CASPOGIN Injection (Caspofungin acetate)

Table of Content

Invasive fungal infections have emerged as a serious nosocomial threat, particularly among critically ill patients. Candida and Aspergillus are the most common causes of invasive fungal infections, accounting for 70–90% and 10–20% of all invasive mycoses, respectively. Invasive candidiasis and aspergillosis are associated with substantial morbidity and high mortality (40–60% and 60–90%, respectively), prolonged hospital stay and increased healthcare costs. Early diagnosis and prompt initiation of antifungal therapy are, thus, essential to reduce morbidity and mortality.

For decades, amphotericin B deoxycholate has been the standard therapy for invasive fungal infections. Unfortunately, amphotericin B deoxycholate is often poorly tolerated and associated with infusion-related acute reactions and nephrotoxicity. In the late 1970s and 1980s, the emergence of azoles (first, miconazole and ketoconazole and, then, fluconazole and itraconazole), a new class of antifungal agents inhibiting the synthesis of the cell membrane,p rovided an alternative therapeutic strategy to amphotericin B deoxycholate. In recent years, several new antifungal agents have become available, offering additional therapeutic options for the management of invasive fungal infections. Today, the antifungal armamentarium has further expanded to include the newer, extended-spectrum triazoles and the echinocandins.

The echinocandins represent the fourth class of antifungal agents available for the treatment of systemic fungal infections. At present,there are three echinocandins approved by the Food and Drug Administration (FDA). Caspofungin was approved first,in 2001,followed by micafungin in 2005 and anidulafungin in 2006.

The echinocandins are a valuable addition to the present-day antifungal armamentarium for the treatment of invasive fungal infections (IFIs). Although they have a narrow antifungal spectrum, these agents cover the two most common fungal pathogens, i .e., Candida and Aspergillus. As a class of antifungal agents, they are safe,well tolerated, and demonstrate favourable pharmacokinetic and pharmacodynamic profiles. The echinocandins do not appear to demonstrate any differences in clinical efficacy in the disease entities studied and it is unlikely that any one agent would be found to be clearly superior with regard to clinical outcome.

All the echinocandins are approved for the treatment of invasive candidiasis; however, caspofungin is the only echinocandin that covers the broadest range of indications (US FDA-approved):

·         Invasive aspergillosis in patients intolerant of or refractory to other therapies

·         Empirical treatment of presumed invasive fungal infections in febrile neutropenic patients

·         Fungal infections in paediatric patients,3 months of age and older

CASPOFUNGIN, the first inhibitor of fungal beta-(1,3)-d-glucan synthesis to receive approval by the US FDA, is effective for the treatment of mucosal and invasive candidiasis and invasive aspergillosis. In comparative clinical trials, caspofungin was no less effective than liposomal amphotericin B in the empirical treatment of neutropenic patients with persistent fever, amphotericin B deoxycholate in the treatment of invasive candidiasis or fluconazole in the treatment of oesophageal candidiasis. Caspofungin also displayed broadly similar efficacy to amphotericin B deoxycholate in oesophageal or oropharyngeal candidiasis and was effective as salvage therapy in patients with invasive aspergillosis who were refractory to or intolerant of standard therapy. The tolerability profile of caspofungin was similar to that of fluconazole and superior to that of amphotericin B deoxycholate and liposomal amphotericin B. Therefore, in the appropriate indications, caspofungin is a viable alternative to amphotericin B  deoxycholate, liposomal amphotericin B or fluconazole.

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only.

Qualitative and Quantitative Composition

CASPOGIN I.V. 50 mg

Each vial contains:

Caspofungin Acetate equivalent to Caspofungin .... 50 mg

Excipients.............................................................. q.s.

CASPOGIN I.V. 70 mg

Each vial contains:

Caspofungin Acetate equivalent to Caspofungin .... 70 mg

Excipients............................................................... q.s.

Dosage Form(s) and Strength(s)

White to off-white compact lyophilized cake and or powder (50 mg/70 mg) for concentrate for solution for intravenous (I.V.) infusion.

Clinical Particulars

Therapeutic Indications

  • Empirical therapy for presumed fungal infections in febrile neutropenic patients.
  • Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections.
  • Treatment of esophageal candidiasis.
  • Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole).

Posology and Method of Administration

Important Administration Instructions for Use in All Patients

Administer caspofungin acetate for injection by slow I.V. infusion over approximately 1 hour. Do not administer caspofungin acetate by I.V. bolus administration.

Recommended Dosage in Adult Patients (18 years of age and older)

The dosage and duration of caspofungin acetate for injection treatment for each indication are as follows:

Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients

Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Continue empirical therapy until resolution of neutropenia. In general, treat patients found to have a fungal infection for a minimum of 14 days after the last positive culture and continue treatment for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50 mg dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg.

Candidemia and Other Candida Infections

Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient's clinical and microbiological response. In general, continue antifungal therapy for at least 14 days after the last positive culture. Patients with neutropenia who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia.

Esophageal Candidiasis

The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70 mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered.

Invasive Aspergillosis

Administer a single 70 mg loading dose on Day 1, followed by 50 mg daily. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. In general, treatment should continue for at least 7 days after resolution of symptoms.

Dosage Adjustments in Patients with Hepatic Impairment

Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg once daily is recommended based upon pharmacokinetic data, with a 70 mg loading dose administered on Day 1 where appropriate. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients with any degree of hepatic impairment.

Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment.

