Ledermix

Demeclocycline Calcium:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Animal pharmacology and animal toxicology
• References
• Ledermix (Demeclocycline Calcium) reviews

INDICATIONS AND USAGE

Ledermix (Demeclocycline Calcium) hydrochloride tablets are indicated in the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions below:

Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by rickettsiae;

Respiratory tract infections caused by Mycoplasma pneumoniae;

Lymphogranuloma venereum due to Chlamydia trachomatis;

Psittacosis (Ornithosis) due to Chlamydia psittaci;

Trachoma due to Chlamydia trachomatis, although the infectious agent is not always eliminated, as judged by immunofluorescence;

Inclusion conjunctivitis caused by Chlamydia trachomatis;

Nongonococcal urethritis in adults caused by Ureaplasma urealyticum or Chlamydia trachomatis;

Relapsing fever due to Borrelia recurrentis;

Chancroid caused by Haemophilus ducreyi;

Plague due to Yersinia pestis;

Tularemia due to Francisella tularensis;

Cholera caused by Vibrio cholerae;

Campylobacter fetus infections caused by Campylobacter fetus;

Brucellosis due to Brucella species (in conjunction with streptomycin);

Bartonellosis due to Bartonella bacilliformis;

Granuloma inguinale caused by Calymmatobacterium granulomatis;

Ledermix (Demeclocycline Calcium) hydrochloride tablets are indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

Escherichia coli;

Enterobacter aerogenes;

Shigella species;

Acinetobacter species;

Respiratory tract infections caused by Haemophilus influenzae;

Respiratory tract and urinary tract infections caused by Klebsiella species.

Ledermix (Demeclocycline Calcium) hydrochloride tablets are indicated for treatment of infections caused by the following gram-positive microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

Upper respiratory infections caused by Streptococcus pneumoniae;

Skin and skin structure infections caused by Staphylococcus aureus. (Note: Tetracyclines, including Ledermix (Demeclocycline Calcium), are not the drugs of choice in the treatment of any type of staphylococcal infection.)

When penicillin is contraindicated, tetracyclines, including Ledermix (Demeclocycline Calcium) hydrochloride, are alternative drugs in the treatment of the following infections:

Uncomplicated urethritis in men due to Neisseria gonorrhoeae, and for the treatment of other uncomplicated gonococcal infections;

Infections in women caused by Neisseria gonorrhoeae;

Syphilis caused by Treponema pallidum subspecies pallidum;

Yaws caused by Treponema pallidum subspecies pertenue;

Listeriosis due to Listeria monocytogenes;

Anthrax due to Bacillus anthracis;

Vincent’s infection caused by Fusobacterium fusiforme;

Actinomycosis caused by Actinomyces israelii;

Clostridial diseases caused by Clostridium species.

In acute intestinal amebiasis, Ledermix (Demeclocycline Calcium) hydrochloride tablets may be a useful adjunct to amebicides.

In severe acne, Ledermix (Demeclocycline Calcium) hydrochloride tablets may be a useful adjunctive therapy.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ledermix (Demeclocycline Calcium) hydrochloride tablets and other antibacterial drugs, Ledermix (Demeclocycline Calcium) hydrochloride tablets 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.

CONTRAINDICATIONS

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or any of the components of the product formulation.

WARNINGS

Ledermix (Demeclocycline Calcium) HYDROCHLORIDE, LIKE OTHER TETRACYCLINE-CLASS ANTIBIOTICS, CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. IF ANY TETRACYCLINE IS USED DURING PREGNANCY, OR IF THE PATIENT BECOMES PREGNANT WHILE TAKING THESE DRUGS, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS.

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED DURING TOOTH DEVELOPMENT UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulation of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated and, if therapy is prolonged, serum level determinations of the drug may be advisable.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Phototoxic reactions can occur in individuals taking Ledermix (Demeclocycline Calcium), and are characterized by severe burns or exposed surfaces resulting from direct exposure of patients to sunlight during therapy with moderate or large doses of Ledermix (Demeclocycline Calcium). Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur, and treatment should be discontinued at the first evidence of erythema of the skin.

Administration of Ledermix (Demeclocycline Calcium) hydrochloride has resulted in appearance of the diabetes insipidus syndrome (polyuria, polydipsia and weakness) in some patients on long-term therapy. The syndrome has been shown to be nephrogenic, dose-dependent and reversible on discontinuance of therapy. Patients who are experiencing central nervous system symptoms associated with Ledermix (Demeclocycline Calcium) therapy should be cautioned about driving vehicles or using hazardous machinery while on Ledermix (Demeclocycline Calcium) therapy.

Clostridium difficile associated with diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Ledermix (Demeclocycline Calcium) hydrochloride, 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 antibiotic 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 antibiotic 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.

PRECAUTIONS

General

Pseudotumor cerebri in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy should be instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy, when indicated. Prescribing Ledermix (Demeclocycline Calcium) hydrochloride tablets 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.

Information for Patients

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective (see Drug Interactions ). Patients should be informed that Ledermix (Demeclocycline Calcium) hydrochloride tablets should be taken at least 1 hour before meals or 2 hours after meals (see DOSAGE AND ADMINISTRATION ). Unused supplies of tetracycline antibiotics should be discarded by the expiration date. Patients who are experiencing headache, dizziness, light-headedness, vertigo, or blurred vision while on Ledermix (Demeclocycline Calcium) therapy, should be cautioned about driving vehicles or using hazardous machinery while receiving Ledermix (Demeclocycline Calcium) therapy (see WARNINGS ).

Patients should be counseled that antibacterial drugs, including Ledermix (Demeclocycline Calcium) hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ledermix (Demeclocycline Calcium) hydrochloride tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Ledermix (Demeclocycline Calcium) hydrochloride tablets or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests

In venereal diseases when coexistent syphilis is suspected, darkfield examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic, should be performed. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with Ledermix hydrochloride should have a follow-up serologic test for syphilis after 3 months.

Drug Interactions

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillins, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin.

Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective.

The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and by iron-containing preparations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of Ledermix hydrochloride have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).

Although mutagenicity studies of Ledermix (Demeclocycline Calcium) hydrochloride have not been conducted, positive results in in vitro mammalian cell assays (i.e., mouse lymphoma and Chinese hamster lung cells) have been reported for related antibiotics (tetracycline hydrochloride and oxytetracycline) (see WARNINGS; ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY ).

Ledermix (Demeclocycline Calcium) hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 45 times the human dose.

Pregnancy

Teratogenic Effects

Pregnancy Category D

.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy.

Nonteratogenic Effects

(See WARNINGS ).

Labor and Delivery

The effect of tetracyclines on labor and delivery is unknown.

