FIRVANQ: Package Insert and Label Information

FIRVANQ- vancomycin hydrochloride
Azurity Pharmaceuticals, Inc

1 INDICATIONS AND USAGE

FIRVANQ is indicated for the treatment of Clostridium difficil e‑associated diarrhea in adults and pediatric patients less than 18 years of age.

FIRVANQ is also indicated for the treatment of enterocolitis caused by Staphylococcus aureus (including methicillin‑resistant strains) in adults and pediatric patients less than 18 years of age.

Important Limitations of Use

Parenteral administration of vancomycin is not effective for the above infections; therefore, vancomycin must be given orally for these infections.
Orally administered vancomycin hydrochloride is not effective for treatment of other types of infections.

To reduce the development of drug‑resistant bacteria and maintain the effectiveness of FIRVANQ and other antibacterial drugs, FIRVANQ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Prior to oral administration, the supplied FIRVANQ powder must be reconstituted by the healthcare provider (i.e., a pharmacist) to produce the oral solution [see Dosage and Administration (2.4) ].

2.2 Adults

C. difficile ‑associated diarrhea: The recommended dose is 125 mg administered orally 4 times daily for 10 days.
Staphylococcal enterocolitis: Total daily dosage is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 to 10 days.

2.3 Pediatric Patients (less than 18 years of age)

For both C. difficile ‑associated diarrhea and staphylococcal enterocolitis, the usual daily dosage of FIRVANQ is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g.

2.4 Preparation and Storage of Solutions of FIRVANQ

Each FIRVANQ kit contains 1 bottle of vancomycin hydrochloride USP powder and 1 bottle of pre‑measured Grape‑Flavored Diluent to be added to the vancomycin bottle. A healthcare provider (i.e., a pharmacist) must reconstitute vancomycin hydrochloride USP powder with the Grape‑Flavored Diluent provided in the kit. FIRVANQ is available in various strengths and volumes in the kit as shown in Table 1.

Table 1: Vancomycin Concentration and Volume after Reconstitution
Vancomycin Concentration after Reconstitution Final Volume of FIRVANQ after Reconstitution Vancomycin Strength per Bottle Diluent for FIRVANQ

25 mg/mL

150 mL

3.75 g

147 mL

300 mL

7.5 g

295 mL

50 mg/mL

150 mL

7.5 g

145 mL

300 mL

15.0 g

289 mL

Steps for the Preparation of Solutions of FIRVANQ

1.
Hold the neck of the bottle containing the vancomycin hydrochloride USP powder for oral solution (see Table 1), and tap the bottom edges on a hard surface to loosen the powder.
2.
Remove the cap from the vancomycin hydrochloride USP powder for oral solution bottle (“Powder Bottle”).
3.
Tap the top of the induction seal liner to loosen any powder that may have adhered to the liner.
4.
Carefully and slowly peel back the inner foil seal liner from the bottle.
5.
Shake the Grape‑Flavored Diluent (see Table 1) for a few seconds.
6.
Remove the cap from the diluent bottle.
7.
Carefully and slowly peel back the inner foil seal from the diluent bottle.
8.
Transfer approximately one-half the contents of Grape-Flavored Diluent into the Powder Bottle.
9.
Replace the Powder Bottle cap, tighten onto the Powder Bottle, and shake the Powder Bottle vertically for approximately 45 seconds. NOTE: DO NOT use the diluent cap on the Powder Bottle as it may cause the solution to leak from the bottle.
10.
Re-open the Powder Bottle and add the remaining Grape‑Flavored Diluent into the Powder Bottle.
11.
Replace the Powder Bottle cap, tighten onto the Powder Bottle, and shake the Powder Bottle for approximately 30 seconds. NOTE: DO NOT use the diluent cap on the Powder Bottle as it may cause the solution to leak from the bottle.
12.
Dispense the Powder Bottle containing reconstituted solution of FIRVANQ oral solution to the patient [see Patient Counseling Information (17) ].
13.
Instruct the patient to shake the reconstituted solution of FIRVANQ well before each use and to use an oral dosing device that measures the appropriate volume of the oral solution in milliliters.
14.
Store the reconstituted solution of FIRVANQ at refrigerated conditions, 2°C to 8°C (36°F to 46°F) when not in use.
15.
Discard the reconstituted solution of FIRVANQ after 14 days, or if it appears hazy or contains particulates.

3 DOSAGE FORMS AND STRENGTHS

Each FIRVANQ kit contains vancomycin hydrochloride USP as white to almost white or tan to brown powder for oral solution, equivalent to 3.75 g, 7.5 g or 15.0 g vancomycin, and Grape‑Flavored Diluent for reconstitution.

4 CONTRAINDICATIONS

FIRVANQ is contraindicated in patients with known hypersensitivity to vancomycin.

5 WARNINGS AND PRECAUTIONS

5.1 Oral Use Only

FIRVANQ must be given orally for treatment of C. difficile ‑associated diarrhea and staphylococcal enterocolitis. Orally administered vancomycin is not effective for treatment of other types of infections.