Recommended Dosing in Paediatric Patients (3 months to 17 years of age)

For all indications, administer a single 70 mg/m2 loading dose on Day 1, followed by 50 mg/m2 once daily thereafter. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosing in pediatric patients (3 months to 17 years of age) should be based on the patient's body surface area (BSA) as calculated by the Mosteller formula.

Following calculation of the patient's BSA, the loading dose in milligrams should be calculated as follows:  Loading dose (mg) = BSA (m2) ´ 70 mg/m2

The maintenance dose in milligrams should be calculated as follows:

Daily maintenance dose (mg) = BSA (m2) ´ 50 mg/m2

Duration of treatment should be individualized to the indication, as described for each indication in adults. If the 50 mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m2 daily (not to exceed 70 mg).

Dosage Adjustments in Patients Receiving Concomitant Inducers of Hepatic Cytochrome (CY) P450 Enzymes

Adult Patients

Adult patients on rifampin should receive 70 mg of caspofungin acetate for injection once daily. When caspofungin acetate for injection is co-administered to adult patients with other inducers of hepatic CYP enzymes such as nevirapine, efavirenz, carbamazepine, dexamethasone or phenytoin, administration of a daily dose of 70 mg of caspofungin acetate for injection should be considered.

Pediatric Patients

Pediatric patients on rifampin should receive 70 mg/m2 of caspofungin acetate for injection daily (not to exceed an actual daily dose of 70 mg. When caspofungin acetate for injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, a caspofungin dose of 70 mg/m2 once daily (not to exceed 70 mg) should be considered.

Preparation for Administration

Reconstitution of Caspofungin Acetate for I.V. Infusion

  1. Equilibrate the refrigerated vial of 50 mg/70 mg caspofungin acetate for injection to room temperature.
  2. Aseptically add 10.0 mL of Water for Injection, 0.9% Sodium Chloride Injection, bacteriostatic Water for Injection (with methyl paraben and propyl paraben), or bacteriostatic Water for Injection (with 0.9% benzyl alcohol) into the vial.
  3. The white to off-white cake will dissolve completely. Mix gently until a clear, concentrated solution is obtained. Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.
  4. The vial containing reconstituted solution of caspofungin acetate for injection may be stored for up to 24 hours at ≤25°C (≤77°F) prior to the preparation of the infusion solution.
  5. Caspofungin acetate for injection vials are for single-dose use only. Discard any unused portion.

Dilution of the Reconstituted Solution for Infusion

FOR CASPOFUNGIN ACETATE 50 mg

A. Aseptically transfer the appropriate volume (mL) of reconstituted caspofungin acetate for injection to an I.V. bag containing 90 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringer’s Injection.

B. This diluted infusion solution must be used within 24 hours if stored at ≤25°C (≤77°F) or within 48 hours if stored refrigerated at 2° to 8°C (36° to 46°F).

FOR CASPOFUNGIN ACETATE 70 mg

A. Aseptically transfer the appropriate volume (mL) of reconstituted caspofungin acetate for injection to an I.V. bag containing 240 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringer’s Injection.

B. This diluted infusion solution must be used within 24 hours if stored at ≤25°C (≤77°F) or within 48 hours if stored refrigerated at 2° to 8°C (36° to 46°F).

Important Reconstitution and Dilution Instructions for Pediatric Patients (3 months of age and older)

Follow the reconstitution procedures described above using either the 70 mg or 50 mg vial to create the reconstituted solution. From the reconstituted solution in the vial, remove the volume of drug equal to the calculated loading dose or calculated maintenance dose based on a concentration of 7 mg/mL (if reconstituted from the 70 mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50 mg vial).

The choice of vial should be based on the total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses <50 mg that 50 mg vials (with a concentration of 5 mg/mL) be used if available. The 70 mg vial should be reserved for pediatric patients requiring doses >50 mg.

The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose.

Drug Incompatibilities

Do not mix or co-infuse caspofungin acetate for injection with other medications, as there are no data available on the compatibility of caspofungin acetate with other I.V. substances, additives, or medications.

Do not use diluents containing dextrose (α-D-glucose), as caspofungin acetate is not stable in diluents containing dextrose.

Contraindications

Caspofungin acetate is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to any component of this product.

Special Warnings and Precautions for Use

Hypersensitivity

Anaphylaxis and other hypersensitivity reactions have been reported during administration of caspofungin acetate.

Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm, have been reported.

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of caspofungin acetate. Caution should apply in patients with history of allergic skin reaction.

Discontinue caspofungin acetate at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment.

Hepatic Effects

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin acetate. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin acetate, isolated cases of clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported; a causal relationship to caspofungin acetate has not been established. Monitor patients who develop abnormal liver function tests during caspofungin acetate therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing caspofungin acetate therapy.

In adult patients with mild and moderate hepatic impairment, the area under the curve (AUC) is increased by about 20% and 75%, respectively. A reduction of the daily dose to 35 mg is recommended for adults with moderate hepatic impairment. There is no clinical experience in adults with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment. A higher exposure than in moderate hepatic impairment is expected and caspofungin should be used with caution in these patients.

Elevated Liver Enzymes During Concomitant Use with Cyclosporine

Elevated liver enzymes have occurred in patients receiving caspofungin acetate and cyclosporine concomitantly. Only use caspofungin acetate and cyclosporine in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated. Close monitoring of liver enzymes should be considered if caspofungin and ciclosporin are used concomitantly.

Other Warnings

Limited data suggest that less common non-Candida yeasts and non-Aspergillus molds are not covered by caspofungin. The efficacy of caspofungin against these fungal pathogens has not been established.

