Toposar

etoposide

Dosage Form: injection
Toposar™ (Etoposide Injection, USP)

Rx only

Toposar (etoposide injection, USP) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with resulting infection or bleeding may occur.

Toposar Description

Toposar (etoposide injection, USP) (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents. It has a molecular weight of 588.58 and a molecular formula of C29H32O13.

Toposar is available for intravenous use as a sterile 20 mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), or 1 g (50 mL) sterile multiple dose vials. The pH of the clear, yellow liquid is 3.0 to 4.0.

Each mL contains: 20 mg etoposide, 2 mg citric acid anhydrous, 80 mg polysorbate 80, 650 mg polyethylene glycol 300, dehydrated alcohol 33.2% (v/v).

The structural formula is:

Toposar - Clinical Pharmacology

Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G2 portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals.

Pharmacokinetics

On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration vs time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days.

The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro, etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. In a study determining the effect of other therapeutic agents on the in vitro binding of carbon-14 labeled etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations achieved in vivo.

Etoposide binding ratio correlates directly with serum albumin in patients with cancer and in normal volunteers. The unbound fraction of etoposide significantly correlated with bilirubin in a population of cancer patients. Data have suggested a significant inverse correlation between serum albumin concentration and free fraction of etoposide. (See PRECAUTIONS section.)

After intravenous administration of 14C-etoposide (100-124 mg/m2), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours.

In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known.

Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-O-(R)-ethylidene-β-D-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

After either intravenous infusion or oral capsule administration, the Cmax and AUC values exhibit marked intra- and inter-subject variability.

In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration, and nonrenal clearance. Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and a lower volume of distribution at steady state. (See PRECAUTIONS section.) Use of cisplatin therapy is associated with reduced total body clearance. In children, elevated serum SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.

Although some minor differences in pharmacokinetic parameters between age and gender have been observed, these differences were not considered clinically significant.

Indications and Usage for Toposar

Toposar is indicated in the management of the following neoplasms:

Refractory Testicular Tumors

Toposar in combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumors who have already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy.

Small Cell Lung Cancer

Etoposide injection and/or capsules in combination with other approved chemotherapeutic agents as first line treatment in patients with small cell lung cancer.

Contraindications

Toposar is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.

Warnings

Patients being treated with Toposar must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of Toposar: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm3 or an absolute neutrophil count below 500/mm3 is an indication to withhold further therapy until the blood counts have sufficiently recovered.

Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain. (See ADVERSE REACTIONS section.) Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.

For parenteral administration, Toposar should be given only by slow intravenous infusion (usually over a 30- to 60-minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection.

Pregnancy

Etoposide can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic in mice and rats.

In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20th of the human dose on a mg/m2 basis) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 1/7th and 1/2 of human dose on a mg/m2 basis) resulted in 90 and 100% embryonic resorptions. In mice, a single 1.0 mg/kg (1/16th of human dose on a mg/m2 basis) dose of etoposide administered intraperitoneally on days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations. An I.P. dose of 1.5 mg/kg (about 1/10th of human dose on a mg/m2 basis) on day 7 of gestation caused an increase in the incidence of intrauterine death and fetal malformations and a significant decrease in the average fetal body weight.

Women of childbearing potential should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be warned of the potential hazard to the fetus.

Etoposide should be considered a potential carcinogen in humans. The occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. The risk of development of a preleukemic or leukemic syndrome is unclear. Carcinogenicity tests with etoposide have not been conducted in laboratory animals.

Precautions

General

In all instances where the use of etoposide is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Toposar therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Patients with low serum albumin may be at an increased risk for etoposide associated toxicities.

Drug Interactions

High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.

Laboratory Tests

Periodic complete blood counts should be done during the course of etoposide treatment. They should be performed prior to each cycle of therapy and at appropriate intervals during and after therapy. At least one determination should be done prior to each dose of etoposide.

Renal Impairment

In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance:

Measured Creatinine Clearance	>50 mL/min	15-50 mL/min
etoposide	100% of dose	75% of dose

Subsequent etoposide dosing should be based on patient tolerance and clinical effect.

Data are not available in patients with creatinine clearances <15 mL/min and further dose reduction should be considered in these patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

(see WARNINGS section)

Etoposide has been shown to be mutagenic in Ames assay.