Nursing Mothers

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from the tetracyclines, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Not for use in patients younger than eight years of age (see WARNINGS ; PRECAUTIONS , General and DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS

The following reactions have been reported in patients receiving tetracyclines:

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, pancreatitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region, increases in liver enzymes, and hepatic toxicity has been reported rarely.

Rarely, hepatitis and liver failure have been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines.

Instances of esophageal ulcerations have been reported in patients receiving oral tetracyclines. Most of the patients were reported to have taken the medication immediately before lying down (see DOSAGE AND ADMINISTRATION ).

Skin: Maculopapular and erythematous rashes, erythema multiforme. Exfoliative dermatitis has been reported but is uncommon. Fixed drug eruptions and Stevens-Johnson syndrome have been reported rarely. Lesions occurring on the glans penis have caused balanitis. Pigmentation of the skin and mucous membranes has also been reported. Photosensitivity is discussed above (see WARNINGS ).

Renal toxicity: Acute renal failure. Rise in BUN has been reported and is apparently dose related. Nephrogenic diabetes insipidus (see WARNINGS ).

Hypersensitivity reactions: Urticaria, angioneurotic edema, polyarthralgia, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus, lupus-like syndrome, pulmonary infiltrates with eosinophilia.

Hematologic: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported.

CNS: Pseudotumor cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants (see PRECAUTIONS, General ). Dizziness, headache, tinnitus, and visual disturbances have been reported. Myasthenic syndrome has been reported rarely.

Other: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur. Very rare cases of abnormal thyroid function have been reported.

Tooth discoloration has occurred in pediatric patients less than 8 years of age (see WARNINGS ), and also has been reported rarely in adults.

OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Tetracyclines are not removed in significant quantities by hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION

Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.

Concomitant Therapy

Absorption of tetracycline is impaired by antacids containing aluminum, calcium, or magnesium, and by iron-containing preparations. Foods and some dairy products also interfere with absorption. Oral forms of tetracycline should be given at least 1 hour before or 2 hours after meals.

In Patients With Renal Impairment

. Tetracyclines should be used cautiously in patients with impaired renal function. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses.

In Patients With Liver Impairment

Tetracyclines should be used cautiously in patients with impaired liver function. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses. Administration of adequate amounts of fluid with the oral formulations of tetracyclines is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS ).

Adults

Usual Daily Dose

Four divided doses of 150 mg each or two divided doses of 300 mg each.

For Pediatric Patients Above Eight Years of Age

Usual daily dose, 7 to 13 mg per kg body weight per day, depending upon the severity of the disease, divided into two to four doses not to exceed adult dosage of 600 mg per day.

Gonorrhea patients sensitive to penicillin may be treated with Ledermix (Demeclocycline Calcium) administered as an initial oral dose of 600 mg followed by 300 mg every 12 hours for four days to a total of 3 grams.

HOW SUPPLIED

Ledermix (Demeclocycline Calcium) Hydrochloride Tablets USP, 150 mg are available as pink, round, biconvex, film-coated, unscored tablets, debossed with “stylized b” 701 on one side and 150 on the other, packaged in bottle of 100 (NDC 0555-0701-02) tablets.

Ledermix (Demeclocycline Calcium) Hydrochloride Tablets USP, 300 mg are available as pink, round, biconvex, film-coated, unscored tablets, debossed with “stylized b” 702 on one side and 300 on the other, packaged in bottle of 48 (NDC 0555-0702-84) tablets.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY

Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO₄ and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO₄, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO₄, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline), in chickens (chlortetracycline), and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

REFERENCES

• Clinical and Laboratory Standards Institute (CLSI.) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard – 9th Edition. CLSI document M7-A9, 950 West Valley Rd. Suite 2500,.Wayne, PA 19087, 2012.
• CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 22^nd Informational Supplement. CLSI document M100-S22. Wayne, PA, 2012.
• CLSI. Methods or Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria: Approved Guideline - 2nd Edition. CLSI document M45-A2. CLSI, Wayne, PA, 2011.
• CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard - 11^th Edition. CLSI document M2-A11. Wayne, PA, 2012.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. B 3/2016

NDC 0555-0701-02

Ledermix (Demeclocycline Calcium)

Hydrochloride

Tablets USP

150 mg

Rx only

100 TABLETS

TEVA

NDC 0555-0702-84

Ledermix (Demeclocycline Calcium)

Hydrochloride

Tablets USP

300 mg

Rx only

48 TABLETS

TEVA

Demeclocycline Hydrochloride:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Animal pharmacology and animal toxicology
• References
• Ledermix (Demeclocycline Hydrochloride) reviews

INDICATIONS AND USAGE

Ledermix (Demeclocycline Hydrochloride) tablets are indicated in the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions below:

Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by rickettsiae;

Respiratory tract infections caused by Mycoplasma pneumoniae;

Lymphogranuloma venereum due to Chlamydia trachomatis;

Psittacosis (Ornithosis) due to Chlamydia psittaci;

Trachoma due to Chlamydia trachomatis, although the infectious agent is not always eliminated, as judged by immunofluorescence;

Inclusion conjunctivitis caused by Chlamydia trachomatis;

Nongonococcal urethritis in adults caused by Ureaplasma urealyticum or Chlamydia trachomatis;

Relapsing fever due to Borrelia recurrentis;

Chancroid caused by Haemophilus ducreyi;

Plague due to Yersinia pestis;

Tularemia due to Francisella tularensis;

Cholera caused by Vibrio cholerae;

Campylobacter fetus infections caused by Campylobacter fetus;

Brucellosis due to Brucella species (in conjunction with streptomycin);

Bartonellosis due to Bartonella bacilliformis;

Granuloma inguinale caused by Calymmatobacterium granulomatis;

Ledermix (Demeclocycline Hydrochloride) tablets are indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

Escherichia coli;

Enterobacter aerogenes;

Shigella species;

Acinetobacter species;

Respiratory tract infections caused by Haemophilus influenzae;

Respiratory tract and urinary tract infections caused by Klebsiella species.

Ledermix (Demeclocycline Hydrochloride) tablets are indicated for treatment of infections caused by the following gram-positive microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

Upper respiratory infections caused by Streptococcus pneumoniae;

Skin and skin structure infections caused by Staphylococcus aureus. (Note: Tetracyclines, including demeclocycline, are not the drugs of choice in the treatment of any type of staphylococcal infection.)

When penicillin is contraindicated, tetracyclines, including Ledermix (Demeclocycline Hydrochloride), are alternative drugs in the treatment of the following infections:

Uncomplicated urethritis in men due to Neisseria gonorrhoeae, and for the treatment of other uncomplicated gonococcal infections;

Infections in women caused by Neisseria gonorrhoeae;

Syphilis caused by Treponema pallidum subspecies pallidum;

Yaws caused by Treponema pallidum subspecies pertenue;

Listeriosis due to Listeria monocytogenes;

Anthrax due to Bacillus anthracis;

Vincent’s infection caused by Fusobacterium fusiforme;

Actinomycosis caused by Actinomyces israelii;

Clostridial diseases caused by Clostridium species.

In acute intestinal amebiasis, Ledermix (Demeclocycline Hydrochloride) tablets may be a useful adjunct to amebicides.

In severe acne, Ledermix (Demeclocycline Hydrochloride) tablets may be a useful adjunctive therapy.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ledermix (Demeclocycline Hydrochloride) tablets and other antibacterial drugs, Ledermix (Demeclocycline Hydrochloride) tablets 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.

CONTRAINDICATIONS

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or any of the components of the product formulation.

WARNINGS

Ledermix (Demeclocycline Hydrochloride), LIKE OTHER TETRACYCLINE-CLASS ANTIBIOTICS, CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. IF ANY TETRACYCLINE IS USED DURING PREGNANCY, OR IF THE PATIENT BECOMES PREGNANT WHILE TAKING THESE DRUGS, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS.

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED DURING TOOTH DEVELOPMENT UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulation of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated and, if therapy is prolonged, serum level determinations of the drug may be advisable.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Phototoxic reactions can occur in individuals taking demeclocycline, and are characterized by severe burns or exposed surfaces resulting from direct exposure of patients to sunlight during therapy with moderate or large doses of demeclocycline. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur, and treatment should be discontinued at the first evidence of erythema of the skin.

Administration of Ledermix (Demeclocycline Hydrochloride) has resulted in appearance of the diabetes insipidus syndrome (polyuria, polydipsia and weakness) in some patients on long-term therapy. The syndrome has been shown to be nephrogenic, dose-dependent and reversible on discontinuance of therapy. Patients who are experiencing central nervous system symptoms associated with demeclocycline therapy should be cautioned about driving vehicles or using hazardous machinery while on demeclocycline therapy.

Clostridium difficile associated with diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Ledermix (Demeclocycline Hydrochloride), 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 antibiotic 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 antibiotic 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.

PRECAUTIONS

General

Pseudotumor cerebri in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy should be instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy, when indicated. Prescribing Ledermix (Demeclocycline Hydrochloride) tablets 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.

Information for Patients

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective (see Drug Interactions ). Patients should be informed that Ledermix (Demeclocycline Hydrochloride) tablets should be taken at least 1 hour before meals or 2 hours after meals (see DOSAGE AND ADMINISTRATION ). Unused supplies of tetracycline antibiotics should be discarded by the expiration date. Patients who are experiencing headache, dizziness, light-headedness, vertigo, or blurred vision while on demeclocycline therapy, should be cautioned about driving vehicles or using hazardous machinery while receiving demeclocycline therapy (see WARNINGS ).

Patients should be counseled that antibacterial drugs, including Ledermix (Demeclocycline Hydrochloride) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ledermix (Demeclocycline Hydrochloride) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Ledermix (Demeclocycline Hydrochloride) tablets or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests

In venereal diseases when coexistent syphilis is suspected, darkfield examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic, should be performed. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with Ledermix should have a follow-up serologic test for syphilis after 3 months.

Drug Interactions

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillins, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin.

Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective.

The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and by iron-containing preparations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of Ledermix have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors).

Although mutagenicity studies of Ledermix (Demeclocycline Hydrochloride) have not been conducted, positive results in in vitro mammalian cell assays (i.e., mouse lymphoma and Chinese hamster lung cells) have been reported for related antibiotics (tetracycline hydrochloride and oxytetracycline) (see WARNINGS; ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY ).

Ledermix (Demeclocycline Hydrochloride) had no effect on fertility when administered in the diet to male and female rats at a daily intake of 45 times the human dose.

Pregnancy

Teratogenic Effects

Pregnancy Category D

.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy.

Nonteratogenic Effects

(See WARNINGS ).

Labor and Delivery

The effect of tetracyclines on labor and delivery is unknown.

Nursing Mothers

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from the tetracyclines, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Not for use in patients younger than eight years of age (see WARNINGS ; PRECAUTIONS , General and DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS

The following reactions have been reported in patients receiving tetracyclines:

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, pancreatitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region, increases in liver enzymes, and hepatic toxicity has been reported rarely.

Rarely, hepatitis and liver failure have been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines.

Instances of esophageal ulcerations have been reported in patients receiving oral tetracyclines. Most of the patients were reported to have taken the medication immediately before lying down (see DOSAGE AND ADMINISTRATION ).

Skin: Maculopapular and erythematous rashes, erythema multiforme. Exfoliative dermatitis has been reported but is uncommon. Fixed drug eruptions and Stevens-Johnson syndrome have been reported rarely. Lesions occurring on the glans penis have caused balanitis. Pigmentation of the skin and mucous membranes has also been reported. Photosensitivity is discussed above (see WARNINGS ).

Renal toxicity: Acute renal failure. Rise in BUN has been reported and is apparently dose related. Nephrogenic diabetes insipidus (see WARNINGS ).

Hypersensitivity reactions: Urticaria, angioneurotic edema, polyarthralgia, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus, lupus-like syndrome, pulmonary infiltrates with eosinophilia.

Hematologic: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported.

CNS: Pseudotumor cerebri (benign intracranial hypertension) in adults and bulging fontanels in infants (see PRECAUTIONS, General ). Dizziness, headache, tinnitus, and visual disturbances have been reported. Myasthenic syndrome has been reported rarely.

Other: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur. Very rare cases of abnormal thyroid function have been reported.

Tooth discoloration has occurred in pediatric patients less than 8 years of age (see WARNINGS ), and also has been reported rarely in adults.

OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Tetracyclines are not removed in significant quantities by hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION

Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.

Concomitant Therapy

Absorption of tetracycline is impaired by antacids containing aluminum, calcium, or magnesium, and by iron-containing preparations. Foods and some dairy products also interfere with absorption. Oral forms of tetracycline should be given at least 1 hour before or 2 hours after meals.

In Patients With Renal Impairment

. Tetracyclines should be used cautiously in patients with impaired renal function. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses.

In Patients With Liver Impairment

Tetracyclines should be used cautiously in patients with impaired liver function. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses. Administration of adequate amounts of fluid with the oral formulations of tetracyclines is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS ).

Adults

Usual Daily Dose

Four divided doses of 150 mg each or two divided doses of 300 mg each.

For Pediatric Patients Above Eight Years of Age

Usual daily dose, 7 to 13 mg per kg body weight per day, depending upon the severity of the disease, divided into two to four doses not to exceed adult dosage of 600 mg per day.

Gonorrhea patients sensitive to penicillin may be treated with demeclocycline administered as an initial oral dose of 600 mg followed by 300 mg every 12 hours for four days to a total of 3 grams.