Drug Interactions

In vitro studies show that caspofungin is not an inhibitor of any enzyme in the CYP450 system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other substances. Caspofungin is not a substrate for the permeability glycoprotein (P-glycoprotein or P-gp) and is a poor substrate for CYP450 enzymes. However, caspofungin has been shown to interact with other medicinal products in pharmacological and clinical studies.

Clinical studies in healthy adult volunteers show that the pharmacokinetics of caspofungin is not altered to a clinically relevant extent by itraconazole, amphotericin B, mycophenolate, nelfinavir or tacrolimus. Caspofungin did not influence the pharmacokinetics of amphotericin B, itraconazole, rifampicin or mycophenolate mofetil. Although safety data are limited, it appears that no special precautions are needed when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil are co-administered with caspofungin.

Cyclosporine

In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin acetate. Caspofungin acetate did not increase the plasma levels of cyclosporine. There were transient increases in liver alanine aminotransferase (ALT) and aspartate aminotransferase (AST) when caspofungin acetate and cyclosporine were co-administered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy.

Tacrolimus

Caspofungin reduced the trough concentration of tacrolimus by 26% in healthy adult volunteers. For patients receiving caspofungin acetate and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Inducers of Hepatic CYP Enzymes

Rifampin

A drug–drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations.

Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin acetate is expected to reduce the plasma concentrations of caspofungin acetate. Therefore, adult patients on rifampin should receive 70 mg of caspofungin acetate for injection daily and pediatric patients on rifampin should receive 70 mg/m2 of caspofungin acetate for injection daily (not to exceed an actual daily dose of 70 mg).

Other Inducers of Hepatic CYP Enzymes

Adults

When caspofungin acetate is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, administration of a daily dose of 70 mg of caspofungin acetate for injection should be considered.

Pediatric Patients

When caspofungin acetate is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, administration of a daily dose of 70 mg/m2 caspofungin acetate for injection (not to exceed an actual daily dose of 70 mg) should be considered.

All adult drug–drug interaction studies described above were conducted at a 50 or 70 mg daily caspofungin dose. The interaction of higher doses of caspofungin with other medicinal products has not been formally studied.

Use in Special Populations

Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis.

Patients with Hepatic Impairment

Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg once daily is recommended based upon pharmacokinetic data. However, where recommended, a 70 mg loading dose should still be administered on Day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment.

Pregnant Women

Risk Summary

Based on animal data, caspofungin may cause fetal harm. There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes with caspofungin use in pregnant women.

In animal studies, caspofungin caused embryo-fetal toxicity, including increased resorptions, increased peri-implantation loss and incomplete ossification at multiple fetal sites, following I.V. administration to pregnant rats and rabbits during organogenesis at doses up to 0.8 and 2 times the clinical dose, respectively. Caspofungin has been shown to cross the placental barrier in animal studies. Advise patients of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Caspofungin should not be used during pregnancy unless clearly necessary.

Data

Animal Data

In animal reproduction studies, pregnant rats dosed with I.V. caspofungin during organogenesis (gestational days 6 to 20) at 0.5, 2, or 5 mg/kg/day (up to 0.8 times the clinical dose based on body surface area comparison) showed increased resorptions and peri-implantation losses at 5 mg/kg/day. Incomplete ossification of the skull and torso and increased incidence of cervical rib were noted in offspring born to pregnant rats treated at doses up to 5 mg/kg/day. In pregnant rabbits treated with I.V. caspofungin during organogenesis (GD 7 to 20) at doses of 1, 3, or 6 mg/kg/day (approximately 2 times the clinical dose based on body surface area comparison), increased fetal resorptions and increased incidence of incomplete ossification of the talus/calcaneus in offspring were observed at the highest dose tested. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma.

In perinatal and postnatal development study in rats, I.V. caspofungin administered at 0.5, 2 or 5 mg/kg/day from GD 6 through GD 20 of lactation was not associated with any adverse effects on reproductive performance or subsequent development of first-generation (F1) offspring or malformations in second-generation (F2) offspring.

Lactating Women

Risk Summary

There are no data on the presence of caspofungin in human milk, the effects on the breastfed child, or the effects on milk production. Caspofungin was found in the milk of lactating, drug-treated rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for caspofungin and any potential adverse effects on the breastfed child from caspofungin or from the underlying maternal condition.

Pediatric Patients

The safety and effectiveness of caspofungin acetate in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications:

  • Empirical therapy for presumed fungal infections in febrile neutropenic patients.
  • Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections.
  • Treatment of esophageal candidiasis.
  • Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies

The efficacy and safety of caspofungin acetate has not been adequately studied in prospective clinical trials involving neonates and infants below 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of central nervous system (CNS) and multi-organ involvement than in older patients; the ability of caspofungin acetate to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown.

Caspofungin acetate has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. Caspofungin acetate has also not been studied as initial therapy for invasive aspergillosis in pediatric patients.

In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given I.V. caspofungin acetate. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin acetate in safety and efficacy studies. The majority of the pediatric patients received caspofungin at a once-daily maintenance dose of 50 mg/m2 for a mean duration of 12 days (median 9, range: 1 to 87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with caspofungin acetate were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased AST (12%), rash (12%), increased ALT (11%), hypotension (11%), and chills (11%).

Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions.

Geriatric Patients

Clinical studies of caspofungin acetate did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% in the AUC) compared with young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

Undesirable Effects

Hypersensitivity reactions (anaphylaxis and, possibly, histamine-mediated adverse reactions) have been reported.

