Leepime

Pneumonia

Leepime is indicated in the treatment of pneumonia (moderate to severe) caused by susceptible strains of Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.

Empiric Therapy For Febrile Neutropenic Patients

Leepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.

Uncomplicated And Complicated Urinary Tract Infections (Including Pyelonephritis)

Leepime is indicated in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by susceptible isolates of Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these bacteria.

Uncomplicated Skin And Skin Structure Infections

Leepime is indicated in the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.

Complicated Intra-Abdominal Infections (Used In Combination With Metronidazole)

Leepime is indicated in the treatment of complicated intra-abdominal infections (used in combination with metronidazole) in adults caused by susceptible isolates of Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Leepime and other antibacterial drugs, Leepime should be used only to treat 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.

Dosage For Adults

The recommended adult dosages and routes of administration are outlined in Table 1 below for patients with creatinine clearance greater than 60 mL/min. Administer Leepime intravenously over approximately 30 minutes.

Table 1: Recommended Dosage Schedule for Leepime in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min Duration

Pediatric Patients (2 Months Up To 16 Years)

The maximum dose for pediatric patients should not exceed the recommended adult dose.

The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is:

• 50 mg per kg per dose, administered every 12 hours for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia (see below).
• For moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every 8 hours.
• 50 mg per kg per dose, every 8 hours for febrile neutropenic patients.

Dosage Adjustments In Patients With Renal Impairment

Adult Patients

Adjust the dose of Leepime in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of Leepime should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of Leepime in patients with renal impairment are presented in Table 2.

When only serum creatinine is available, the following formula (Cockcroft and Gault equation)⁴ may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Table 2: Recommended Dosing Schedule for Leepime in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/min Creatinine Recommended Maintenance Schedule Clearance (mL/min)

In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), Leepime may be administered at the recommended doses at a dosage interval of every 48 hours (see Table 2).

In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of Leepime for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours.

Leepime should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

Pediatric Patients

Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients , changes in the dosing regimen proportional to those in adults (see Tables 1 and 2) are recommended for pediatric patients.

Preparation Of Leepime For Intravenous Infusion

Vials

• Constitute the 0.5 gram, 1 gram, or 2 grams vial, of Leepime with the one of the following diluents:
  • Sterile Water for Injection
  • 0.9% Sodium Chloride Injection
  • 5% Dextrose Injection
  • 0.5% or 1% Lidocaine Hydrochloride Injection
  • Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol
• Dilute the reconstituted solution with one of the following compatible infusion solutions prior to intravenous infusion (Refer to Table 3 below for the amount of diluent to be added to each vial and the amount of the reconstituted solution to be withdrawn):
  • 0.9% Sodium Chloride Injection
  • 5% and 10% Dextrose Injection
  • M/6 Sodium Lactate Injection
  • 5% Dextrose and 0.9% sodium Chloride Injection
  • Lactated Rings and 5% Dextrose Injection
  • Normosol™-R and Normosol™-M in 5% Dextrose Injection
• Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.
• Administer the resulting intravenous infusion over approximately 30 minutes.
• Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.

ADD-Vantage

Vials Constitute only with 50 mL or 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection in ADD-Vantage flexible diluent containers as described in the instructions for reconstitution.

Preparation For Intramuscular Administration

Constitute Leepime vials 0.5 gram, 1 gram and 2 grams with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol. Refer to Table 3 below for the amount of diluent to be added to each vial and the amount of reconstituted volume to be withdrawn.

Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

Table 3: Preparation of Reconstituted Solutions of Leepime for Injection

Compatibility And Stability

Intravenous Leepime

Intravenous Infusion Compatibility

Leepime vials are compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol™-R, and Normosol™-M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or 7 days in a refrigerator 2°C to 8°C (36°F to 46°F).

Leepime in ADD-Vantage vials are stable at concentrations of 10 to 40 mg per mL in 5% Dextrose Injection or 0.9% Sodium Chloride Injection for 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or 7 days in a refrigerator 2°C to 8°C (36°F to 46°F).

Admixture Compatibility

Leepime admixture compatibility information is summarized in Table 4.

Table 4: Cefepime Admixture Stability

Leepime Admixture Incompatibility

Do not add solutions of Leepime, to solutions of ampicillin at a concentration greater than 40 mg per mL, or to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate, or aminophylline because of potential interaction. However, if concurrent therapy with Leepime is indicated, each of these antibiotics can be administered separately.

Intramuscular Leepime

Leepime constituted as directed is stable for 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or for 7 days in a refrigerator 2°C to 8°C (36°F to 46°F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.

