CITRIC ACID: 204 Adverse Event Reports & Safety Profile

ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A is designed to be added to blood products collected for extracorporeal processing, to prevent platelet activation and coagulation as blood moves throughout the extracorporeal processing set. The content of the solution bag is considered sterile. This product has a sterile fluid path only. The clear overwrap is not considered a sterile barrier. The solution is non-pyrogenic, and it contains no bacteriostatic or antimicrobial agents. The formulas of the active ingredients are provided in Table 1.

Table

1: Active Ingredients Ingredients Molecular Formula Molecular Weight (%w/v)

Citric

Acid, Monohydrate C 6 H 8 O 7

192.12 Dextrose Monohydrate C 6 H 12 O 6 ∙ H 2 O

198.17 Sodium Citrate Dihydrate C 6 H 9 Na 3 O 9

294.10 Water for Injection H 2 O

18.00 Each 100 mL of ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A contains: (%w/v)

Citric

Acid, Monohydrate 0.8 g; Dextrose Monohydrate 2.45 g; Sodium Citrate Dihydrate 2.2 g; and Water for Injection. The solution bag is not made with natural rubber latex or PVC. The solution bag is made from a polyolefin film. It contains materials that have been tested to demonstrate the suitability of the solution bag for storing pharmaceutical solutions. The solution contact layer is a polyolefin. The solution bag is nontoxic and biologically inert. The solution bag is a closed system and is not dependent upon entry of external air during administration. The solution bag is covered with a clear overwrap to provide protection from the physical environment. The content of the solution bag is considered sterile. This product has a sterile fluid path only. The clear overwrap is not considered a sterile barrier.

INDICATIONS AND USAGE Potassium Citrate and Citric Acid Oral Solution USP is an effective alkalinizing agent useful in those conditions where long-term maintenance of an alkaline urine is desirable, such as in patients with uric acid and cystine calculi of the urinary tract, especially when the administration of sodium salts is undesirable or contraindicated. In addition, it is a valuable adjuvant when administered with uricosuric agents in gout therapy, since urates tend to crystallize out of an acid urine. It is also effective in correcting the acidosis of certain renal tubular disorders where the administration of potassium citrate may be preferable. This product is highly concentrated, and when administered after meals and before bedtime, allows one to maintain an alkaline urinary pH around the clock, usually without the necessity of a 2 A.M. dose. This product alkalinizes the urine without producing a systemic alkalosis in recommended dosage. It is highly palatable, pleasant tasting and tolerable, even when administered for long periods. Potassium citrate does not neutralize the gastric juice or disturb digestion.

AND ADMINISTRATION ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A is added to blood products collected for extracorporeal processing. ( 2 ) ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A may only be used with devices that prepare Platelet Rich Plasma (PRP) products for extracorporeal use. For instructions on the use of the solution see the device operator's manual. ( 2.1 ) Follow the directions for drawing ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A into a syringe for further processing of the collected blood product. ( 2.2 )

2.1 General Dosing Information ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A is added to blood products collected for extracorporeal processing. The solution is manually added to collected blood products to facilitate extracorporeal processing. The amount of solution added is specified by the manufacturer of the processing set. It is not intended for direct intravenous infusion. For instructions on the use of the solution with the processing set, see the device operator's manual.

2.2 Administration Ensure solution is the ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A and is within the expiration date. Inspect the solution bag. Do not use if the solution bag is damaged, leaking or if there is any visible sign of deterioration. Use only if solution is clear and free of particulate matter. Protect from sharp objects. Directions for drawing the ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A from the solution bag. When directed by the processing set instructions and device operator&apos;s manual: Open the foil pouch containing the solution by finding the notch in the foil overwrap and pulling down to present the clear overwrapped solution bag. Open the clear overwrap material by holding the peelable tabs between your thumb and forefinger. Gently pull the peelable tabs along the top to open the overwrap at both corners. Once both corners are opened, gently peel along the length of the overwrap. Do not place the ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A solution bag into the sterile field. The clear overwrap is not considered a sterile barrier. Before use, perform the following checks <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span> : Check for leaks by gently squeezing the bag. If leaks are found, discard the solution bag. Ensure that the solution is the ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A and is within the expiration date. Inspect the solution in adequate light. Solution showing cloudiness, haze, or particulate matter should not be used. Aseptically prepare the Needleless Access Valve (NAV). Using an appropriate syringe and luer, connect to the NAV. Draw into the syringe the amount of ANTICOAGULANT CITRATE DEXTROSE SOLUTION USP (ACD) SOLUTION A required by the processing set instructions and device operator&apos;s manual. Remove the syringe from the NAV and proceed according to the processing set instructions and device operator&apos;s manual. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and solution bag permit.

CONTRAINDICATIONS Severe renal impairment with oliguria or azotemia, untreated Addison's disease, or severe myocardial damage. In certain situations, when patients are on a sodium-restricted diet, the use of potassium citrate may be preferable; or, when patients are on a potassium-restricted diet, the use of sodium citrate may be preferable.