Also, in patients with invasive aspergillosis, pulmonary edema, adult respiratory distress syndrome (ARDS), and radiographic infiltrates were reported.

Adult Patients

In clinical studies, 1,865 adult individuals received single or multiple doses of caspofungin: 564 febrile neutropenic patients (empirical therapy study), 382 patients with invasive candidiasis, 228 patients with invasive aspergillosis, 297 patients with localized Candida infections, and 394 individuals enrolled in Phase I studies. In the empirical therapy study, patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation (including 39 allogeneic transplantations). In the studies involving patients with documented Candida infections, the majority of the patients with invasive Candida infections had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the non-comparative aspergillus study often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications.

Phlebitis was a commonly reported local injection-site adverse reaction in all patient populations. Other local reactions included erythema, pain/tenderness, itching, discharge, and a burning sensation.

Reported clinical and laboratory abnormalities among all adults treated with caspofungin (total 1,780) were typically mild and rarely led to discontinuation.

Tabulated List of Adverse Reactions

The following adverse reactions were reported during clinical studies and/or

postmarketing use:

Table 1: Adverse Reactions in Adult Patients

System Organ Class

Common (≥1/100 to

<1/10)

Uncommon (≥1/1,000 to <1/100)

Not Known

(cannot be

estimated from

available data)

Blood and lymphatic

system disorders

hemoglobin

decreased,

hematocrit

decreased, white

blood cell count

decreased

anemia, thrombocytopenia, coagulopathy, leukopenia, eosinophil count increased, platelet count decreased, platelet count increased,

lymphocyte count decreased, white blood cell count increased, neutrophil count decreased

 

Metabolism and

nutrition disorders

hypokalemia

fluid overload, hypomagnesemia, anorexia, electrolyte imbalance, hyperglycemia, hypocalcemia, metabolic acidosis

 

Psychiatric disorders

 

anxiety, disorientation, insomnia

 

Nervous system

disorders

headache

dizziness, dysgeusia, paresthesia, somnolence, tremor, hypoesthesia

 

 

 

Eye disorders

 

ocular icterus, vision blurred, eyelid edema, lacrimation increased

 

 

Cardiac disorders

 

palpitations, tachycardia, arrhythmia, atrial fibrillation, cardiac failure congestive

 

Vascular disorders

phlebitis

thrombophlebitis, flushing, hot flush, hypertension, hypotension

 

 

 

 

Respiratory, thoracic

and mediastinal

disorders

dyspnea

nasal congestion, pharyngolaryngeal pain, tachypnea, bronchospasm, cough, dyspnea paroxysmal nocturnal, hypoxia, rales, wheezing

 

 

 

 

 

Gastrointestinal

disorders

nausea, diarrhea,

vomiting

abdominal pain, abdominal pain upper, dry mouth, dyspepsia, stomach discomfort, abdominal distension, ascites, constipation, dysphagia, flatulence

 

 

 

 

 

Hepatobiliary

disorders

elevated liver values

(ALT, AST, blood alkaline

phosphatase,

bilirubin conjugated,

blood bilirubin)

cholestasis, hepatomegaly, hyperbilirubinemia, jaundice, hepatic function abnormal, hepatotoxicity,

liver disorder, gamma-glutamyltransferase

increased

 

Skin and

subcutaneous tissue

disorders

rash, pruritus,

erythema,

hyperhidrosis

erythema multiforme, rash macular, rash maculo-papular, rash pruritic, urticaria, dermatitis allergic, pruritus generalized, rash erythematous, rash generalized, rash morbilliform, skin lesion

TEN and

SJS

Musculoskeletal and

connective tissue

disorders

arthralgia

back pain, pain in extremity, bone pain, muscular weakness, myalgia

 

Renal and urinary

disorders

 

renal failure, renal failure acute

 

General disorders and

administration site

conditions

pyrexia, chills,

infusion-site pruritus

pain, catheter-site pain, fatigue, feeling cold, feeling hot, infusion-site erythema, infusion-site induration, infusion-site pain, infusion-site swelling, injection-site phlebitis, edema peripheral, tenderness, chest discomfort, chest pain, face edema, feeling of body temperature change, induration, infusion-site extravasation, infusion-site irritation, infusion-site phlebitis, infusion-site rash, infusion-site urticaria, injection-site erythema, injection-site edema, injection-site pain, injection-site swelling, malaise, edema

 

Investigations

blood potassium

decreased, blood

albumin decreased

blood creatinine increased, red blood cells urine positive, protein total decreased, protein urine present, prothrombin time prolonged, prothrombin time shortened, blood sodium decreased, blood sodium increased, blood calcium decreased, blood

calcium increased, blood chloride decreased, blood glucose increased, blood magnesium decreased, blood phosphorus decreased, blood phosphorus increased, blood urea increased, activated partial thromboplastin time prolonged, blood bicarbonate decreased, blood chloride increased, blood potassium increased, blood pressure increased, blood uric acid decreased, blood urine present, breath sounds abnormal, carbon dioxide decreased, immunosuppressant drug level increased, International Normalized Ratio increased, urinary casts, white blood cells urine positive, and pH urine increased.

 

Caspofungin has also been evaluated at 150 mg daily (for up to 51 days) in 100 adult patients. The study compared caspofungin at 50 mg daily (following a 70 mg loading dose on Day 1) versus 150 mg daily in the treatment of invasive candidiasis. In this group of patients, the safety of caspofungin at this higher dose appeared generally similar to patients receiving the 50 mg daily dose of caspofungin. The proportion of patients with a serious drug-related adverse reaction or a drug-related adverse reaction leading to caspofungin discontinuation was comparable in the two treatment groups.