Treatment of Swiss-Albino mice with 1.5 mg/kg I.P. of etoposide on day 7 of gestation increased the incidence of intrauterine death and fetal malformations as well as significantly decreased the average fetal body weight. Maternal weight gain was not affected.

Irreversible testicular atrophy was present in rats treated with etoposide intravenously for 30 days at 0.5 mg/kg/day (about 1/16th of the human dose on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy "Category D."

(See WARNINGS section.)

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etoposide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Toposar contains polysorbate 80. In premature infants, a life-threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80. Anaphylactic reactions have been reported in pediatric patients. (See WARNINGS section.)

Geriatric Use

Clinical studies of etoposide for the treatment of refractory testicular tumors did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received etoposide or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine, and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence, and elevated BUN levels than younger patients.

In five single-agent studies of etoposide phosphate in patients with a variety of tumor types, 34% of patients were age 65 years or more. WHO Grade III or IV leukopenia, granulocytopenia, and asthenia were more frequent among elderly patients.

Postmarketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications, and alopecia.

Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically significant.

Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse 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 it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment for recommended dosing adjustments in patients with renal impairment).

Adverse Reactions

The following data on adverse reactions are based on both oral and intravenous administration of etoposide as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.

Hematologic Toxicity

Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported.

The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with etoposide in association with other antineoplastic agents. (See WARNINGS section.)

Gastrointestinal Toxicity

Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy. Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion.

Hypotension

Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that etoposide injection be administered by slow intravenous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used.

Allergic Reactions

Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous etoposide and in less than 1% of the patients treated with the oral capsules. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; however, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic-like reactions have occurred during the initial infusion of etoposide.

Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely.

Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported.

Alopecia

Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients.

Other Toxicities

The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis.

Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with etoposide. Metabolic acidosis has also been reported in patients receiving higher doses.

Reports of extravasation with swelling have been received postmarketing. Rarely extravasation has been associated with necrosis and venous induration.

The incidences of adverse reactions in the table that follows are derived from multiple data bases from studies in 2,081 patients when etoposide was used either orally or by injection as a single agent.

ADVERSE DRUG EFFECT	PERCENT RANGE OF REPORTED INCIDENCE
Hematologic toxicity
Leukopenia (less than 1,000 WBC/mm3)	3-17
Leukopenia (less than 4,000 WBC/mm3)	60-91
Thrombocytopenia (less than 50,000 platelets/mm3)	1-20
Thrombocytopenia (less than 100,000 platelets/mm3)	22-41
Anemia	0-33
Gastrointestinal toxicity
Nausea and vomiting	31-43
Abdominal pain	0-2
Anorexia	10-13
Diarrhea	1-13
Stomatitis	1-6
Hepatic	0-3
Alopecia	8-66
Peripheral neurotoxicity	1-2
Hypotension	1-2
Allergic reaction	1-2

Overdosage

No proven antidotes have been established for etoposide overdosage.

Toposar Dosage and Administration

Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used withundiluted etoposide injection.

Toposar

The usual dose of Toposar in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5.

In small cell lung cancer, the Toposar dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days.

For recommended dosing adjustments in patients with renal impairment see PRECAUTIONS section.

Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.

The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Administration Precautions

As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of Toposar. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If Toposar solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.

Preparation for Intravenous Administration

Toposar must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the Toposar solution be administered over a 30- to 60-minute period. A longer duration of administration may be used if the volume of fluid to be infused is a concern. Toposar should not be given by rapid intravenous injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration (see DESCRIPTION section) prior to administration whenever solution and container permit.

Stability

Unopened vials of Toposar are stable until the date indicated on the package at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How is Toposar Supplied

Toposar (etoposide injection, USP) 20 mg/mL is supplied as follows:

NDC Number	Contents	Size
0703-5653-01	100 mg	5 mL Multiple Dose Vials
0703-5656-01	500 mg	25 mL Multiple Dose Vials
0703-5657-01	1 gram	50 mL Multiple Dose Vials

All are available individually packaged.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

DO NOT FREEZE.

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.


2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621.


3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591.


4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.


5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.


6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.


7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.


8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.). Am J Health-SystPharm. 1996;53:1669-1685.

Manufactured by:

Teva Parenteral Medicines, Inc.

Irvine, CA 92618

Rev. A 9/2011

PRINCIPAL DISPLAY PANEL

Toposar (etoposide injection, USP) 20 mg/mL (100 mg/5 mL) Vial Carton Text

NDC 0703-5653-01

Rx only

Toposar™

(etoposide

injection, USP)

20 mg/mL

(100 mg/5 mL)

Warning: Cytotoxic Agent

Must Be Diluted Before IV Infusion

5 mL Multiple Dose Vial

TEVA

PRINCIPAL DISPLAY PANEL

Toposar (etoposide injection, USP) 20 mg/mL (500 mg/25 mL) Vial Carton Text

NDC 0703-5656-01

Rx only

Toposar™

(etoposide

injection, USP)

20 mg/mL

(500 mg/25 mL)

Warning: Cytotoxic Agent

Must Be Diluted Before IV Infusion

25 mL Multiple Dose Vial

TEVA

PRINCIPAL DISPLAY PANEL

Toposar (etoposide injection, USP) 20 mg/mL (1 gram/ 50 mL)Vial Carton Text

NDC 0703-5657-01

Rx only

Toposar™

(etoposide

injection, USP)

20 mg/mL

(1 gram/50 mL)

Warning: Cytotoxic Agent

Must Be Diluted Before IV Infusion

50 mL Multiple Dose Vial

TEVA

Toposar  etoposide  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0703-5653 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ETOPOSIDE (ETOPOSIDE) ETOPOSIDE 20 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength ANHYDROUS CITRIC ACID   POLYSORBATE 80   POLYETHYLENE GLYCOL 300   ALCOHOL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0703-5653-01 1 VIAL In 1 CARTON contains a VIAL, MULTI-DOSE 1 5 mL In 1 VIAL, MULTI-DOSE This package is contained within the CARTON (0703-5653-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA074529	10/06/2011

Toposar  etoposide  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0703-5656 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ETOPOSIDE (ETOPOSIDE) ETOPOSIDE 20 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength ANHYDROUS CITRIC ACID   POLYSORBATE 80   POLYETHYLENE GLYCOL 300   ALCOHOL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0703-5656-01 1 VIAL In 1 CARTON contains a VIAL, MULTI-DOSE 1 25 mL In 1 VIAL, MULTI-DOSE This package is contained within the CARTON (0703-5656-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA074529	10/06/2011

Toposar  etoposide  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0703-5657 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ETOPOSIDE (ETOPOSIDE) ETOPOSIDE 20 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength ANHYDROUS CITRIC ACID   POLYSORBATE 80   POLYETHYLENE GLYCOL 300   ALCOHOL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0703-5657-01 1 VIAL In 1 CARTON contains a VIAL, MULTI-DOSE 1 50 mL In 1 VIAL, MULTI-DOSE This package is contained within the CARTON (0703-5657-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA074529	10/06/2011

Labeler - Teva Parenteral Medicines, Inc (794362533)

Revised: 10/2011Teva Parenteral Medicines, Inc

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Lotrimin AF Lotion

Pronunciation: kloe-TRIM-uh-zole
Generic Name: Clotrimazole
Brand Name: Lotrimin AF

Lotrimin AF Lotion is used for:

Treating athlete's foot, jock itch, and ringworm. It may also be used for other conditions as determined by your doctor.

Lotrimin AF Lotion is an antifungal agent. It kills sensitive fungi by binding to the fungal cell membrane and weakening it. This allows the cell contents to leak out and results in the death of the fungus.

Do NOT use Lotrimin AF Lotion if:

• you are allergic to any ingredient in Lotrimin AF Lotion

Contact your doctor or health care provider right away if any of these apply to you.

Before using Lotrimin AF Lotion:

Some medical conditions may interact with Lotrimin AF Lotion. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with Lotrimin AF Lotion. Because little, if any, of Lotrimin AF Lotion is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Lotrimin AF Lotion may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Lotrimin AF Lotion:

Use Lotrimin AF Lotion as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Lotrimin AF Lotion is for topical use on the skin only.


• Clean the affected area with soap and water and dry thoroughly.


• Shake well before each use.


• Apply a thin layer of medicine to the affected area. Rub it in gently. Do not cover unless directed to by your doctor.


• Wash your hands immediately after using Lotrimin AF Lotion, unless your hands are part of the treated area.


• To clear up your infection completely, use Lotrimin AF Lotion for the full course of treatment. Keep using it even if you feel better in a few days. Do not miss any doses.


• If you miss a dose of Lotrimin AF Lotion, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Lotrimin AF Lotion.

Important safety information:

• Lotrimin AF Lotion is for external use only. If you get Lotrimin AF Lotion in your eyes, immediately flush them with cool tap water.


• Be sure to use Lotrimin AF Lotion for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The fungus could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Lotrimin AF Lotion while you are pregnant. It is not known if Lotrimin AF Lotion is found in breast milk. If you are or will be breast-feeding while you use Lotrimin AF Lotion, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Lotrimin AF Lotion:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Mild stinging.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); reddening, blistering, peeling, itching, or burning of the skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Lotrimin AF side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Lotrimin AF Lotion may be harmful if swallowed.

Proper storage of Lotrimin AF Lotion:

Store Lotrimin AF Lotion at room temperature, 59 to 86 degrees F (15 to 30 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Lotrimin AF Lotion out of the reach of children and away from pets.

General information:

• If you have any questions about Lotrimin AF Lotion, please talk with your doctor, pharmacist, or other health care provider.


• Lotrimin AF Lotion is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Lotrimin AF Lotion. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Kombiglyze XR

saxagliptin and metformin hydrochloride

Dosage Form: tablet, film coated, extended release
FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS

Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.

The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, Kombiglyze XR should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions (5.1).]

Indications and Usage for Kombiglyze XR

Kombiglyze XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. [See Clinical Studies (14).]

Important Limitations of Use

Kombiglyze XR should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Kombiglyze XR has not been studied in combination with insulin.

 Kombiglyze XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Kombiglyze XR. [See Warnings and Precautions (5.2).]

Kombiglyze XR Dosage and Administration

Recommended Dosing

The dosage of Kombiglyze XR should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability. Kombiglyze XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The following dosage forms are available:

• Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/500 mg


• Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/1000 mg


• Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets 2.5 mg/1000 mg

The recommended starting dose of Kombiglyze XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.

In patients treated with metformin, the dose of Kombiglyze XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.

Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with Kombiglyze XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are either metformin naive or who require a dose of metformin higher than 1000 mg should use the individual components.

The maximum daily recommended dose is 5 mg for saxagliptin and 2000 mg for metformin extended-release.

No studies have been performed specifically examining the safety and efficacy of Kombiglyze XR in patients previously treated with other antihyperglycemic medications and switched to Kombiglyze XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that Kombiglyze XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of Kombiglyze XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

Strong CYP3A4/5 Inhibitors

The maximum recommended dose of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the Kombiglyze XR dose to 2.5 mg/1000 mg once daily. [See Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3).]

Dosage Forms and Strengths

• Kombiglyze XR (saxagliptin and metformin HCl extended-release) 5 mg/500 mg tablets are light brown to brown, biconvex, capsule-shaped, film-coated tablets with “5/500” printed on one side and “4221” printed on the reverse side, in blue ink.


• Kombiglyze XR (saxagliptin and metformin HCl extended-release) 5 mg/1000 mg tablets are pink, biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one side and “4223” printed on the reverse side, in blue ink.


• Kombiglyze XR (saxagliptin and metformin HCl extended-release) 2.5 mg/1000 mg tablets are pale yellow to light yellow, biconvex, capsule-shaped, film-coated tablets with “2.5/1000” printed on one side and “4222” printed on the reverse side, in blue ink.

Contraindications

Kombiglyze XR is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.


• Hypersensitivity to metformin hydrochloride.


• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.


•  History of a serious hypersensitivity reaction to Kombiglyze XR or saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions. [See Warnings and Precautions (5.13) and Adverse Reactions (6.2).]

Warnings and Precautions

Lactic Acidosis

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Kombiglyze XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake when taking metformin since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure [see Warnings and Precautions (5.3, 5.6, 5.7, 5.11)].

The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur [see Warnings and Precautions (5.12)]. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal, but less than 5 mmol/L, in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. [See Warnings and Precautions (5.8).]

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4) and Warnings and Precautions (5.6, 5.7, 5.10, 5.11, 5.12)].

Pancreatitis

 There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After initiation of Kombiglyze XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Kombiglyze XR should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Kombiglyze XR.

Assessment of Renal Function

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, Kombiglyze XR is contraindicated in patients with renal impairment [see Contraindications (4)].

Before initiation of Kombiglyze XR, and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and Kombiglyze XR discontinued if evidence of renal impairment is present.