Intramuscular and Intravenous

Leepime As with other cephalosporins, the color of Leepime powder, as well as its solutions tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

ADD-Vantage Instructions For Reconstitution And Intravenous Administration

To Open

Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

Assembly Of Vial And Flexible Diluent Container

1. Use Aseptic Technique
2. Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:
   1. To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (See Figure 1), then pull straight up to remove the cap (See Figure 2)
   2. Once the breakaway cap has been removed, do not access vial with syringe.
   3. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover (See Figure 3.)
3. Screw the vial into the vial port until it will go no further. The Vial Must Be Screwed In Tightly To Assure a Seal. This occurs approximately 1/2 turn (180°) after the first audible click (see Figure 4). The clicking sound does not assure a seal; the vial must be turned as far as it will go. Once vial is seated, do not attempt to remove (See Figure 4).
4. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
5. Label appropriately.

Instructions For Reconstitution Leepime ADD-Vantage Vial In Flexible Diluent Container

1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
2. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container (see Figure 5).
3. Pull the inner cap from the drug vial (see Figure 6). Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
4. Mix container contents thoroughly and use within the specified time.
5. Look through the bottom of the vial to verify that the stopper has been removed and complete mixing has occurred (see Figure 7).
6. If the rubber stopper is not removed from the vial and medication is not released on the first attempt, the inner cap may be manipulated back into the rubber stopper without removing the drug vial from the diluent container. Repeat steps 3 through 5.

Instructions For Intravenous Administration Of Leepime ADD-Vantage Vial

1. Use Aseptic Technique
2. Confirm the activation and admixture of vial contents.
3. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
4. Close flow control clamp of administration set.
5. Remove cover from outlet port at bottom of container.
6. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. Refer to full directions on administration set carton prior to use.
7. Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
8. Squeeze and release drip chamber to establish proper fluid level in chamber.
9. Open flow control clamp and clear air from set. Close clamp.
10. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
11. Regulate rate of administration with flow control clamp.
12. Do not use flexible container in series connections

Leepime is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hypersensitivity Reactions

Before therapy with Leepime for Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Leepime occurs, discontinue the drug and institute appropriate supportive measures.

Neurotoxicity

Serious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.

Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Leepime, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development Of Drug-Resistant Bacteria

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

As with other antimicrobials, prolonged use of Leepime may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient’s condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

Drug/Laboratory Test Interactions

Urinary Glucose

The administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest™ tablets).

Coombs’ Tests

Positive direct Coombs’ tests have been reported during treatment with Leepime. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs’ test may be observed in newborns whose mothers have received cephalosporin antibiotics before parturition.

Prothrombin Time

Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No animal carcinogenicity studies have been conducted with cefepime. In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity. No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a body surface area basis).

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a body surface area basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a body surface area basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a body surface area basis).

Labor And Delivery

Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.

Nursing Mothers

Cefepime is excreted in human breast milk. Caution should be exercised when cefepime is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Leepime in these age groups is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials.

Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of Leepime in pediatric patients for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b. In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.

Geriatric Use

Of the more than 6400 adults treated with Leepime in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in non-geriatric adult patients.

Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

Renal Impairment

Adjust the dose of Leepime in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination.

The following adverse reactions are discussed in the Warnings and Precautions section and below:

• Hypersensitivity Reactions
• Neurotoxicity
• Clostridium difficile-Associated Diarrhea

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.

In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenous every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty-four (1.5%) patients discontinued medication due to adverse reactions. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses.

The following adverse reactions (Table 5) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients).

Table 5: Adverse Reactions in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America

At the higher dose of 2 g every 8 hours, the incidence of adverse reactions was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%).

The following (Table 6) adverse laboratory changes, with cefepime, were seen during clinical trials conducted in North America.

Table 6: Adverse Laboratory Changes in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America

A similar safety profile was seen in clinical trials of pediatric patients

Postmarketing Experience

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

In addition to the adverse reactions reported during the North American clinical trials with cefepime, the following adverse reactions have been reported during worldwide postmarketing experience. Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus have been reported.

Anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia, have been reported.

Cephalosporin-Class Adverse Reactions

In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibacterial drugs:

Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.

Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, neuromuscular excitability and nonconvulsive status epilepticus.

Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of cefepime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamics relationship for cefepime has not been evaluated in patients.

Pharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30-minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 7. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.

Table 7: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intravenous Administration

Pharmacokinetic parameters for cefepime following a single intramuscular injection are summarized in Table 8. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.

Table 8: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intramuscular Administration

Absorption

Following intramuscular (IM) administration, cefepime is completely absorbed.

Distribution

The average steady-state volume of distribution of cefepime is 18 (±2) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.

Cefepime is excreted in human milk at a concentration of 0.5 mcg/mL. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day.

Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 9.

Table 9: Mean Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g) Mean Time of Sample Mean Tissue or Fluid Dose/Route # of Patients Post-Dose Concentration

Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.

Metabolism And Excretion

Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain