Vancomycin

Vancomycin is an antibiotic agent belonging to the pharmacological class of Glycopeptide Antibiotics.

Vancomycin has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cerebrospinal fluid shunt infection, Clostridioides difficile infection, prophylaxis, Clostridioides difficile infection, treatment, Cystic fibrosis, acute pulmonary exacerbation, moderate to severe, Diabetic foot infection, moderate to severe, Endocarditis, treatment, Endophthalmitis, treatment, Intra-abdominal infection, health care–associate, Intracranial abscess or spinal epidural abscess, Meningitis, Bacterial, osteomyelitis, Peritonitis, treatment, Pneumonia, Prosthetic joint infection, Sepsis/septic shock, Septic arthritis, without prosthetic material, Skin and soft tissue infection, Streptococcus, maternal prophylaxis for prevention of neonatal disease, Surgical prophylaxis, Surgical site infection, Toxic shock syndrome, staphylococcal.

Vancomycin is poorly absorbed from the gastrointestinal tract, but systemic absorption of up to 60% can occur following intraperitoneal administration. The volume of distribution ranges between 0.4-1 L/kg, indicating that vancomycin is distributed extensively throughout the body. Approximately 50% of the drug is bound to serum proteins. Metabolism of vancomycin appears to be minimal, as about 75-80% of the drug is excreted unchanged in the urine within the first 24 hours after administration. There is no significant concentration of vancomycin detected in the liver tissue or bile 24 hours after administration. The primary route of elimination is through urine, where the majority of an administered dose is excreted within the first 24 hours via glomerular filtration.

The common side effects involved in using Vancomycin are Nausea, Vomiting, Diarrhea, Abdominal pain, Gastrointestinal discomfort, Skin rash, Itching, Hives (urticaria), Injection site pain, Injection site redness, Injection site swelling, Allergic reactions.

Vancomycin is available in the form of Capsules, Lyophilized powder for reconstitution , Powder for oral solution, Single dose injection solution.

Vancomycin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Vancomycin belongs to the pharmacological class of Glycopeptide Antibiotics

The primary mechanism of action for vancomycin's bactericidal effect is the inhibition of cell-wall biosynthesis. Specifically, vancomycin hinders the integration of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) peptide subunits into the peptidoglycan matrix, which is a crucial component of Gram-positive cell walls. By forming hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG peptides, vancomycin prevents the incorporation of these subunits into the peptidoglycan matrix. Additionally, vancomycin affects bacterial cell membrane permeability and RNA synthesis. It's important to note that there is no cross-resistance observed between vancomycin and other antibiotics. Furthermore, vancomycin does not exhibit activity against gram-negative bacilli, mycobacteria, or fungi in vitro.

Vancomycin has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cerebrospinal fluid shunt infection, Clostridioides difficile infection, prophylaxis, Clostridioides difficile infection, treatment, Cystic fibrosis, acute pulmonary exacerbation, moderate to severe,. Diabetic foot infection, moderate to sever, Endocarditis, treatment, Endophthalmitis, treatment, Intra-abdominal infection, health care–associate, Intracranial abscess or spinal epidural abscess, Meningitis, bacteria, Osteomyeliti, Peritonitis, treatment, Pneumonia, Prosthetic joint infection, Sepsis/septic shock, Septic arthritis, without prosthetic material, Skin and soft tissue infection, Streptococcus, maternal prophylaxis for prevention of neonatal disease, Surgical prophylaxis, Surgical site infection, Toxic shock syndrome, staphylococcal.

Vancomycin, administered intravenously, achieves peak concentrations (Cmax) ranging from 20 to 60 μg/mL, while oral administration results in Cmax ranging from 5 to 20 μg/mL. For IV administration, peak concentration (Tmax) is typically attained immediately at the end of infusion, whereas with oral ingestion, Tmax ranges from 1 to 4 hours. Vancomycin exerts a bactericidal effect against susceptible organisms, and the onset of action can vary based on the site of infection and individual immune response. Generally, within 24 to 48 hours of therapy initiation, symptom improvement and reduction in bacterial load can be observed. The duration of action is dose-dependent and varies among patients, with doses usually administered every 8 to 12 hours to maintain therapeutic levels. Vancomycin has a half-life of approximately 4 to 6 hours in individuals with normal renal function.

Vancomycin is found to be available in the form of Capsules, Lyophilized powder for reconstitution , Powder for oral solution, Single dose injection solution.