Overall Safety Experience of Caspofungin in Clinical Trials

The overall safety of caspofungin was assessed in 2,036 individuals (including 1,642 adult or pediatric patients and 394 volunteers) from 34 clinical studies. Additional adverse reaction which occurred in 5% or greater of all individuals who received caspofungin in these trials was pneumonia.

Additional clinically significant adverse reactions, regardless of causality or incidence which occurred in <5% of patients were as follows: febrile neutropenia, bradycardia, cardiac arrest, myocardial infarction, asthenia, mucosal inflammation, hepatic failure, bacteremia, sepsis, urinary tract infection, anorexia, decreased appetite, hypercalcemia, convulsion, confusional state, depression, hematuria, epistaxis, and petechiae.

Postmarketing Experience

The following additional adverse reactions have been identified during the post-approval use of caspofungin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: pancreatitis, hepatic necrosis, skin exfoliation, and clinically significant renal dysfunction.

Pediatric Patients

Data from 5 clinical studies completed in 171 pediatric patients suggest that the overall incidence of clinical adverse experiences (26.3%; 95% CI: –19.9, 33.6) is not worse than reported for adults treated with caspofungin (43.1%; 95% CI: –40.0, 46.2). However, pediatric patients probably have a different adverse event profile compared with adult patients. The most common drug-related clinical adverse experiences reported in pediatric patients treated with caspofungin were pyrexia (11.7%), rash (4.7%), and headache (2.9%).

Tabulated List of Adverse Reactions

The following adverse reactions were reported:

Table 2: Adverse Reactions in Pediatric Patients

System Organ Class

Very Common (≥1/10)

Common (≥1/100 to <1/10)

 

 

Blood and lymphatic system

disorders

 

eosinophil count increased

 

 

 

Nervous system disorders

 

headache

 

Cardiac disorders

 

tachycardia

 

Vascular disorders

 

flushing, hypotension

 

Hepatobiliary disorders

 

elevated liver enzyme levels (AST, ALT)

 

Skin and subcutaneous tissue

disorders

 

rash, pruritus

 

General disorders and

administration site conditions

fever

chills, catheter-site pain

 

Investigations

 

decreased potassium, hypomagnesemia, increased glucose,

decreased phosphorus, and increased phosphorus

 

Other Adverse Reactions

Other adverse reactions observed among pediatric patients (0 months to 17 years of age) with incidence of 7.5% or greater for at least one treatment group (caspofungin any dose; N=115 and caspofungin 70 mg/m2 on Day 1, then 50 mg/m2 once daily; N=56) were as follows: blood potassium increased, mucosal inflammation, edema, diarrhea, vomiting, abdominal pain, nausea, central line infection, erythema, hypertension, hypokalemia, back pain, and anemia.

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@Cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable.

In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on Day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported.

Inadvertent administration of up to 400 mg of caspofungin in one day has been reported. These occurrences did not result in clinically important adverse reactions.

Pharmacological Properties

Mechanism of Action

Caspofungin acetate is a semi-synthetic lipopeptide (echinocandin) antifungal compound synthesized from a fermentation product of Glarea lozoyensis. Caspofungin acetate inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. Beta (1,3)-D-glucan is not present in mammalian cells.

Fungicidal activity with caspofungin has been demonstrated against Candida yeasts. In vitro and in vivo studies have demonstrated that exposure of Aspergillus to caspofungin results in lysis and death of hyphal apical tips and branch points where cell growth and division occur.

Pharmacodynamic Properties

Antimicrobial Activity

Caspofungin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

Aspergillus flavus

Aspergillus fumigatus

Aspergillus terreus

Candida albicans

Candida glabrata

Candida guilliermondii

Candida krusei

Candida parapsilosis

Candida tropicalis

Caspofungin has in vitro activity against Aspergillus niger, Aspergillus nidulans and Aspergillus candidus.

Caspofungin also has in vitro activity against Candida dubliniensis, Candida kefyr, Candida lipolytica, Candida lusitaniae and Candida rugosa, including isolates with multiple-resistance transport mutations and those with acquired or intrinsic resistance to fluconazole, amphotericin B, and 5-flucytosine.

Resistance

There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistant Candida or Aspergillus species. Some of these reports have identified specific mutations in the Fks subunits, encoded by the fks1 and/or fks2 genes, of the glucan synthase enzyme. These mutations are associated with higher minimum inhibitory concentrations (MICs) and breakthrough infection. Candida species that exhibit reduced susceptibility to caspofungin as a result of an increase in the chitin content of the fungal cell wall have also been identified, although the significance of this phenomenon in vivo is not well known.

Development of in vitro resistance to caspofungin by Aspergillus species has been identified. In limited clinical experience, resistance to caspofungin in patients with invasive aspergillosis has been observed. The mechanism of resistance has not been established. The incidence of resistance to caspofungin by various clinical isolates of Aspergillus is rare. Caspofungin resistance in Candida has been observed but the incidence may differ by species or region.

Interaction with Other Antimicrobials

In vitro and in vivo studies of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either Aspergillus fumigatus or Candida albicans. The clinical significance of these results is unknown.

Pharmacokinetic Properties

Adult and pediatric pharmacokinetic parameters are presented in Table 3.

Distribution

Caspofungin is extensively bound to albumin. The unbound fraction of caspofungin in plasma varies from 3.5% in healthy volunteers to 7.6% in patients with invasive candidiasis.