HOW SUPPLIED

Ledermix (Demeclocycline Hydrochloride) Tablets USP, 150 mg are available as pink, round, biconvex, film-coated, unscored tablets, debossed with “stylized b” 701 on one side and 150 on the other, packaged in bottle of 100 (NDC 0555-0701-02) tablets.

Ledermix (Demeclocycline Hydrochloride) Tablets USP, 300 mg are available as pink, round, biconvex, film-coated, unscored tablets, debossed with “stylized b” 702 on one side and 300 on the other, packaged in bottle of 48 (NDC 0555-0702-84) tablets.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY

Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO₄ and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO₄, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO₄, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline), in chickens (chlortetracycline), and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

REFERENCES

• Clinical and Laboratory Standards Institute (CLSI.) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard – 9th Edition. CLSI document M7-A9, 950 West Valley Rd. Suite 2500,.Wayne, PA 19087, 2012.
• CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 22^nd Informational Supplement. CLSI document M100-S22. Wayne, PA, 2012.
• CLSI. Methods or Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria: Approved Guideline - 2nd Edition. CLSI document M45-A2. CLSI, Wayne, PA, 2011.
• CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard - 11^th Edition. CLSI document M2-A11. Wayne, PA, 2012.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. B 3/2016

NDC 0555-0701-02

Demeclocycline

Hydrochloride

Tablets USP

150 mg

Rx only

100 TABLETS

TEVA

NDC 0555-0702-84

Demeclocycline

Hydrochloride

Tablets USP

300 mg

Rx only

48 TABLETS

TEVA

Eugenol:

• Ledermix (Eugenol) reviews

Active Ingredient Ledermix (Eugenol) 85%

Purpose Toothache Relief Agent

Uses For the temporary relief of throbbing, persisitent toothache due to a cavity. Visit Dentist within 48 hours of use.

Warnings

Allergy alert: do not use if you are allergic to Ledermix (Eugenol) (clove oil).

When using this product: . use only in teeth with persistent, throbbing pain . avoid touching tissuers othere than tooth cavity . DO NOT

SWALLOW to avoid irritation . avoid contact with eyes.

Do not use:. for more than 7 days . more than the recommended dosage.

Stop use and ask a dentist or doctor if:. irritation persists . inflammation develops . if fever and infection develop.

Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away.

Directions Adults and children 12 year of age and older: Rinse the tooth with water to remove any food particles from the cavity. Moisten a cotton swab with Ledermix (Eugenol) and place in the cavity for approximately 1 minute. Avoid touching tissue other than the tooth cavity. Apply the dose not more than four times daily or as directed by dentist or physician.

Adults and children 12 years and older use up to 4 times daily or as directed by a dentist or doctor.

Children under 12 years ask a dentist or doctor.

Inactive ingredient: sesame oil

Other information Do not purchase if package has been opened. Store at 68-77 ^o F. Cap tightly to avoid evaporation.

front and back of card

Triamcinolone Acetonide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Ledermix (Triamcinolone Acetonide) reviews

1 INDICATIONS AND USAGE

Ledermix (Triamcinolone Acetonide) (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra-articular injection for the management of osteoarthritis pain of the knee.

Ledermix (Triamcinolone Acetonide) is an extended-release synthetic corticosteroid indicated as an intra-articular injection for the management of osteoarthritis pain of the knee. ( 1)

Limitation of Use

Ledermix (Triamcinolone Acetonide) is not intended for repeat administration. ( 1)

Limitation of Use

Ledermix (Triamcinolone Acetonide) is not intended for repeat administration .

2 DOSAGE AND ADMINISTRATION

• 32 mg administered as a single intra-articular injection in the knee.
• See Instructions for Use (IFU) for instructions on reconstitution of Ledermix (Triamcinolone Acetonide) with the supplied diluent. ( 2.2)
• It is normal for some residue to be left behind on the vial walls after withdrawing the suspension. ( 2.2)
• Not interchangeable with other formulations of injectable Ledermix (Triamcinolone Acetonide). ( 2.3)

2.1 Important Dosage and Administration Information

• Ledermix (Triamcinolone Acetonide) is administered as a single intra-articular extended-release injection of Ledermix (Triamcinolone Acetonide), to deliver 32 mg (5 mL).
• Ledermix (Triamcinolone Acetonide) is for intra-articular use only and should not be administered by the following routes: epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, subcutaneous.
• Ledermix (Triamcinolone Acetonide) is not suitable for use in small joints, such as the hand.
• The efficacy and safety of repeat administration of Ledermix (Triamcinolone Acetonide) for the management of osteoarthritis pain of the knee have not been evaluated.
• The efficacy and safety of Ledermix (Triamcinolone Acetonide) for management of osteoarthritis pain of shoulder and hip have not been evaluated.

2.2 Preparation and Administration of Intra-Articular Suspension

Refer to the Instructions for Use for directions on the preparation and administration of Ledermix.

Ledermix (Triamcinolone Acetonide) is supplied as a single-dose kit containing a vial of Ledermix (Triamcinolone Acetonide) microsphere powder, a vial of sterile diluent, and a sterile vial adapter.

Ledermix (Triamcinolone Acetonide) must be prepared using the diluent supplied in the kit.

Preparation of Ledermix (Triamcinolone Acetonide) requires close attention to the Instructions for Use to ensure successful administration.

Use proper aseptic technique throughout the dose preparation and administration procedure.

Ledermix (Triamcinolone Acetonide) is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.

Promptly inject Ledermix (Triamcinolone Acetonide) after preparation to avoid settling of the suspension. If needed, the Ledermix (Triamcinolone Acetonide) suspension can be stored in the vial for up to 4 hours at ambient conditions. Gently swirl the vial to resuspend any of the settled microspheres prior to preparing the syringe for injection.

The usual technique for intra-articular injection should be followed. Aspiration of synovial fluid may be performed based on clinical judgment prior to administration of Ledermix (Triamcinolone Acetonide).

2.3 Non-Interchangeability with Other Formulations of Ledermix (Triamcinolone Acetonide) for Intra-articular Use

Ledermix (Triamcinolone Acetonide) is not interchangeable with other formulations of injectable Ledermix (Triamcinolone Acetonide).

3 DOSAGE FORMS AND STRENGTHS

Ledermix (Triamcinolone Acetonide) is an injectable suspension that delivers 32 mg of Ledermix (Triamcinolone Acetonide). Ledermix (Triamcinolone Acetonide) is supplied as a single-dose kit, containing:

• One vial of Ledermix (Triamcinolone Acetonide) white to off-white microsphere powder
• One vial of 5 mL sterile, clear diluent
• One sterile vial adapter

Ledermix (Triamcinolone Acetonide) is an injectable suspension that delivers 32 mg of Ledermix (Triamcinolone Acetonide). It is supplied as a single-dose kit containing one vial of Ledermix (Triamcinolone Acetonide) microsphere powder, one vial of 5 mL diluent, and one sterile vial adapter. ( 3)

4 CONTRAINDICATIONS

Ledermix (Triamcinolone Acetonide) is contraindicated in patients who are hypersensitive to Ledermix (Triamcinolone Acetonide), corticosteroids or any components of the product .