Vancomycin can be used in the following treatment:

• Bloodstream infection
• Cerebrospinal fluid shunt infection
• Clostridioides difficile infection, prophylaxis
• Clostridioides difficile infection, treatment
• Cystic fibrosis, acute pulmonary exacerbation, moderate to severe
• Diabetic foot infection, moderate to severe
• Endocarditis, treatment
• Endophthalmitis, treatment
• Intra-abdominal infection, healthcare–associated
• Intracranial abscess or spinal epidural abscess
• Meningitis, bacterial
• Osteomyelitis
• Peritonitis, treatment
• Pneumonia
• Prosthetic joint infection
• Sepsis/septic shock
• Septic arthritis, without prosthetic material
• Skin and soft tissue infection
• Streptococcus, maternal prophylaxis for prevention of neonatal disease
• Surgical prophylaxis
• Surgical site infection
• Toxic shock syndrome, staphylococcal

Vancomycin can help to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cerebrospinal fluid shunt infection, Clostridioides difficile infection, prophylaxis, Clostridioides difficile infection, treatment, Cystic fibrosis, acute pulmonary exacerbation, moderate to severe,. Diabetic foot infection, moderate to sever, Endocarditis, treatment, Endophthalmitis, treatment, Intra-abdominal infection, health care–associate, Intracranial abscess or spinal epidural abscess, Meningitis, bacteria, Osteomyelitis, Peritonitis, treatment, Pneumonia, Prosthetic joint infection, Sepsis/septic shock, Septic arthritis, without prosthetic material, Skin and soft tissue infection, Streptococcus, maternal prophylaxis for prevention of neonatal disease, Surgical prophylaxis, Surgical site infection, Toxic shock syndrome, staphylococcal.

Vancomycin is approved for use in the following clinical indications:

• Bloodstream infection
• Cerebrospinal fluid shunt infection
• Clostridioides difficile infection, prophylaxis
• Clostridioides difficile infection, treatment
• Cystic fibrosis, acute pulmonary exacerbation, moderate to severe
• Diabetic foot infection, moderate to severe
• Endocarditis, treatment
• Endophthalmitis, treatment
• Intra-abdominal infection, healthcare–associated
• Intracranial abscess or spinal epidural abscess
• Meningitis, bacterial
• Osteomyelitis
• Peritonitis, treatment
• Pneumonia
• Prosthetic joint infection
• Sepsis/septic shock
• Septic arthritis, without prosthetic material
• Skin and soft tissue infection
• Streptococcus, maternal prophylaxis for prevention of neonatal disease
• Surgical prophylaxis
• Surgical site infection
• Toxic shock syndrome, staphylococcal

• Bloodstream infection:
• IV: Initial: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Cerebrospinal fluid shunt infection:
• Intraventricular or intrathecal: Usual dose range: 5 to 20 mg/day; usual dose: 10 or 20 mg/day.
• Clostridioides difficile infection, prophylaxis:
• Oral: 125 to 500 mg once daily.
• Clostridioides difficile infection, treatment:
• Oral: 125 to 500 mg four times daily or 500 mg every 6 hours.
• Cystic fibrosis, acute pulmonary exacerbation, moderate to severe:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Diabetic foot infection, moderate to severe:
• IV: Initial: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Endocarditis treatment:
• IV: Initial: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Endophthalmitis treatment:
• Intravitreal: 1 to 2 mg in 0.1 mL undiluted vancomycin solution.
• Intra-abdominal infection, health care-associated:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Intracranial abscess or spinal epidural abscess:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Meningitis, bacterial:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Osteomyelitis:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Peritonitis treatment:
• Intraperitoneal: 1 g in 2 L of dialysate solution.
• Pneumonia:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels of 15 to 20 mg/L.
• Prosthetic joint infection:
• IV: 15 to 20 mg/kg/dose every 8 to 12 hours.
• Dosing should be adjusted based on patient-specific serum concentrations to achieve target trough levels

Capsules

• 25mg
• 250mg

Generic injection, lyophilized powder for reconstitution:

• 500mg
• 750mg
• 1g
• 5g
• 10g

Firvanq kit, powder for oral solution:

• 3.75g
• 7.5g
• 10.5g
• 15g

Generic injection, single-dose flexible bag:

• 500mg/100mL
• 750mg/150mL
• 1g/200mL
• 1.25g/250mL
• 1.5g/300mL
• 1.75g/350mL

Capsules, Lyophilized powder for reconstitution , Powder for oral solution, Single dose injection solution.

• Dosage Adjustments in Kidney Patients:

Mild to moderate impairment: The manufacturer's labeling does not recommend any dosage adjustments.

Severe impairment: Caution should be exercised, and the dose should be reduced by 70% to 75%.

