocompromised patients.

Dosage

An initial dose of 70 mg by intravenous infusion is given followed by 50 mg intravenous daily. If no response is seen or if inducers of caspofungin clearance (see above) are coadministered the daily dose may be increased to 70 mg. An infusion should take approximately 1 hour.

Dosage forms

• Cancidas 50 mg for intravenous infusion (manufacturer Merck)
• Cancidas 70 mg for intravenous infusion (manufacturer Merck)
• Brand names in countries other than the U.S. may vary.

Semisynthesis

Caspofungin is semisynthesized from pneumocandin B0, a fermentation product of Glarea lozoyensis.^[3]

Spectrum of fungal susceptibility and resistance

Caspofungin has been effective in treating fungal infections caused by Aspergillus and Candida species. The following represents MIC susceptibility for a few medically significant organisms.

• Candida albicans 0.015 - 16 μg/ml
• Candida krusei 0.03 - 8 μg/ml
• Cryptococcus neoformans 16 μg/ml

Product Details

Pharmacology

Inhibits synthesis of beta (1,3)-D-glucan, an integral component of the fungal cell wall.

Slideshow: Vaccination Safety: Your Questions Answered

 Vaccination Safety: Your Questions Answered

Pharmacokinetics

Distribution

Approximately 97% protein bound (albumin).

Metabolism

Slowly metabolized by hydrolysis and N-acetylation, and undergoes spontaneous chemical degradation.

Elimination

The half-life is approximately 13 h (adults) and 8 to 11 h (children). 35% is excreted in feces and 41% in urine (approximately 1.4% as unchanged drug). Renal Cl is approximately 0.15 mL/min. Total Cl is 12 mL/min.

Special Populations

Renal Function Impairment

AUC is increased 30% to 49% in patients with CrCl 49 mL/min or less after single-dose administration. No effect on caspofungin concentrations was seen in patients with mild to end-stage renal impairment after administration of multiple daily doses. Caspofungin is not dialyzable.

Hepatic Function Impairment

AUC is increased by approximately 55% in patients with mild hepatic impairment (Child-Pugh score 5 to 6) and by 76% in patients with moderate hepatic impairment (Child-Pugh score 7 to 9).

Elderly

AUC is increased by approximately 28%. No dosage adjustment is needed.

Gender

AUC in women was approximately 22% higher than in men after repeat dosing. No dosage adjustment is necessary based on gender.

Race

No dosage adjustment is needed based on race.

Indications and Usage

Treatment of invasive aspergillosis in patients refractory to or intolerant of other antifungal therapies; empirical treatment for presumed fungal infections in febrile neutropenic patients; treatment of esophageal candidiasis; treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections.

Contraindications

Standard considerations.

Dosage and Administration

Esophageal Candidiasis

Adults

IV 50 mg daily by slow infusion over approximately 1 h. Continue therapy for 7 to 14 days after symptomresolution. Consider oral suppressive therapy in patients with HIV infection.

Invasive Aspergillosis, Candidemia and Other Candida Infections, Empirical Treatment of Fungal Infections

Adults Loading dose

IV 70 mg by slow infusion over approximately 1 h on day 1.

Maintenance dose

IV 50 mg daily by slow infusion over approximately 1 h.

Duration of therapy Candidemia and other Candida infections

Antifungal therapy should be continued for at least 14 days after the last positive culture. Patients who remain neutropenic may warrant a longer duration of therapy pending resolution of the neutropenia.

Invasive aspergillosis

Duration of treatment should be based upon the severity of the underlying disease, recovery from immunosuppression, and clinical response.

Concomitant therapy

IV Daily maintenance dosage should be increased to 70 mg once daily if coadministered with rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin.

Empirical treatment

If the 50 mg dose is well tolerated but does not provide adequate clinical response, the daily dose can be increased to 70 mg. Treatment should be continued until resolution of neutropenia. Patients with a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved.

Hepatic Function Impairment

In adults with moderate hepatic insufficiency (Child-Pugh score 7 to 9), reduce maintenance dosage to 35 mg daily. A 70 mg loading dose should still be given on day 1 where recommended.

Pediatric Dosing

Children 3 mo to 17 yr of age Loading dose

IV 70 mg/m 2 by slow infusion over approximately 1 h on day 1.

Maintenance dose

IV 50 mg/m 2 daily. The maximum loading and maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. If the 50 mg/m 2 dose is well tolerated but does not provide adequate clinical response, the daily dose can be increased to 70 mg/m 2 (max, 70 mg/day). The duration of treatment should be individualized to each indication as described in adults.

Concomitant therapy

IV Consider a dose of 70 mg/m 2 IV infusion once daily when administered with inducers of drug Cl, such as rifampin, efavirenz, carbamazepine, dexamethasone, or phenytoin.

General Advice

For slow IV infusion only; not for IV bolus administration.

Reconstitute each vial with 10.8 mL of sodium chloride 0.9%, sterile water for injection, bacteriostatic water for injection with methylparaben and propylparaben, or bacteriostatic water for injection with benzyl alcohol 0.9%. Resulting concentration is 5 mg/mL (50 mL vial) or 7 mg/mL (70 mg vial).

For dilution, transfer reconstituted solution to an IV bag (or bottle) containing 250 mL of sodium chloride 0.9%, 0.45%, or 0.225% injection or Ringer's lactate injection. A reduced volume of IV solution may be used, provided the final concentration does not exceed 0.5 mg/mL

Do not mix or coinfuse with other medications.

Do not use diluents containing dextrose.

Visually inspect reconstituted solution. Do not use if particulate matter, cloudiness, or discoloration is noted.