Patients with hypersensitivity to Ledermix (Triamcinolone Acetonide) or any component of the product. ( 4)

5 WARNINGS AND PRECAUTIONS

• Intra-articular Use Only: Do not administer Ledermix by epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous routes. ( 5.1)
• Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration: Serious neurologic events have been reported following epidural or intrathecal corticosteroid administration. Corticosteroids are not approved for this use. ( 5.2)
• Hypersensitivity Reactions: Serious reactions have been reported with Ledermix (Triamcinolone Acetonide) injection. Institute appropriate care upon occurrence of an anaphylactic reaction. ( 5.3)
• Joint Infection and Damage: May cause joint pain accompanied by joint swelling. If this occurs, conduct appropriate evaluation to exclude septic arthritis and institute appropriate antimicrobial therapy if septic arthritis is confirmed. ( 5.4)

5.1 Warnings and Precautions Specific for Ledermix (Triamcinolone Acetonide)

Ledermix (Triamcinolone Acetonide) has not been evaluated and should not be administered by the following routes:

• Epidural
• Intrathecal
• Intravenous
• Intraocular
• Intramuscular
• Intradermal
• Subcutaneous

.

5.2 Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration

Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke . These serious neurologic events have been reported with and without use of fluoroscopy.

Reports of serious medical events have been associated with the intrathecal route of corticosteroid administration .

The safety and effectiveness of epidural and intrathecal administration of corticosteroids have not been established, and corticosteroids are not approved for this use. In particular, the formulation of Ledermix (Triamcinolone Acetonide) should not be considered safe to use for epidural or intrathecal administration.

5.3 Hypersensitivity Reactions

Rare instances of anaphylaxis have occurred in patients with hypersensitivity to corticosteroids. Cases of serious anaphylaxis, including death, have been reported in individuals receiving Ledermix (Triamcinolone Acetonide) injection, regardless of the route of administration . Institute appropriate care upon occurrence of an anaphylactic reaction.

5.4 Joint Infection and Damage

Intra-articular injection of corticosteroid may be complicated by joint infection. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and a diagnosis of septic arthritis is confirmed, institute appropriate antimicrobial therapy .

Avoid injection of a corticosteroid into an infected site. Local injection of a corticosteroid into a previously infected joint is not usually recommended. Examine any joint fluid present to exclude a septic process.

Corticosteroid injection into unstable joints is generally not recommended.

Intra-articular injection may result in damage to joint tissues.

5.5 Increased Risk of Infections

Intra-articularly injected corticosteroids are systemically absorbed. Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection.

Advise patients to inform their health care provider if they develop fever or other signs or symptoms of infection. Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed .

5.6 Alterations in Endocrine Function

Corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis suppression, with the potential for adrenal insufficiency after withdrawal of treatment, which may persist for months.

In situations of stress during that period, institute corticosteroid replacement therapy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients.

5.7 Cardiovascular Effects

Corticosteroids can cause elevations of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives.

Monitor patients with congestive heart failure or hypertension for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary.

5.8 Renal Effects

Corticosteroids can cause salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives. All corticosteroids increase calcium excretion.

Monitor patients with renal insufficiency for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary.

5.9 Increased Intraocular Pressure

Corticosteroid use may be associated with development or exacerbation of increased intraocular pressure.

Monitor patients with elevated intraocular pressure for potential treatment adjustment.

5.10 Gastrointestinal Perforation

Corticosteroid administration is associated with increased risk of gastrointestinal perforation in patients with certain GI disorders such as active or latent peptic ulcers, diverticulosis, diverticulitis, ulcerative colitis and in patients with fresh intestinal anastomoses.

Avoid corticosteroids in these patients because signs of peritoneal irritation following gastrointestinal perforation may be minimal or absent.

5.11 Alterations in Bone Density

Corticosteroids decrease bone formation and increase bone resorption through their effect on calcium regulation and inhibition of osteoblast function.

Special consideration should be given to patients with or at increased risk of osteoporosis before initiating corticosteroid therapy.

5.12 Behavioral and Mood Disturbances

Corticosteroid use may be associated with new or aggravated adverse psychiatric reactions ranging from euphoria, insomnia, mood swings, and personality changes to severe depression and frank psychotic manifestations.

Special consideration should be given to patients with previous or current emotional instability or psychiatric illness before initiating corticosteroid therapy. Advise patients and/or caregivers to immediately report any new or worsening behavior or mood disturbances to their health care provider.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling.

• Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration [ see Warnings and Precautions ( 5.2) ]
• Hypersensitivity Reactions [ see Warnings and Precautions ( 5.3) ]
• Joint Infection and Damage [ see Warnings and Precautions ( 5.4) ]
• Increased Risk of Infections [ see Warnings and Precautions ( 5.5) ]
• Alterations in Endocrine Function [ see Warnings and Precautions ( 5.6) ]
• Cardiovascular Effects [ see Warnings and Precautions ( 5.7) ]
• Renal Effects [ see Warnings and Precautions ( 5.8) ]
• Increased Intraocular Pressure [ see Warnings and Precautions ( 5.9) ]
• Gastrointestinal Perforation [ see Warnings and Precautions ( 5.10) ]
• Alternations in Bone Density [ see Warnings and Precautions ( 5.11) ]
• Behavioral and Mood Disturbances [ see Warnings and Precautions ( 5.12) ]

Because clinical studies 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 data below reflect exposure to a single 32 mg intra-articular injection of Ledermix (Triamcinolone Acetonide) in clinical studies in patients with moderate to severe pain due to osteoarthritis of the knee. Clinical studies included randomized, double-blind, parallel-group, placebo and/or active-controlled, and pharmacokinetic/pharmacodynamic studies with follow-up ranging from 6-24 weeks. A total of 424 patients received Ledermix (Triamcinolone Acetonide) and 262 received placebo. Treatment emergent adverse reactions reported by greater than or equal to 1% of patients in the Ledermix (Triamcinolone Acetonide) arms are summarized below ( Table 1 and 2 ).

Overall, the incidence and nature of adverse reactions was similar to that observed with placebo.

Most commonly reported adverse reactions (incidence ≥1%) in clinical studies include sinusitis, cough, and contusions. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Flexion Therapeutics, Inc. at 1-844-FLEXION (353-9466) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Corticosteroid Adverse Reactions

The following adverse reactions, presented alphabetically by body system, are from voluntary reports or clinical studies of corticosteroids. Because some of 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.

Anaphylactic reactions: Anaphylaxis including death, angioedema .

Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, hypertension , fat embolism, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine: Decreased carbohydrate and glucose tolerance, development of Cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients , fluid retention, sodium retention.

Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration) , elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease) , ulcerative esophagitis.

Metabolic: Negative nitrogen balance due to protein catabolism.

Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders , vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids .

Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure , posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

7 DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with Ledermix (Triamcinolone Acetonide). Table 3 contains drug interactions associated with systemic corticosteroids.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data regarding the use of Ledermix in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published studies on the association between corticosteroids and fetal outcomes have reported inconsistent findings and have important methodological limitations. The majority of published literature with corticosteroid exposure during pregnancy includes the oral, topical and inhaled dosage formulations; therefore, the applicability of these findings to a single intra-articular injection of Ledermix (Triamcinolone Acetonide) is limited. In animal reproductive studies from the published literature, pregnant mice, rats, rabbits, or primates administered Ledermix (Triamcinolone Acetonide) during the period of organogenesis at doses that produced exposures less than the maximum recommended human dose (MRHD) caused resorptions, decreased fetal body weight, craniofacial and/or other abnormalities such as omphalocele .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

The exposure margins listed below are based on body surface area comparisons (mg/m ²) to the highest daily Ledermix (Triamcinolone Acetonide) exposure at the MRHD of 32 mg Ledermix (Triamcinolone Acetonide) via Ledermix (Triamcinolone Acetonide).

Pregnant mice dosed with Ledermix (Triamcinolone Acetonide) via intramuscular or subcutaneous injection at doses equivalent to 0.8 times the MRHD or higher during organogenesis caused cleft palate and a higher rate of resorption. In pregnant rats dosed with Ledermix (Triamcinolone Acetonide) via intramuscular or subcutaneous injection at doses equivalent to 0.3 times the MRHD or higher during organogenesis caused developmental abnormality (cleft palate, omphalocele, late resorption, and growth retardation) and fetal mortality. No notable maternal toxicity was observed in rodents.

Pregnant rabbits dosed with Ledermix (Triamcinolone Acetonide) via intramuscular injection for 4 days during organogenesis at doses equivalent to 0.15 times the MRHD or higher caused resorption and cleft palate. No notable maternal toxicity was observed.

Pregnant primates dosed with Ledermix (Triamcinolone Acetonide) via intramuscular injection for 4 days during organogenesis at doses equivalent to 3 times the MRHD or higher caused severe craniofacial CNS and skeletal/visceral malformation and higher prenatal death. No notable maternal toxicity was observed.

No peri- and post-natal development studies of Ledermix (Triamcinolone Acetonide) in animals have been conducted.

8.2 Lactation

Risk Summary

There are no available data on the presence of Ledermix (Triamcinolone Acetonide) in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, corticosteroids have been detected in human milk and may suppress milk production. It is not known whether intra-articular administration of Ledermix (Triamcinolone Acetonide) could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ledermix (Triamcinolone Acetonide) and any potential adverse effects on the breastfed infant from Ledermix (Triamcinolone Acetonide) or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Corticosteroids may result in menstrual pattern irregularities such as deviations in timing and duration of menses and an increased or decreased loss of blood.

8.4 Pediatric Use

The safety and effectiveness of Ledermix in pediatric patients have not been established.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults. Carefully observe pediatric patients, including weight, height, linear growth, blood pressure, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Weigh potential growth effects of treatment against clinical benefits obtained and the availability of treatment alternatives.

8.5 Geriatric Use

Of the total number of patients administered 32 mg Ledermix (Triamcinolone Acetonide) in clinical studies (N=424), 143 patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between elderly and younger subjects, and other reported clinical experience with Ledermix (Triamcinolone Acetonide) has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

Ledermix (Triamcinolone Acetonide) (triamcinolone acetonide extended-release injectable suspension) is a microsphere formulation of Ledermix (Triamcinolone Acetonide), a corticosteroid, to be administered by intra-articular injection.

Ledermix (Triamcinolone Acetonide) is formulated in 75:25 poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (w/w) and is provided as a sterile white to off-white powder. Ledermix (Triamcinolone Acetonide) is prepared with a supplied diluent containing an isotonic, sterile, aqueous solution of sodium chloride (NaCl; 0.9% w/w), sodium carboxymethylcellulose (CMC; 0.5% w/w) and polysorbate-80 (0.1% w/w) to form a 5 mL sterile suspension intended for intra-articular injection.

Active Ingredient

The chemical name for Ledermix (Triamcinolone Acetonide) is 9-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene- 3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is:

Ledermix (Triamcinolone Acetonide) occurs as a white to almost white, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. Each vial of Ledermix (Triamcinolone Acetonide) powder contains 40 mg of Ledermix (Triamcinolone Acetonide) in 160 mg of microspheres, resulting in 32 mg of deliverable Ledermix (Triamcinolone Acetonide) when prepared according to the Instructions for Use.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ledermix is a corticosteroid with anti-inflammatory and immunomodulating properties. It binds to and activates the glucocorticoid receptor, leading to activation of anti-inflammatory transcription factors such as lipocortins and inhibition of inflammatory transduction pathways by blocking the release of arachidonic acid and preventing the synthesis of prostaglandins and leukotrienes.

12.2 Pharmacodynamics

Studies indicate that following a single intramuscular dose of 60 to 100 mg of immediate-release Ledermix (Triamcinolone Acetonide) injectable suspension, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. To assess potential effects of the systemic levels of Ledermix (Triamcinolone Acetonide) associated with a single intra-articular (IA) administration of Ledermix (Triamcinolone Acetonide) on hypothalamic pituitary adrenal (HPA) axis function, serum and urine cortisol levels were monitored over 6 weeks post injection. Adrenal suppression with Ledermix (Triamcinolone Acetonide) occurred within 12-24 hours and then gradually returned to normal, within 30-42 days.

Corticosteroids may increase blood glucose concentrations.

In a study where 18 patients with osteoarthritis knee pain and controlled type 2 diabetes mellitus received a single IA injection of Ledermix (Triamcinolone Acetonide) into the knee, the change from baseline in average blood glucose over the 72 hours after injection as measured by a continuous glucose monitoring device was 8.2 mg/dL (95% confidence interval 0.1, 29.2).

12.3 Pharmacokinetics

Ledermix (Triamcinolone Acetonide) is an extended-release dosage form consisting of microspheres of poly(lactic-co-glycolic acid) (PLGA) containing Ledermix (Triamcinolone Acetonide). Plasma pharmacokinetic parameters for Ledermix (Triamcinolone Acetonide) following IA administration of Ledermix (Triamcinolone Acetonide) or 40 mg immediate-release Ledermix (Triamcinolone Acetonide) into the knee are provided in Table 4.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of Ledermix (Triamcinolone Acetonide) have not been conducted.

Mutagenesis

Adequate mutagenicity studies have not been conducted with Ledermix (Triamcinolone Acetonide).