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour I.V. infusions. A short alfa- phase occurs immediately post-infusion, followed by a beta-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours post-dose during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, gamma-phase, (half-life of 40 to 50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed into the tissues by 36 to 48 hours after a single 70 mg dose of caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration.

It is likely that only a small fraction of the caspofungin taken up into the tissues later returns to plasma as parent compound. Therefore, elimination occurs in the absence of distribution equilibrium, and a true estimate of the volume of distribution of caspofungin is currently impossible to obtain.

Metabolism

Caspofungin undergoes spontaneous degradation to an open ring compound. Further metabolism involves peptide hydrolysis and N-acetylation. Two intermediate products, formed during the degradation of caspofungin to this open ring compound, form covalent adducts to plasma proteins, resulting in a low-level, irreversible binding to plasma proteins.

Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (≥5 days post-dose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.

In vitro studies show that caspofungin is not an inhibitor of CYP450 enzymes 1A2, 2A6, 2C9, 2C19, 2D6 or 3A4. In clinical studies, caspofungin did not induce or inhibit the CYP3A4 metabolism of other medicinal products. Caspofungin is not a substrate for P-gp and is a poor substrate for CYP450 enzymes.

Elimination

The elimination of caspofungin from plasma is slow, with a clearance of 10 to 12 mL/min. Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour I.V. infusions. A short alfa-phase occurs immediately post-infusion, followed by a beta-phase with a half-life of 9 to 11 hours. An additional gamma-phase also occurs with a half-life of 45 hours. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance.

Approximately 75% of a radioactive dose was recovered during 27 days: 41% in urine and 34% in faeces. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Excretion is slow and the terminal half-life of radioactivity was 12 to 15 days. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4% of dose).

Caspofungin displays moderate non-linear pharmacokinetics with increased accumulation as the dose is increased, and a dose dependency in the time to reach steady state upon multiple-dose administration.

Renal clearance of parent drug is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min.

Special Populations

Increased caspofungin exposure was seen in adult patients with renal impairment and mild liver impairment, in female subjects, and in the elderly. Generally, the increase was modest and not large enough to warrant dosage adjustment. In adult patients with moderate liver impairment or in higher-weight patients, a dosage adjustment may be necessary (see below).

Patients with Renal Impairment

In a clinical study of single 70 mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end–stage renal impairment (creatinine clearance less than 10 mL/min and dialysis-dependent) moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% of the AUC). However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of caspofungin acetate for injection 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis.

Patients with Hepatic Impairment

Plasma concentrations of caspofungin after a single 70 mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were increased by approximately 55% in the AUC compared with healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in adult patients with mild hepatic impairment were increased modestly (19 to 25% in the AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic impairment.

Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70 mg dose of caspofungin had an average plasma caspofungin increase of 76% in the AUC compared with control subjects. A dosage reduction is recommended for adult patients with moderate hepatic impairment based upon these pharmacokinetic data.

There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) or in pediatric patients with any degree of hepatic impairment.

Gender

Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70 mg dose. After thirteen 50 mg doses daily, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in the AUC) relative to men. No dosage adjustment is necessary based on gender.

Race

Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, Hispanics and Mestizos. No dosage adjustment is necessary on the basis of race.

Weight

Weight was found to influence caspofungin pharmacokinetics in the population pharmacokinetic analysis in adult candidiasis patients. The plasma concentrations decrease with increasing weight. The average exposure in an adult patient weighing 80 kg was predicted to be about 23% lower than in an adult patient weighing 60 kg.

Geriatric Patients

Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% in the AUC) compared with young healthy men after a single 70 mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly.

Pediatric Patients

Caspofungin acetate has been studied in 5 prospective studies involving pediatric patients below 18 years of age, including 3 pediatric pharmacokinetic studies .

Pharmacokinetic parameters following multiple doses of caspofungin acetate in pediatric and adult patients are presented in Table 3.

Table 3: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin Acetate in Pediatric (3 months to 17 years of age) and Adult Patients

Population

N

Daily

Dose

AUC0-24hr

(μg·hr/mL)

C1hr

(μg/mL)

C24hr

(μg/mL)

t1/2

(hr)*

CI

(mL/min)

Pediatric Patients

 

 

 

 

 

Adolescents,

8

50

124.9 ± 50.4

14.0 ± 6.9

2.4 ± 1.0

11.2 ± 1.7

12.6 ± 5.5

12 to17

 

mg/m2

 

 

 

 

 

years of age

 

 

 

 

 

 

 

Children,

9

50

120.0 ± 33.4

 

 

8.2 ± 2.4

6.4 ± 2.6

2 to 11 years of age

 

mg/m2

 

16.1 ± 4.2

1.7 ± 0.8

 

 

 

8

50

131.2 ± 17.7

 

 

8.8 ± 2.1

3.2 ± 0.4

Young children, 3 to 23

 

mg/m2

 

17.6 ± 3.9

1.7 ± 0.7

 

 

Months of age

 

 

 

 

 

 

 

Adult Patients

 

 

 

 

 

 

Adults with

6

50 mg

87.3 ± 30.0

8.7 ± 2.1

1.7 ± 0.7

13.0 ± 1.9

10.6 ± 3.8

esophageal candidiasis

 

 

 

 

 

 

 

Adults receiving

empirical

therapy

119

50 mg§

--

8.0 ± 3.4

1.6 ± 0.7

--

--

* Harmonic mean ± jackknife standard deviation
  • N=5 for C1hr and AUC0-24hr; N=6 for C24hr

N=117 for C24hr; N=119 for C1hr

§ Following an initial 70 mg loading dose on Day 1

Non-Clinical Properties

Animal Toxicology or Pharmacology

In one 5-week study in monkeys at doses that produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70 mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2 out of 8 monkeys at 5 mg/kg, and 4 out of 8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks’ duration at similar doses.