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cystitis and Pyelonephritis [see Warnings and Precautions (5.1) ] Most common adverse reactions (≥2%) were vulvovaginal burning sensation, vulvovaginal pruritus, vulvovaginal mycotic infection, urinary tract infection, vulvovaginal discomfort, bacterial vaginosis, vaginal discharge, genital discomfort, dysuria, and vulvovaginal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Evofem at toll-free phone 1-833-EVFMBIO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PHEXXI (pre-filled applicator with 5-gram dose) has been evaluated in two clinical trials (Study 1 and Study 2) in 2804 subjects (over 19,000 cycles of exposure) . The racial/ethnic distribution was 66% White, 27% Black or African American, 2% Asian, 1% American Indian or Alaska Native, 0.3% Native Hawaiian or Pacific Islander, and 5% other; 32% of the study population was Hispanic.

Study

1 included a one-year extension phase where 342 U.S. subjects were exposed to PHEXXI for 13 cycles.

Hypersensitivity

Reaction Of the 2804 PHEXXI-treated subjects in Studies 1 and 2, one subject reported a suspected drug hypersensitivity. Avoid PHEXXI use in females of reproductive potential with suspected hypersensitivity to the ingredients in PHEXXI. The most common adverse reactions (≥10%) in the U.S. population in Studies 1 and 2 (n = 2480) were: vulvovaginal burning sensation (18.0%) and vulvovaginal pruritus (14.5%). The majority of these adverse reactions were mild and few led to discontinuation.

Table

1 summarizes the most common adverse reactions (≥2%) reported by subjects using PHEXXI in the U.S.

Table

1.

Adverse

Reactions that Occurred in ≥ 2% of Subjects Who Used PHEXXI to Prevent Pregnancy (Studies 1 and 2 – U.S. population only)

Adverse

Reaction PHEXXI (N=2480) (%)

Vulvovaginal Burning

Sensation

18.0 Vulvovaginal Pruritus

14.5 Vulvovaginal Mycotic Infection Includes preferred terms (PT) vulvovaginal mycotic infection and vulvovaginal candidiasis.

9.1 Urinary Tract Infection Includes PTs urinary tract infection, streptococcal urinary tract infection, Escherichia urinary tract infection, and urinary tract infection bacterial. Does not include PTs cystitis, kidney infection, and pyelonephritis <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span>.

9.0 Vulvovaginal Discomfort

9.0 Bacterial Vaginosis

8.4 Vaginal Discharge

5.5 Genital Discomfort

4.1 Dysuria

3.1 Vulvovaginal pain

2.1 Among subjects who used PHEXXI in Studies 1 and 2, 1.6% discontinued from the clinical trials due to an adverse reaction. The most common adverse reactions leading to study discontinuation were vulvovaginal burning sensation (0.7%); and vulvovaginal pruritus and vulvovaginal discomfort (0.1% each).

Adverse

Reactions in Male Partners Among male partners of subjects who used PHEXXI for contraception in Study 2, 9.8% (131 of 1330) reported symptoms of local discomfort (burning, itching, pain, and "other"). Of these local discomfort symptoms, 74.7% were mild, 21.4% were moderate, and 3.9% were severe. Two subjects discontinued participation in the study due to male partner symptoms.

PRECAUTIONS AND WARNINGS Should be used with caution by patients with low urinary output or reduced glomerular filtration rates unless under the supervision of a physician. Aluminum-based antacids should be avoided in these patients. Patients should be directed to dilute adequately with water and, preferably, to take each dose after meals, to minimize the possibility of gastrointestinal injury associated with oral ingestion of potassium salt preparations and to avoid saline laxative effect. Sodium salts should be used cautiously in patients with cardiac failure, hypertension, peripheral and pulmonary edema, and toxemia of pregnancy. Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, or cardiac glycosides may lead to toxicity. Periodic examination and determinations of serum electrolytes, particularly serum bicarbonate level, should be carried out in those patients with renal disease in order to avoid these complications.

Should be used with caution by patients with low urinary output or reduced glomerular filtration rates unless under the supervision of a physician. Aluminum-based antacids should be avoided in these patients. Patients should be directed to dilute adequately with water and, preferably, to take each dose after meals, to minimize the possibility of gastrointestinal injury associated with oral ingestion of potassium salt preparations and to avoid saline laxative effect. Sodium salts should be used cautiously in patients with cardiac failure, hypertension, peripheral and pulmonary edema, and toxemia of pregnancy. Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, or cardiac glycosides may lead to toxicity. Periodic examination and determinations of serum electrolytes, particularly serum bicarbonate level, should be carried out in those patients with renal disease in order to avoid these complications.

Active Ingredients Anhydrous citric acid 1000 mg.................................………Antacid Potassium bicarbonate 344 mg.…..………………….……..Antacid Sodium bicarbonate (heat-treated) 1050 mg………………Antacid

Inactive ingredients Artificial flavors, Gelatin, Delta 8 Tetrahydrocannabinol, Light corn syrup, Potassium Sorbate, Sorbitol, Spirulina platensis powder, Sugar, Water.