Parenteral administration of vancomycin is not effective for treatment of C. difficile ‑associated diarrhea and staphylococcal enterocolitis. If parenteral vancomycin therapy is desired, use an intravenous preparation of vancomycin and consult the Full Prescribing Information accompanying that preparation.

5.2 Potential for Systemic Absorption

Significant systemic absorption has been reported in some patients (e.g., patients with renal insufficiency and/or colitis) who have taken multiple oral doses of vancomycin hydrochloride for C. difficile ‑associated diarrhea. In these patients, serum vancomycin concentrations reached therapeutic levels for the treatment of systemic infections. Some patients with inflammatory disorders of the intestinal mucosa also may have significant systemic absorption of vancomycin. These patients may be at risk for the development of adverse reactions associated with higher doses of FIRVANQ; therefore, monitoring of serum concentrations of vancomycin may be appropriate in some instances, e.g., in patients with renal insufficiency and/or colitis or in those receiving concomitant therapy with an aminoglycoside antibacterial drug.

5.3 Nephrotoxicity

Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) has occurred following oral vancomycin hydrochloride therapy in randomized controlled clinical trials and can occur either during or after completion of therapy. The risk of nephrotoxicity is increased in patients over 65 years of age [see Adverse Reactions (6.1) and Use in Specific Populations (8.5)].

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 FIRVANQ to detect potential vancomycin- induced nephrotoxicity.

5.4 Ototoxicity

Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given high intravenous doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity [see Adverse Reactions (6.2) ].

5.5 Severe Dermatologic Reactions

Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear lgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin. Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters. Discontinue FIRVANQ at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.

5.6 Potential for Microbial Overgrowth

Use of FIRVANQ may result in the overgrowth of non‑susceptible bacteria. If superinfection occurs during therapy, appropriate measures should be taken.

5.7 Development of Drug-Resistant Bacteria

Prescribing FIRVANQ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug‑resistant bacteria.

5.8 Hemorrhagic Occlusive Retinal Vasculitis (HORV)

Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or intravitreal route have not been established by adequate and well‑controlled studies. Vancomycin is not indicated for prophylaxis of endophthalmitis.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to vancomycin hydrochloride in 260 adult subjects in two Phase 3 clinical trials for the treatment of C. difficile ‑associated diarrhea. In both trials, subjects received vancomycin hydrochloride 125 mg orally four times daily. The mean duration of treatment was 9.4 days. The median age of patients was 67, ranging between 19 and 96 years of age. Patients were predominantly Caucasian (93%), and 52% were male.

Adverse reactions occurring in ≥ 5% of vancomycin hydrochloride‑treated subjects are shown in Table 2. The most common adverse reactions associated with vancomycin hydrochloride (≥ 10%) were nausea, abdominal pain, and hypokalemia.

Table 2: Common (≥ 5%) Adverse Reactions* for Vancomycin Hydrochloride Reported in Clinical Trials for Treatment of C. difficile Associated Diarrhea
* Adverse reaction rates were derived from the incidence of treatment‑emergent adverse events.

System/Organ Class

Adverse Reaction

Vancomycin Hydrochloride (%) (N=260)

Gastrointestinal disorders

Nausea

17

Abdominal pain

15

Vomiting

9

Diarrhea

9

Flatulence

8

General disorders and administration site conditions

Pyrexia

9

Edema peripheral

6

Fatigue

5

Infections and infestations

Urinary tract infection

8

Metabolism and nutrition disorders

Hypokalemia

13

Musculoskeletal and connective tissue disorders

Back pain

6

Nervous system disorders

Headache

7

Nephrotoxicity (e.g., reports of renal failure, renal impairment, blood creatinine increased) occurred in 5% of subjects treated with vancomycin hydrochloride. Nephrotoxicity following vancomycin hydrochloride typically first occurred within one week after completion of treatment (median day of onset was Day 16). Nephrotoxicity following vancomycin hydrochloride occurred in 6% of subjects over 65 years of age and 3% of subjects 65 years of age and younger [see Warnings and Precautions (5.3) ]. Nephrotoxicity can also occur during oral vancomycin administration.

The incidences of hypokalemia, urinary tract infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension were higher among subjects over 65 years of age than in subjects 65 years of age and younger [see Use in Specific Populations (8.5) ].

Discontinuation of study drug due to adverse events occurred in 7% of subjects treated with vancomycin hydrochloride. The most common adverse events leading to discontinuation of vancomycin hydrochloride were C. difficile colitis (< 1%), nausea (< 1%), and vomiting (< 1%).

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 and Precautions (5.4) ]. Vertigo, dizziness, and tinnitus have been reported.

Skin and Subcutaneous Tissue Disorders: Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear lgA bullous dermatosis (LABD) [see Warnings and Precautions (5.5) ], rashes (including exfoliative dermatitis).

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, 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.

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