Impairment of Fertility

Studies in animals to evaluate the impairment of fertility of Ledermix (Triamcinolone Acetonide) have not been conducted.

14 CLINICAL STUDIES

The efficacy of Ledermix (Triamcinolone Acetonide) was demonstrated in a multi-center, international, randomized, double-blind, parallel-arm, placebo- and active-controlled study in patients with osteoarthritis pain of the knee. A total of 484 patients (ZILRETTA 32 mg, N=161; placebo [saline], N=162; active control [a crystalline suspension, immediate-release formulation of Ledermix (Triamcinolone Acetonide) 40 mg], N=161) were treated and followed for up to 24 weeks. Patients had a mean age of 62 (range 40 to 85 years); baseline demographics and disease characteristics were balanced across treatment arms. Twenty-five percent (25%) of patients had received at least one prior corticosteroid intra-articular injection more than 3 months prior to treatment. A total of 470 patients (97%) completed follow-up to Week 12, the time point for primary efficacy determination, and 443 (91.5%) completed to Week 24.

The primary efficacy endpoint comparing Ledermix (Triamcinolone Acetonide) to placebo was change from baseline at Week 12 in the weekly mean of the Average Daily Pain intensity scores (ADP) as assessed by a 0-10 Numeric Rating Scale (NRS). Ledermix (Triamcinolone Acetonide) demonstrated a statistically significant reduction in pain intensity at the primary endpoint vs placebo. Ledermix (Triamcinolone Acetonide) also demonstrated a reduction in pain intensity scores each week from Weeks 1 through 12 ( Figure 1 ).

In a secondary exploratory analysis, statistical significance was not demonstrated between the Ledermix (Triamcinolone Acetonide) and the active control (immediate-release Ledermix (Triamcinolone Acetonide)) treatment groups for the change from baseline at Week 12 in weekly mean ADP.

Figure 1: Weekly Change from Baseline to Week 12 in Average Daily Pain

Figure 1

16 HOW SUPPLIED/STORAGE AND HANDLING

STORAGE

To maintain expiry period, refrigerate the Ledermix (Triamcinolone Acetonide) single-dose kit (36°-46°F; 2°-8°C) before use.

If refrigeration is unavailable, store the Ledermix (Triamcinolone Acetonide) single-dose kit in the sealed, unopened kit at temperatures not exceeding 77°F (25°C) for up to six weeks and then discard. Do not expose the Ledermix (Triamcinolone Acetonide) single-dose kit to temperatures above 77°F (25°C).

Do not freeze. Store vials in carton.

17 PATIENT COUNSELING INFORMATION

Increased Risk of Infections

Inform patients that they may be more likely to develop infections when taking corticosteroids. Instruct patients to contact their health care provider if they develop fever or other signs or symptoms of infection.

Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed .

Risk of Drug Interactions

There are a number of medicines that can interact with corticosteroids such as Ledermix (Triamcinolone Acetonide). Advise patients to alert their health care provider(s) to assess the need to adjust their medication(s) .

Risk of Adverse Psychiatric Reactions

Inform patients that corticosteroid use may be associated with adverse psychiatric reactions. Advise patients and/or caregivers to immediately report any new or worsening behavioral or mood disturbances to their health care provider .

Manufactured for Flexion Therapeutics, Inc., 10 Mall Rd, Suite 301, Burlington, MA 01803

Ledermix (Triamcinolone Acetonide) and Flexion are trademarks of Flexion Therapeutics, Inc.

Copyright © 2017 Flexion Therapeutics, Inc. All rights reserved.

For more information, go to Ledermix (Triamcinolone Acetonide).com or call 1-844-FLEXION (353-9466).

Part Number: 60-004-01

Version: 1, 10/2017

Instructions for Use

Ledermix (Triamcinolone Acetonide)

(triamcinolone acetonide

extended-release injectable suspension)

For intra-articular injection only

Single-dose device

Do not reuse.

IMPORTANT INFORMATION

• Ledermix (Triamcinolone Acetonide) must be prepared using only the diluent supplied in the kit.
• To ensure proper dosing, it is important that you follow the preparation and administration steps outlined in these instructions.
• Promptly inject Ledermix (Triamcinolone Acetonide) after preparation to avoid settling of the suspension.
• Ledermix (Triamcinolone Acetonide) is supplied as a single-dose kit and administered as a suspension containing microspheres.
• The Ledermix (Triamcinolone Acetonide) powder vial contains an overfill to allow the appropriate dose to be withdrawn. Ledermix (Triamcinolone Acetonide) is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
• Use proper aseptic technique throughout the dose preparation and administration procedure.
• Inspect all kit components to confirm they have not expired and the seals are intact.
• For additional information, visit www.zilretta.com or call Flexion Therapeutics at 1-844-FLEXION (353-9466).

MATERIALS REQUIRED

(Fig.1)

Supplied

• One 32 mg vial of Ledermix (Triamcinolone Acetonide) microsphere powder
• One 5 mL vial of sterile diluent
• One sterile vial adapter

Not Supplied

• Three sterile needles, 21-gauge, 1½” length
• One sterile Luer Lock compatible syringe, 5 mL
• Sterile alcohol pads
• Paper towels or pad to cushion vial tapping (not shown in Fig. 1)
• Medical-grade gloves (not shown in Fig. 1)

Figure 1

1. Vial Preparation

Loosen Powder.

Place two paper towels or a pad on a properly-cleaned hard surface.

Grip the top of the Ledermix (Triamcinolone Acetonide) powder vial and tap firmly and repeatedly on the padded surface. Tap the vial until excess powder is dislodged from the vial and stopper ( Fig. 2). Before continuing, ensure that powder moves freely within the vial.

Figure 2

Inspect Ledermix (Triamcinolone Acetonide) Powder Vial.

As shown in Figure 3, the vial on the left, with the X, requires additional tapping because the powder is not properly dislodged. The vial on the right shows the powder properly dislodged and ready for the next step.

Figure 3

Remove Caps.

Remove the flip-off caps from the Ledermix (Triamcinolone Acetonide) powder and diluent vials ( Fig. 4).

Figure 4

Clean Vials.

Clean the Ledermix (Triamcinolone Acetonide) powder and diluent vial tops with an alcohol pad.

Use a separate alcohol pad for each vial.

Peel Off Vial Adapter Cover.

Peel off the paper cover from the vial adapter package ( Fig. 5).

Leave the adapter in the plastic holder.

Figure 5

Attach Vial Adapter to Ledermix (Triamcinolone Acetonide) Powder Vial.

Grip the plastic holder that contains the vial adapter.

As shown in Figure 6, place the Ledermix (Triamcinolone Acetonide) powder vial on a flat surface. In a vertical orientation, gently push the adapter down onto the Ledermix (Triamcinolone Acetonide) powder vial until the spike on the adapter penetrates the rubber stopper on the Ledermix (Triamcinolone Acetonide) powder vial. The adapter will snap into place.

