Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

CASPOFUNGIN ACETATE (NDA-206110)

(CASPOFUNGIN ACETATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/01/2021 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Caspofungin acetate for Injection is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions (6)].

5 Warnings and Precautions

5.1 Hypersensitivity

(Additions and/or revisions underlined)

Anaphylaxis and other hypersensitivity reactions have been reported during administration of caspofungin acetate for injection. 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 for injection [see Adverse Reactions (6.2)].

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

5.2 Hepatic Effects

(Additions and/or revisions underlined)

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

5.3 Elevated Liver Enzymes During Concomitant Use with Cyclosporine

(Additions and/or revisions underlined)

Elevated liver enzymes have occurred in patients receiving caspofungin acetate for injection and cyclosporine concomitantly. Only use Caspofungin acetate for Injection 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following additional adverse reactions have been identified during the post-approval use of caspofungin acetate for injection. 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.

Gastrointestinal disorders: pancreatitis

Hepatobiliary disorders: hepatic necrosis

Skin and subcutaneous tissue disorders: erythema multiforme, toxic epidermal necrolysis, Stevens- Johnson syndrome, and skin exfoliation

Renal and urinary disorders: clinically significant renal dysfunction

General disorders and administration site conditions: swelling and peripheral edema

Laboratory abnormalities: gamma-glutamyltransferase increased

7 Drug Interactions

(Additions and/or revisions underlined)

Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin acetate for injection. Caspofungin acetate for injection did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin acetate for injection and cyclosporine were co-administered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Tacrolimus: For patients receiving Caspofungin acetate for Injection and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Inducers of Hepatic CYP Enzymes

Rifampin: Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin acetate for injection is expected to reduce the plasma concentrations of caspofungin acetate for injection. 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) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Other Inducers of Hepatic CYP Enzymes

Adults: When Caspofungin acetate for Injection 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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Pediatric Patients: 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, 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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on animal data, Caspofungin acetate for Injection may cause fetal harm (see Data). 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 acetate for Injection use in pregnant women.

In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri- implantation loss, and incomplete ossification at multiple fetal sites when administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.8 and 2 times the clinical dose, respectively (see Data). 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In animal reproduction studies, pregnant rats dosed intravenously with caspofungin during organogenesis (gestational days [GD] 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 incidences 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 intravenous 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 peri- and postnatal development study in rats, intravenous caspofungin administered at 0.5, 2 or 5 mg/kg/day from Day 6 of gestation through Day 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.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of caspofungin in human milk, the effects on the breast-fed 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 acetate for Injection and any potential adverse effects on the breastfed child from Caspofungin acetate for Injection or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of caspofungin acetate for injection 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 [see Indications and Usage (1)]:

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 (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole).

The efficacy and safety of caspofungin acetate for injection has not been adequately studied in prospective clinical trials involving neonates and infants under 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 CNS and multi-organ involvement than in older patients; the ability of caspofungin acetate for injection to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown.

Caspofungin acetate for injection has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. Caspofungin acetate for injection 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 intravenous caspofungin acetate for injection. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin acetate for injection in safety and efficacy studies [see Clinical Pharmacology (12.3) and Clinical Studies (14.5)]. The majority of the pediatric patients received caspofungin acetate for injection 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 for injection were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%) [see Adverse Reactions (6.2)].

Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions [see Warnings and Precautions (5.3)].

8.5 Geriatric Use

(Additions and/or revisions underlined)

Clinical studies of caspofungin acetate for injection did not include sufficient numbers of patients aged 65 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 AUC) compared to 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.

8.6 Patients with Hepatic Impairment

(Additions and/or revisions underlined)

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 acetate for Injection 35 mg once daily is recommended based upon pharmacokinetic data [see Clinical Pharmacology (12.3)].

However, where recommended, a 70 mg loading dose should still be administered on Day 1 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Hypersensitivity

Inform patients that anaphylactic reactions have been reported during administration of caspofungin acetate for injection. Caspofungin acetate for Injection can cause hypersensitivity reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm. Inform patients to report these signs or symptoms to their healthcare providers.

Hepatic Effects

Inform patients that there have been isolated reports of serious hepatic effects from caspofungin acetate for injection therapy.

Use in Pregnancy and Breastfeeding Mothers

Advise female patients of the potential risks to a fetus. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant.

06/28/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity

(additions underlined)

…

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported after postmarketing use of caspofungin acetate. Caution should apply in patients with history of allergic skin reactions.