Prescription Drug Information: FIRVANQ (Page 2 of 4)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of vancomycin hydrochloride. 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.

Ototoxicity: Cases of hearing loss associated with intravenously administered vancomycin have been reported. Most of these patients had kidney dysfunction or a preexisting hearing loss or were receiving concomitant treatment with an ototoxic drug [ see Warnings a nd Precautions ( 5.4) ]. Vertigo, dizziness, and tinnitus have been reported.

Hematopoietic: Reversible neutropenia, usually starting 1 week or more after onset of intravenous therapy with vancomycin or after a total dose of more than 25 g, has been reported. Neutropenia appears to be promptly reversible when vancomycin is discontinued. Thrombocytopenia has been reported.

Miscellaneous: Anaphylaxis, drug fever, chills, nausea, eosinophilia, rashes (including exfoliative dermatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis, and vasculitis have been reported with the administration of vancomycin.

A condition has been reported with oral vancomycin that is similar to the IV–induced syndrome with symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (“Red Man Syndrome”), pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours.

7 DRUG INTERACTIONS

No drug interaction studies have been conducted using orally administered vancomycin hydrochloride products.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on FIRVANQ use in pregnant women to inform a drug associated risk of major birth defects or miscarriage. Available published data on vancomycin use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes ( see Data). Vancomycin did not show adverse developmental effects when administered intravenously to pregnant rats and rabbits during organogenesis at doses less than or equal to the recommended maximum human dose based on body surface area (see Data).

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

Human Data

A published study evaluated hearing loss and nephrotoxicity in infants of pregnant intravenous drug users treated with vancomycin for suspected or documented methicillin-resistant S. aureus in the second or third trimester. The comparison groups were 10 non-intravenous drug-dependent patients who received no treatment, and 10 untreated intravenous drug-dependent patients served as substance abuse controls. No infant in the vancomycin exposed group had abnormal sensorineural hearing at 3 months of age or nephrotoxicity.

A published prospective study assessed outcomes in 55 pregnant women with a positive Group B S treptococcus culture and a high-risk penicillin allergy with resistance to clindamycin or unknown sensitivity who were administered vancomycin at the time of delivery. Vancomycin dosing ranged from the standard 1 g intravenously every 12 hours to 20 mg/kg intravenous every 8 hours (maximum individual dose 2 g). No major adverse reactions were recorded either in the mothers or their newborns. None of the newborns had sensorineural hearing loss. Neonatal renal function was not examined, but all of the newborns were discharged in good condition.

Animal Data

Vancomycin did not cause fetal malformations when administered during organogenesis to pregnant rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18) at the equivalent recommended maximum human dose (based on body surface area comparisons) of 200 mg/kg/day IV to rats or 120 mg/kg/day IV to rabbits. No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg/kg/day (approximately 1 and 0.8 times the recommended maximum human dose based on body surface area, respectively). Maternal toxicity was observed in rats (at doses 120 mg/kg and above) and rabbits (at 80 mg/kg and above).

8.2 Lactation

Risk Summary

There are insufficient data to inform the levels of vancomycin in human milk. However, systemic absorption of vancomycin following oral administration is expected to be minimal [see Clinical Pharmacology ( 12.3)]. There are no data on the effects of FIRVANQ on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FIRVANQ and any potential adverse effects on the breastfed infant from Firvanq or from the underlying maternal condition.

8.4 Pediatric Use

FIRVANQ is indicated in pediatric patients less than 18 years of age for the treatment of C. difficile -associated diarrhea and enterocolitis caused by S. aureus (including methicillin-resistant strains) [ see Indications and Usage ( 1) and Dosage and Administration ( 2.3) ].

8.5 Geriatric Use

In clinical trials, 54% of vancomycin hydrochloride-treated subjects were > 65 years of age. Of these, 40% were between the ages of > 65 and 75, and 60% were > 75 years of age.

Clinical studies with vancomycin hydrochloride in C . difficile -associated diarrhea have demonstrated that geriatric subjects are at increased risk of developing nephrotoxicity following treatment with oral vancomycin hydrochloride, which may occur during or after completion of therapy. In patients over 65 years of age, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin hydrochloride to detect potential vancomycin induced nephrotoxicity [ see Warnings a nd Precautions ( 5.3) , Adverse Reactions ( 6.1) and Clinical Studies ( 14.1) ].

Patients over 65 years of age may take longer to respond to therapy compared to patients 65 years of age and younger [ see Clinical Studies ( 14.1) ]. Clinicians should be aware of the importance of appropriate duration of vancomycin hydrochloride treatment in patients over 65 years of age and not discontinue or switch to alternative treatment prematurely.

10 OVERDOSAGE

Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance.

For current information on the management of overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

11 DESCRIPTION

FIRVANQ for oral administration contains the hydrochloride salt of vancomycin, a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis), which has the chemical formula C 66 H 75 Cl 2 N 9 O 24 •HCl. The molecular weight of vancomycin hydrochloride is 1485.71 g/mol.

Vancomycin hydrochloride has the structural formula:

The structural formula for vancomycin, a tricyclic glycopeptide antibiotic derived from Amycolatopsis orientalis (formerly Nocardia orientalis), which has the chemical formula C66H75Cl2N9O24•HCl. Th
(click image for full-size original)

Each FIRVANQ kit contains a bottle of vancomycin hydrochloride USP, as white to almost white or tan to brown powder for oral solution, and a bottle of pre-measured Grape-Flavored Diluent, in the strengths and volumes listed in Table 3.

Table 3: Vancomycin Strength, Diluent Volume and Vancomycin Concentration after Reconstitution
Vancomycin S trength per B ottle Equivalent A mount of V ancomycin H ydrochloride per B ottle Diluent for FIRVANQ Vancomycin Concentration after Reconstitution
3.75 g3.8 g147 mL25 mg/mL
7.5 g7.7 g295 mL
7.5 g7.7 g145 mL50 mg/mL
15 g15.4 g289 mL

The Grape-Flavored Diluent used to reconstitute the oral solution contains: artificial grape flavor, citric acid (anhydrous), D&C Yellow No. 10, FD&C Red No. 40, purified water, sodium benzoate and sucralose.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Vancomycin is an antibacterial drug [ see Microbiology ( 12.4) ].

12.3 Pharmacokinetics

Vancomycin is poorly absorbed after oral administration. During multiple dosing of vancomycin hydrochloride capsules at 250 mg every 8 hours for 7 doses, fecal concentrations of vancomycin in volunteers exceeded 100 mcg/g in the majority of samples. No blood concentrations were detected and urinary recovery did not exceed 0.76%. In anephric subjects with no inflammatory bowel disease who received vancomycin oral solution 2 g for 16 days, blood concentrations of vancomycin were ≤ 0.66 mcg/mL in 2 of 5 subjects. No measurable blood concentrations were attained in the other 3 subjects. Following doses of 2 g daily, concentrations of drug were > 3100 mcg/g in the feces and < 1 mcg/mL in the serum of subjects with normal renal function who had C. difficile -associated diarrhea. After multiple-dose oral administration of vancomycin, measurable serum concentrations may occur in patients with active C. difficile -associated diarrhea, and, in the presence of renal impairment, the possibility of accumulation exists. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly [s ee Use i n Specific Populations ( 8.5) ].

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