No treatment-related findings were seen in a 5-week study in infant monkeys at doses that produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m2 daily.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin.

Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at I.V. doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on BSA comparisons).

Fertility and reproductive performance were not affected by the I.V. administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg, exposures were similar to those seen in patients treated with the 70 mg dose.

Description

Caspofungin acetate is chemically 1--N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-pneumocandinB0diacetate (salt). The empirical formula is C52H88N10O15•2C2H4O2 and the formula weight is 1,213.42.

Pharmaceutical Particulars

Incompatibilities

Do not mix with diluents containing glucose as caspofungin acetate is not stable in such diluents. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf-Life

As on the pack.

Packaging Information

CASPOGIN I.V. 50 mg: White to off-white compact lyophilized cake and or powder filled in a 10 mL tubular glass vial USP Type I, with a gray bromobutyl rubber stopper.

CASPOGIN I.V. 70 mg: White to off-white compact lyophilized cake and or powder filled in a 10 mL tubular glass vial USP Type I, with a gray bromobutyl rubber stopper.

Storage and Handling Instructions

Keep out of the reach of children.

Before Opening

Store at 2°C-8°C.

Reconstituted Solution

It is recommended that the reconstituted solution be used immediately. However, the reconstituted solution may be stored at ≤25°C (≤77°F) for 24 hours prior to the preparation of the infusion solution for the patient.

Diluted Solution

It is recommended to use the reconstituted solution immediately; however, the final infusion solution for the patient in the I.V. bag or bottle can be stored at <25°C (<77°F) for up to 24 hours, or up to 48 hours when refrigerated at 2° to 8°C (36° to 46°F).

Patient Counselling Information

1. What CASPOGIN I.V. (caspofungin acetate for intravenous injection) is and what it is used for

CASPOGIN I.V. contains a medicine called caspofungin acetate, which belongs to a group of medicines called antifungals.

Caspofungin acetate is used to treat the following infections in children, adolescents and adults:

Serious fungal infections in the tissues or organs (called ‘invasive candidiasis’). This infection is caused by fungal (yeast) cells called Candida. People who might get this type of infection include those who have just had an operation or those whose immune systems are weak. Fever and chills that do not respond to an antibiotic are the most common signs of this type of infection.

Fungal infections in the nose, nasal sinuses or lungs (called ‘invasive aspergillosis’) if other antifungal treatments have not worked or have caused side effects. This infection is caused by a mold called Aspergillus. People who might get this type of infection include those having chemotherapy, those who have had a transplant and those whose immune systems are weak.

Suspected fungal infections in case of a fever and a low white cell count that has not improved on treatment with an antibiotic. People who are at risk of getting a fungal infection include those who have just had an operation or those whose immune systems are weak.

2. How CASPOGIN I.V. works

CASPOGIN I.V. makes fungal cells fragile and stops the fungus from growing properly. This stops the infection from spreading and gives the body’s natural defenses a chance to completely get rid of the infection.

3. What you need to know before you are given CASPOGIN I.V.

Do not use CASPOGIN I.V.

if you are allergic to caspofungin or any of the other ingredients of this medicine.

If you are not sure, talk to your doctor, nurse or pharmacist before you are given your medicine.

Warnings and precautions

Talk to your doctor, nurse or pharmacist before you are given CASPOGIN I.V. if:

• you are allergic to any other medicines;

• you have ever had liver problems—you might need a different dose of this medicine;

• you are already taking cyclosporin (used to help prevent organ transplant rejection or to suppress your immune system)— your doctor may need to run extra blood tests during your treatment; and,

• if you have ever had any other medical problem.

If any of the above applies to you (or you are not sure), talk to your doctor, nurse or pharmacist before you are given CASPOGIN I.V.

CASPOGIN I.V. may also cause serious cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Other medicines and CASPOGIN I.V.

Please tell your doctor, nurse or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because CASPOGIN I.V. can affect the way some other medicines work. Also, some other medicines can affect the way CASPOGIN I.V. works.

Tell your doctor, nurse or pharmacist if you are taking any of the following medicines:

• Cyclosporin or tacrolimus (used to help prevent organ transplant rejection or to suppress your immune system) as your doctor may need to run extra blood tests during your treatment

• Some HIV medicines such as efavirenz or nevirapine

• Phenytoin or carbamazepine (used for the treatment of seizures)

• Dexamethasone (a steroid used for the treatment of inflammations)

• Rifampicin (an antibiotic).

If any of the above apply to you (or you are not sure), talk to your doctor, nurse or pharmacist before you are given CASPOGIN I.V.

Pregnancy and breastfeeding

Ask your doctor for advice before taking any medicine, if you are pregnant or breastfeeding or think you are pregnant.

CASPOGIN I.V. has not been studied in pregnant women. It should be used in pregnancy only if the potential benefit justifies the potential risk to the unborn baby.

• Women taking CASPOGIN I.V. should not breastfeed.

Driving and using machines

There is no information to suggest that CASPOGIN I.V. affects your ability to drive or operate machinery.

4. How to use CASPOGIN I.V.

CASPOGIN I.V. will always be prepared and given to you by a healthcare professional.