Storage/Stability

Store unopened vials in refrigerator (36° to 46°F). Reconstituted solution may be stored at less than 77°F for 1 h prior to preparing diluted IV infusion solution. Vials are for single use only; discard any remaining solution. IV infusion solution in IV bag or bottle can be stored at less than 77°F for 24 h or in refrigerator (36° to 46°F) for 48 h.

Drug Interactions

Cyclosporine

Avoid coadministration if possible. Caspofungin plasma levels may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Use concomitantly only if potential benefit outweighs the potential risk. Closely monitor liver function.

Enzyme inducers (eg, carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin, rifampin)

Caspofungin plasma levels may be reduced, decreasing the efficacy. In adults, coadministration may require an increase in dose to caspofungin 70 mg daily. In children, coadministration may require an increase in dose to caspofungin 70 mg/m 2 daily (max, 70 mg/day).

Tacrolimus

Tacrolimus blood levels may be decreased, reducing the efficacy. Monitor tacrolimus blood concentrations and adjust dose accordingly.

Adverse Reactions

Cardiovascular

Hypotension (20%); phlebitis (18%); tachycardia (11%); hypertension (10%); arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, flushing, MI (less than 5%).

CNS

Headache (15%); anxiety, asthenia, confusional state, convulsion, depression, dizziness, fatigue, insomnia, somnolence, tremor (less than 5%).

Dermatologic

Rash (23%); erythema (9%); pruritus (7%); petechiae, skin lesion, urticaria (less than 5%); decubitus ulcer (3%); erythema multiforme, skin exfoliation, Stevens-Johnson syndrome (postmarketing).

GI

Diarrhea (27%); vomiting (17%); nausea (15%); abdominal pain (9%); abdominal distension, constipation, dyspepsia, upper abdominal pain (less than 5%); pancreatitis (postmarketing).

Genitourinary

Hematuria, renal failure, UTI (less than 5%); clinically significant renal dysfunction (postmarketing).

Hepatic

Hepatic failure, hepatomegaly, hepatotoxicity, hyperbilirubinemia, jaundice (less than 5%); hepatic necrosis (postmarketing).

Hematologic-Lymphatic

Anemia (11%); coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia (less than 5%).

Lab Tests

Decreased serum potassium (23%); increased alkaline phosphatase (22%); decreased hemoglobin, (21%); decreased hematocrit, increased ALT (18%); increased AST (17%); increased serum bilirubin (13%); decreased WBC (12%); increased serum creatinine (11%); positive urine RBC (10%); increased blood urea (9%); increased conjugated bilirubin (8%); decreased serum albumin, decreased serum magnesium (7%); increased blood glucose (6%); increased serum potassium (3%).

Local

Infusion-site pain/pruritus/swelling (less than 5%).

Metabolic-Nutritional

Peripheral edema (11%); hypokalemia (8%); anorexia, decreased appetite, edema, fluid overload, hypercalcemia, hyperglycemia, hypomagnesemia (less than 5%).

Musculoskeletal

Arthralgia, back pain, pain in extremity (less than 5%).

Respiratory

Respiratory failure (20%); cough, pneumonia (11%); dyspnea, pleural effusion (9%); respiratory distress (8%); rales (7%); epistaxis, hypoxia, tachypnea (less than 5%).

Miscellaneous

Infusion-related reaction (35%); pyrexia (30%); chills (23%); septic shock (13%); mucosal inflammation (10%); central line infection (9%); sepsis (5%); bacteremia (less than 5%); graft-versus-host disease (4%); swelling (postmarketing).

Precautions

Monitor

Evaluate LFTs prior to treatment and periodically thereafter. If abnormal LFTs are noted, monitor patient's liver function more frequently. If worsening hepatic function is noted, evaluate risk/benefit of continued therapy with caspofungin.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 3 mo of age.

Hypersensitivity

Anaphylaxis and possible histamine-mediated symptoms, including rash, facial swelling, pruritus, sensation of warmth, and bronchospasm, have been reported during administration of caspofungin.

Renal Function

No dosage adjustment is needed in patients with renal insufficiency.

Hepatic Function

Dosage adjustment required in moderate hepatic impairment. No clinical experience in adults with severe hepatic impairment or children with any degree of hepatic impairment.

Hepatic effects

LFT abnormalities may occur. Isolated cases of clinically significant hepatic dysfunction, hepatic failure, and hepatitis have been reported.

Overdosage

Symptoms

In clinical studies, single doses of 210 mg were generally well tolerated.

Patient Information

Advise patient or caregiver that medication will be prepared and administered by a health care provider in a hospital setting.

Advise patient to immediately report any discomfort at injection site or the vein above the injection site.

Inform patients that there have been isolated reports of serious hepatic effects.

Inform patients that caspofungin may cause hypersensitivity reactions, including rash, facial swelling, pruritus, sensation of warmth, or bronchospasm.

Instruct patient to report any of the following to health care provider: chills, fever, headache, nausea, any unusual or unexplained symptoms.

Packaging 

The packaging can be customized, normally, 1kgs/Tin, or 5kgs/Tin or per drums

Company Introduction

Top Pharm Chemical Group is specialized in the New Drug Researching and Developing, and mainly manufacture Chemical Intermediates,  Pharmaceutical APIs and Pilot Production. To meet customers regulatory needs, we can offer products from gram to kilo and tons scale, and we can also support our customers with the DMF and other documents to Complete the registration.  

Our Targets:

"Best Technic; Better Quality; Better Price; Better Service"

Main Products:

Anidulafungin,Micafungin,Caspofungin,Posaconazole etc. (Anti-Infective)

Ixabepilone, Argatroban, Decitabine, Everolimus etc. (Anti-Tumor)

Epothilone B, Tacrolimus, Rapamycin,Temsirolimus etc. (Fermentation)

Bimatoprost, Latanoprost, Travoprost, Cloprostenol etc.(Prostaglandins)

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