Figure 6

2. Diluent Preparation

Attach Needle.

Attach a needle to the syringe and remove the needle guard.

Withdraw Diluent.

With a syringe and needle, withdraw 5 mL of diluent.

Replace the needle guard.

3. Dose Preparation

Remove Holder.

Remove the plastic holder from the vial adapter ( Fig. 7).

Figure 7

Remove Needle.

Remove the needle from the syringe containing diluent.

Attach Diluent Syringe.

Attach the syringe onto the vial adapter by pushing down and turning clockwise until you feel resistance ( Fig. 8).

Figure 8

Transfer Diluent.

Slowly and completely push down the syringe plunger to transfer the diluent into the Ledermix (Triamcinolone Acetonide) powder vial ( Fig. 9).

Note: Equalize the pressure in the syringe by slowly pulling back the plunger to the 5 mL mark. Ensure that no solution is drawn back into the syringe at this stage.

Figure 9

Mix Diluent and Powder ( Fig. 10).

With the syringe still attached to the Ledermix (Triamcinolone Acetonide) powder vial, hold the syringe and vial at a slight angle. Tap the bottom edge of the vial firmly and repeatedly, in a circular motion, on the padded surface.

Swirl gently every five or six taps.

Tap for at least one minute until all powder is completely dispersed.

Note: Avoid vigorous shaking of the vial to minimize foaming.

Note: At least one minute of tapping and gentle swirling is required to achieve uniform suspension.

Figure 10

Inspect Vial.

Inspect the Ledermix (Triamcinolone Acetonide) powder vial to ensure no clumped powder is visible and a uniform suspension has been achieved. A properly mixed suspension will be milky white, contain no clumps, and move freely down the vial wall.

As shown in Figure 11, the vial on the left, with the X, requires more tapping and gentle swirling because the powder is not mixed properly with the diluent. The vial on the right shows the powder properly mixed and ready for the next step.

Figure 11

Note: If needed, the Ledermix (Triamcinolone Acetonide) suspension can be stored in the vial for up to 4 hours at ambient conditions. The syringe must remain on the vial adapter while the suspension remains in the vial.

Withdraw Contents into Syringe.

Swirl the vial gently for at least 10 seconds to ensure the powder is fully suspended. Immediately depress the plunger fully and then invert the syringe so the vial is directly on top of the syringe ( Fig. 12).

Hold the syringe in a completely vertical position, per the illustration on the right, in Figure 12.

Withdraw the full contents from the Ledermix (Triamcinolone Acetonide) vial into the syringe.

Figure 12

Note: Ledermix (Triamcinolone Acetonide) is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.

Remove Syringe.

Remove the syringe from the vial adapter by turning counter-clockwise.

Remove Air Bubbles.

Attach a new needle to the syringe and remove the needle guard.

Inspect for bubbles with the syringe held in a completely vertical position (needle upward). If bubbles are observed, gently tap the syringe with your finger until the bubbles rise to the top. Eliminate all bubbles by slowly depressing the plunger to displace the air from the syringe.

Replace the needle guard.

Attach New Needle.

Remove and discard the needle.

Attach a new needle.

4. Administration

Invert Syringe.

To ensure the powder is suspended, gently invert the syringe containing Ledermix (Triamcinolone Acetonide) several times just prior to administration, as shown in Figure 13.

Grip the syringe firmly and turn it so the syringe plunger is pointing straight down. Then turn the syringe gently, 180 degrees, until the plunger is pointing straight up.

Invert the syringe several times to ensure a properly mixed suspension.

Figure 13

A properly mixed suspension will be uniformly milky white and contain no clumps.

Inspect Syringe.

As shown in Figure 14, the syringe on the left, with the X, requires more inversions (turning) to properly mix the suspension. The syringe on the right shows the suspension properly mixed and ready for the next step.

Figure 14

Administer Ledermix (Triamcinolone Acetonide).

The usual technique for intra-articular injection should be followed.

Aspiration of synovial fluid may be performed based on clinical judgment prior to administration of Ledermix (Triamcinolone Acetonide).

Do not reuse excess Ledermix (Triamcinolone Acetonide). Any excess suspension in the vial should be thrown away immediately after the injection. Leftover Ledermix (Triamcinolone Acetonide) in the vial must never be reused for another injection.

Note: The entire contents of the syringe must be injected to ensure the intended dose of Ledermix (Triamcinolone Acetonide) is delivered.

Note: Discard all used components in an appropriate medical waste container according to local regulations.

Note: Ledermix (Triamcinolone Acetonide) is for intra-articular use only. Ledermix (Triamcinolone Acetonide) is not intended for epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous use.

Part Number: 60-005-01

Rev: 10/2017

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14

Principal Display Panel - Ledermix (Triamcinolone Acetonide) Cart 32mg Carton Label

NDC 70801-003-01 Rx Only

Ledermix (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Single-dose kit. Discard unused portion.

Must be reconstituted

with the supplied diluent.

This carton contains:

1 Vial of Ledermix (Triamcinolone Acetonide)

microsphere powder

1 Vial of diluent (5 mL)

for Ledermix (Triamcinolone Acetonide)

1 sterile vial adapter

flexion

Principal Display Panel - Ledermix (Triamcinolone Acetonide) Cart 32mg Professional Carton Label

NDC 70801-003-02 Rx Only

Ledermix (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Single-dose kit. Discard unused portion.

Must be reconstituted

with the supplied diluent.

PROFESSIONAL SAMPLE

NOT FOR SALE

OR REIMBURSEMENT

This carton contains:

1 Vial of Ledermix (Triamcinolone Acetonide)

microsphere powder

1 Vial of diluent (5 mL)

for Ledermix (Triamcinolone Acetonide)

1 sterile vial adapter

flexion

Principal Display Panel - Ledermix (Triamcinolone Acetonide) 32mg Vial Label

NDC 70801-001-01 Rx Only

Ledermix (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Must be reconstituted

with the supplied diluent.

flexion

Principal Display Panel - Ledermix (Triamcinolone Acetonide) 32mg Professional Vial Label

NDC 70801-001-02 Rx Only

Ledermix (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Must be reconstituted

with the supplied diluent.

flexion

Principal Display Panel - Ledermix (Triamcinolone Acetonide) Diluent 5mL Vial Label

NDC 70801-002-01 Rx Only

DILUENT

for use with Ledermix (Triamcinolone Acetonide)

5 mL

Sterile single-use vial

Do not administer directly.

flexion

Principal Display Panel - Ledermix (Triamcinolone Acetonide) Diluent 5mL Professional Vial Label

NDC 70801-002-02 Rx Only

DILUENT

for use with Ledermix (Triamcinolone Acetonide)

5 mL

Sterile single-use vial

Do not administer directly.

flexion