You will be given CASPOGIN I.V. in the following manner:

• Once each day

• By I.V. infusion (slow injection into a vein) for about 1 hour

Your doctor will determine the duration of your treatment and how much CASPOGIN I.V. you will be given each day. Your doctor will monitor how well the medicine works for you. If you weigh more than 80 kg, you may need a different dose.

Children and adolescents

The dose for children and adolescents may differ from the adult dose.

If you have been given more CASPOGIN I.V. than you should

Your doctor will decide how much CASPOGIN I.V. you need and for how long each day. If you are worried that you may have been given too much CASPOGIN I.V., tell your doctor or nurse straight away.

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist.

5. Possible side effects of CASPOGIN I.V.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or nurse straight away if you notice any of the following side effects—you may need urgent medical treatment:

• Rash, itching, feeling warm, swelling of your face, lips or throat or difficulty breathing—you may be having a histamine reaction to the medicine.

• Difficulty breathing with wheezing or a rash that gets worse—you may be having an allergic reaction to the medicine.

• Cough, serious breathing difficulties—if you are an adult and have invasive aspergillosis, you may be experiencing a serious respiratory problem that could result in respiratory failure.

• rash, skin peeling, mucous membrane sores, hives, large areas of peeling skin.

As with any prescription medicine, some side effects may be serious. Ask your doctor for more information.

Other side effects in adults include the following:

Common (may affect up to 1 in 10 people)

• Decreased hemoglobin (decreased oxygen carrying substance in the blood), decreased white blood cells

• Decreased blood albumin (a type of protein) in your blood, decreased potassium or low potassium levels in the blood

• Headache

• Inflammation of the vein

• Shortness of breath

• Diarrhea, nausea or vomiting

• Changes in some laboratory blood tests (including increased values of some liver tests)

• Itching, rash, skin redness or sweating more than usual

• Joint pain

• Chills, fever

• Itching at the injection site.

Uncommon (may affect up to 1 in 100 people)

• Changes in some laboratory blood tests (including disease of blood clotting, platelets, red blood cells and white blood cells)

• Loss of appetite, increase in amount of body fluid, imbalance of salt in the body, high sugar level in the blood, low calcium level in the blood, increase calcium level in the blood, low magnesium level in the blood, increase in acid level in the blood

• Disorientation, feeling nervous, being unable to sleep

• Feeling dizzy, decreased feeling or sensitivity (especially in the skin), shaking, feeling sleepy, change in the way things taste, tingling or numbness

• Blurred vision, increase in tears, swollen eyelids, yellowing of the whites of the eyes

• Sensation of fast or irregular heartbeats, rapid heartbeat, irregular heartbeat, abnormal heart rhythm, heart failure

• Flushing, hot flush, high blood pressure, low blood pressure, redness along a vein that is extremely tender when touched

• Tightening of the bands of muscle around the airways resulting in wheezing or coughing, fast breathing rate, shortness of breath that wakes you up, shortage of oxygen in the blood, abnormal breath sounds, crackling sounds in the lungs, wheezing, nasal congestion, cough, throat pain

• Belly pain, upper belly pain, bloating, constipation, difficulty swallowing, dry mouth, indigestion, passing gas, stomach discomfort, swelling due to build-up of fluid around the belly

• Decreased flow of bile, enlarged liver, yellowing of the skin and/or whites of the eyes, liver injury caused by a drug or chemical, liver disorder

• Abnormal skin tissue, generalized itching, hives, rash of varying appearance, abnormal skin, red often itchy spots on the arms and legs and sometimes on the face and the rest of the body

• Back pain, pain in an arm or leg, bone pain, muscle pain, muscle weakness

• Loss of kidney function, sudden loss of kidney function

• Catheter-site pain, injection-site complaints (redness, hard lump, pain, swelling, irritation, rash, hives, leaking of fluid from the catheter into the tissue), inflammation of vein at injection site

• Increased blood pressure and alterations in some laboratory blood tests (including kidney electrolyte and clotting tests), increased levels of the medicines you are taking that weaken the immune system

• Chest discomfort, chest pain, feeling of body temperature change, generally feeling unwell, general pain, swelling of the face, swelling of the ankles, hands or feet, swelling, tenderness, feeling tired.

Side effects in children and adolescents

Very common (may affect more than 1 in 10 people)

• Fever

Common (may affect up to 1 in 10 people)

• Headache

• Fast heartbeat

• Flushing, low blood pressure

• Changes in some laboratory blood tests (increased values of some liver tests)

• Itching, rash

• Catheter-site pain

• Chills

• Changes in some laboratory blood tests

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

6. How to store CASPOGIN I.V.

Keep out of the reach of children.

Shelf-Life: Please see the manufacturing date and expiry date printed on the pack.

Store at 2°C-8°C.

7. Contents of the pack and other information

The active substance in CASPOGIN I.V. is caspofungin acetate.

Packaging Information

CASPOGIN I.V. 50 mg: White to off-white compact lyophilized cake and or powder filled in a 10 mL tubular glass vial.

CASPOGIN I.V. 70 mg: White to off-white compact lyophilized cake and or powder filled in a 10 mL tubular glass vial.

Details of The Manufacturer

Mfd. by: Gufic Biosciences Limited,

N.H. No. 8, Near Grid, Kabilpore – 396 424,

Navsari, Gujarat (INDIA).

Marketed by CIPLA LTD.

Registered Office:

Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg,

Lower Parel, Mumbai – 400 013, INDIA

Details of Permission or License Number with Date

G/28/64 dated 01/01/2017            

Date of Revision

18/10/2021