End-stage renal disease (ESRD) on hemodialysis: The manufacturer's labeling does not provide specific dosage adjustments. However, caution should be exercised when using the medication, as it is not effectively removed by hemodialysis.

Peritoneal dialysis: The manufacturer's labeling does not specify dosage adjustments. Use the medication with caution, as it is not effectively removed by peritoneal dialysis.

Dosage Adjustments in Pediatric Patients:

• Antibiotic lock therapy; catheter salvage:
• Intracatheter: Usual concentrations of lock solution: 2 to 5 mg/mL of vancomycin with or without heparin additive.
• Dosing regimens vary based on age, size of the patient, and catheter size. Refer to institutional protocol if available.
• C. difficile infection; treatment:
• Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10 days; maximum daily dose: 2,000 mg/day.
• Endocarditis treatment:
• Dosage adjustment to target through serum concentrations of 10 to 15 mg/L is recommended.
• Dosage varies based on the specific organism:
• Streptococcus (including enterococcus): IV: Initial: 40 mg/kg/day divided every 8 to 12 hours; initial maximum daily dose: 2,000 mg/day.
• S. aureus (non-methicillin resistant): IV: Initial: 40 mg/kg/day divided every 8 to 12 hours; initial maximum daily dose: 2,000 mg/day.
• Methicillin-resistant S. aureus (MRSA): IV: Initial: 40 mg/kg/day divided every 8 to 12 hours for at least 6 weeks; usual initial maximum daily dose: 2,000 mg/day.
• Enterocolitis (S. aureus):
• Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10 days; maximum daily dose: 2,000 mg/day.
• Meningitis, including healthcare-associated meningitis:
• IV: Initial: 15 mg/kg/dose every 6 hours.
• Dosage adjustment may be necessary for serious MRSA infections.
• MRSA infection, serious; treatment:
• Dosage adjustment based on patient-specific serum concentrations to a target AUC24 of 400 mg•hour/L.
• Infants ≥3 months and Children <12 years: IV: Initial: 60 to 80 mg/kg/day in divided doses every 6 hours; initial maximum daily dose: 3,600 mg/day.
• Children ≥12 years and Adolescents: IV: Initial: 60 to 70 mg/kg/day in divided doses every 6 to 8 hours; initial maximum daily dose: 3,600 mg/day.
• Peritonitis (peritoneal dialysis):
• Prophylaxis (touch contamination of PD line): Intraperitoneal: 25 mg per liter.
• Treatment (intermittent): Intraperitoneal: Initial dose: 30 mg/kg in the long dwell; subsequent doses: 15 mg/kg/dose every 3 to 5 days during the long dwell.
• Treatment (continuous): Intraperitoneal: Loading dose: 1,000 mg per liter of dialysate; maintenance dose: 25 mg per liter.
• Pneumonia, community-acquired:
• Infants >3 months, Children, and Adolescents: IV: Initial: 40 to 60 mg/kg/day in divided doses every 6 to 8 hours.
• Dosage adjustment may be necessary for MRSA infections.
• Skin and skin structure infection, complicated:
• Necrotizing infections, mixed (non-MRSA): Infants, Children, and Adolescents: IV: Initial: 10 to 13 mg/kg/dose every 8 hours.
• Serious MRSA infection, including necrotizing infection and pyomyositis: Infants ≥3 months and Children <12 years: IV: Initial: 60 mg/kg/day in divided doses every 6 hours; maximum daily dose: 3,600 mg/day.
• Surgical prophylaxis:
• Infants, Children, and Adolescents: IV: 15 mg/kg/dose within 120 minutes prior to surgical incision.
• Ventriculitis (including healthcare-associated ventriculitis and CSF shunt infections):

• Intraventricular or intrathecal: Usual dose range: 5 to 20 mg/day; usual dose: 10 or 20 mg/day.

There are no specific dietary restrictions associated with the use of Vancomycin.

Vancomycin may be contraindicated under the following conditions:

• Vancomycin should not be used in individuals with a known hypersensitivity or allergic reaction to the drug Vancomycin.

General

• Poor oral absorption of vancomycin hydrochloride makes toxic serum levels unlikely from oral dosage. However, clinically significant serum concentrations have been reported in some patients with active C. difficile-induced pseudomembranous colitis who have taken multiple oral doses. Therefore, monitoring of serum concentrations may be appropriate in these patients.
• Intravenous administration of vancomycin can lead to toxic serum levels. The risk of toxicity during parenteral therapy is significantly increased by high blood concentrations or prolonged treatment.

Ear/Nose/Throat

• Exceeding serum levels of 80 mcg/mL has been associated with ototoxicity, which may manifest as hearing loss preceded by tinnitus. The elderly are more susceptible to auditory damage, and deafness may be progressive despite discontinuation of treatment. Patients with previous hearing loss should avoid vancomycin hydrochloride if possible. If used in such patients, dose regulation should be based on periodic determination of drug levels in the blood. Auditory function and vancomycin blood levels should be regularly monitored in patients with renal insufficiency and individuals over the age of 60.

Gastrointestinal

• Inflammatory disorders of the intestinal mucosa in some patients may lead to significant systemic absorption of oral vancomycin, increasing the risk of adverse reactions associated with parenteral administration. The risk is higher in the presence of renal impairment.

Hematologic

• Neutropenia may occur after one week or more of vancomycin hydrochloride therapy or after a total dose exceeding 25 g. Discontinuation of treatment promptly reverses neutropenia.

Renal

• Due to its nephrotoxicity and ototoxicity, vancomycin hydrochloride should be used with caution in patients with renal insufficiency. Reduced renal clearance results in a marked increase in blood levels. Patients with underlying renal dysfunction or receiving concomitant aminoglycoside therapy are at risk of developing interstitial nephritis, requiring serial monitoring of renal function.

Susceptibility/Resistance

• Prolonged use of vancomycin hydrochloride may lead to overgrowth of non-susceptible organisms. If new infections caused by bacteria or fungi emerge during therapy, appropriate measures should be taken, including discontinuation of vancomycin hydrochloride. Some enterococcal and staphylococcal isolates have shown resistance to vancomycin in vitro. Vancomycin is ineffective against gram-negative bacilli, mycobacteria, or fungi. Prescribing vancomycin hydrochloride without a proven or strongly suspected bacterial infection is unlikely to benefit the patient and carries the risk of developing drug-resistant bacteria.

While there is no specific food interaction between Vancomycin and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and may also exacerbate certain side effects.

Vancomycin hydrochloride is eliminated in breast milk. Caution is advised when administering vancomycin hydrochloride to breastfeeding women. Due to the possibility of adverse effects, a decision should be made considering the significance of the drug to the mother, whether to discontinue nursing or discontinue the administration of the medication.

Pregnancy Category C

Vancomycin hydrochloride should be administered to pregnant women only when it is clearly necessary. A study was conducted to assess the potential ototoxic and nephrotoxic effects of Vancomycin hydrochloride on infants born to 10 pregnant women with serious staphylococcal infections related to intravenous drug abuse. Cord blood samples from two patients showed Vancomycin hydrochloride levels of 13.2 and 16.6 mcg/mL. No instances of sensorineural hearing loss or nephrotoxicity associated with Vancomycin hydrochloride were observed. One infant whose mother received Vancomycin hydrochloride during the third trimester experienced conductive hearing loss unrelated to the administration of Vancomycin hydrochloride. It should be noted that the study had a limited number of patients, and Vancomycin hydrochloride was only given during the second and third trimesters. Thus, the potential fetal risks of Vancomycin hydrochloride remain unknown.

The adverse reactions related to Vancomycin can be categorized as follows:

Common:

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Rash or itching
• Redness or swelling at the injection site (with intravenous administration)
• Kidney problems (such as changes in urine output or decreased kidney function)
• Hearing loss or changes in hearing

Less Common:

• Headache
• Dizziness
• Fever
• Chills
• Low blood pressure
• Fluctuations in blood cell counts
• Muscle pain or weakness
• Tingling or numbness in extremities

Rare:

• Allergic reactions (such as difficulty breathing, chest tightness, or swelling of the face, lips, tongue, or throat)
• Severe skin reactions (such as blistering, peeling, or severe rash)
• Severe diarrhea (which may be a sign of a serious intestinal condition called pseudomembranous colitis)
• Blood disorders (such as low platelet count or low white blood cell count)
• Liver problems (such as jaundice or elevated liver enzymes)
• Severe kidney damage
• Red man syndrome (a condition characterized by flushing and rash, usually occurring with rapid intravenous administration)

Interactions with Other Drugs:

Caution should be exercised when vancomycin is used concurrently or sequentially with other medications that may have neurotoxic or nephrotoxic effects. These may include ethacrynic acid, neuromuscular blocking agents, aminoglycoside antibiotics, polymyxin B, colistin, viomycin, and cisplatin. Close monitoring is necessary in such cases.

Interactions with Anesthetic Agents:

When vancomycin is administered concomitantly with anesthetic agents, it has been associated with erythema and histamine-like flushing in children.

Interactions with Food:

There have been no studies conducted to evaluate the interactions between vancomycin hydrochloride and food.

Interactions with Herbal Products:

No studies have been conducted to assess the interactions between vancomycin hydrochloride and herbal products.

Interactions with Laboratory Tests:

No studies have been conducted to evaluate the interactions between vancomycin hydrochloride and laboratory tests.

The following are the side effects involving Vancomycin:

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Rash or itching
• Redness or swelling at the injection site
• Low blood pressure
• Kidney problems
• Hearing loss or ringing in the ears (ototoxicity) - especially with high doses or prolonged use

Pregnancy:

Pregnancy Category C

Vancomycin hydrochloride should be administered to pregnant women only when it is clearly necessary. A study was conducted to assess the potential ototoxic and nephrotoxic effects of Vancomycin hydrochloride on infants born to 10 pregnant women with serious staphylococcal infections related to intravenous drug abuse. Cord blood samples from two patients showed Vancomycin hydrochloride levels of 13.2 and 16.6 mcg/mL. No instances of sensorineural hearing loss or nephrotoxicity associated with Vancomycin hydrochloride were observed. One infant whose mother received Vancomycin hydrochloride during the third trimester experienced conductive hearing loss unrelated to the administration of Vancomycin hydrochloride. It should be noted that the study had a limited number of patients, and Vancomycin hydrochloride was only given during the second and third trimesters. Thus, the potential fetal risks of Vancomycin hydrochloride remain unknown.

Lactation:

Vancomycin hydrochloride is eliminated in breast milk. Caution is advised when administering vancomycin hydrochloride to breastfeeding women. Due to the possibility of adverse effects, a decision should be made considering the significance of the drug to the mother, whether to discontinue nursing or discontinue the administration of the medication.

Pediatric:

Verifying the desired levels of vancomycin in the bloodstream may be necessary. When vancomycin is administered together with anesthetic agents, children have reported instances of erythema and flushing resembling histamine reactions.

Geriatric Use:

The age-related decline in glomerular filtration rate can result in higher levels of vancomycin in the bloodstream if the dosage is not adjusted. Therefore, dosage schedules of vancomycin should be modified for elderly patients. It is important to recognize that both the overall systemic clearance and renal clearance of vancomycin are decreased in the elderly population. Additionally, the elderly are more vulnerable to experiencing auditory damage.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of over dosage of Vancomycin.

The use of polysulfone resins in hemofiltration and hemoperfusion has been reported to enhance the clearance of vancomycin. In the absence of a specific antidote, supportive treatment is recommended. It is important to note that dialysis does not effectively remove significant amounts of vancomycin.

Pharmacodynamics

Vancomycin is a glycosylated nonribosomal peptide with a branched tricyclic structure. It is commonly considered as a "drug of last resort" and is used when other antibiotics have been unsuccessful. Vancomycin has demonstrated activity against various microorganisms, both in laboratory settings and in clinical infections. These include Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae (including strains resistant to penicillin), Streptococcus agalactiae, Actinomyces species, and Lactobacillus species. When combined with an aminoglycoside, vancomycin exhibits synergistic effects in vitro against several strains of Staphylococcus aureus, Streptococcus bovis, enterococci, and the viridian group streptococci.

Pharmacokinetics

Absorption:

Clindamycin is poorly absorbed from the gastrointestinal tract, but there is a potential for systemic absorption of up to 60% following intraperitoneal administration.

The volume of distribution:

According to literature sources, the volume of distribution of clindamycin ranges from 0.4 to 1 L/kg.

Protein binding:

Approximately 50% of clindamycin is bound to serum proteins.

Metabolism:

There appears to be minimal metabolism of clindamycin, as almost 75-80% of the drug is excreted unchanged in the urine within the first 24 hours following administration. There are no significant reports of apparent metabolism of the drug, and the concentration of clindamycin in liver tissue and bile after 24 hours of administration is generally below detection limits.

Route of elimination:

Within the first 24 hours of administration, approximately 75-80% of an administered dose of clindamycin is excreted in the urine through glomerular filtration.

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2. https://www.drugs.com/vancomycin.html
3. https://www.mayoclinic.org/drugs-supplements/vancomycin-intravenous-route/description/drg-20068900
4. https://reference.medscape.com/drug/firvanq-vancocin-vancomycin-342573
5. https://go.drugbank.com/drugs/DB00512
6. https://www.pfizer.com/products/product-detail/vancomycin
7. https://my.clevelandclinic.org/health/drugs/19594-vancomycin-capsules
8. https://pdf.hres.ca/dpd_pm/00042279.PDF
9. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/060180s047lbl.pdf