Impaired Hepatic Function

Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, Kombiglyze XR is not recommended in patients with hepatic impairment.

Vitamin B12 Concentrations

In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Kombiglyze XR and any apparent abnormalities should be appropriately investigated and managed [see Adverse Reactions (6.1)].

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.

Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving Kombiglyze XR.

Surgical Procedures

Use of Kombiglyze XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.

Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes previously well controlled on Kombiglyze XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Kombiglyze XR must be stopped immediately and other appropriate corrective measures initiated.

Use with Medications Known to Cause Hypoglycemia

Saxagliptin

Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, when used in combination with saxagliptin, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia. [See Adverse Reactions (6.1).]

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.

Concomitant Medications Affecting Renal Function or Metformin Disposition

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.2)], should be used with caution.

Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, Kombiglyze XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic States

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Kombiglyze XR therapy, the drug should be promptly discontinued.

Hypersensitivity Reactions

 There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue Kombiglyze XR, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]

 Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with Kombiglyze XR.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Kombiglyze XR or any other antidiabetic drug.

Adverse Reactions

Clinical Trials Experience

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

Monotherapy and Add-On Combination Therapy

Metformin hydrochloride

In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.

Saxagliptin

In two placebo-controlled monotherapy trials of 24-week duration, patients were treated with saxagliptin 2.5 mg daily, saxagliptin 5 mg daily, and placebo. Three 24-week, placebo-controlled, add-on combination therapy trials were also conducted: one with metformin immediate-release, one with a thiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide. In these three trials, patients were randomized to add-on therapy with saxagliptin 2.5 mg daily, saxagliptin 5 mg daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of the monotherapy trials and in the add-on combination trial with metformin immediate-release.

In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the two monotherapy trials, the add-on to metformin immediate-release trial, the add-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated with saxagliptin 2.5 mg and saxagliptin 5 mg was similar to placebo (72.0% and 72.2% versus 70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse events (reported in at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The adverse reactions in this pooled analysis reported (regardless of investigator assessment of causality) in ≥5% of patients treated with saxagliptin 5 mg, and more commonly than in patients treated with placebo are shown in Table 1.

Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo

	Number (%) of Patients
	Saxagliptin 5 mg N=882	Placebo N=799
*  The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.
Upper respiratory tract infection	68 (7.7)	61 (7.6)
Urinary tract infection	60 (6.8)	49 (6.1)
Headache	57 (6.5)	47 (5.9)

In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo.

In this pooled analysis, adverse reactions that were reported in ≥2% of patients treated with saxagliptin 2.5 mg or saxagliptin 5 mg and ≥1% more frequently compared to placebo included: sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).

The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone.

An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known.

Adverse Reactions Associated with Saxagliptin Coadministered with Metformin Immediate-Release in Treatment-Naive Patients with Type 2 Diabetes

Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin in treatment-naive patients.

Table 2: Coadministration of Saxagliptin and Metformin Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin Immediate-Release (and More Commonly than in Patients Treated with Metformin Immediate-Release Alone)

	Number (%) of Patients
	Saxagliptin 5 mg + Metformin* N=320	Placebo + Metformin* N=328
*  Metformin immediate-release was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.
Headache	24 (7.5)	17 (5.2)
Nasopharyngitis	22 (6.9)	13 (4.0)

In patients treated with the combination of saxagliptin and metformin immediate-release, either as saxagliptin add-on to metformin immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence ≥5% in any treatment group in both studies. In the saxagliptin add-on to metformin immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When saxagliptin and metformin immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg + metformin immediate-release group and 7.3% in the placebo + metformin immediate-release group.

Hypoglycemia

In the saxagliptin clinical trials, adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4.0% and 5.6% versus 4.1%, respectively. In the add-on to metformin immediate-release trial, the incidence of reported hypoglycemia was 7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5.0% with placebo. When saxagliptin and metformin immediate-release were coadministered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given saxagliptin 5 mg + metformin immediate-release and 4.0% in patients given placebo + metformin immediate-release.

Hypersensitivity Reactions

Saxagliptin

Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. None of these events in patients who received saxagliptin required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.

Infections

Saxagliptin

In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.

There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use.

Vital Signs

Saxagliptin

No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin alone or in combination with metformin.

Laboratory Tests

Absolute Lymphocyte Counts

Saxagliptin

There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when saxagliptin 5 mg and metformin were coadministered in treatment-naive patients compared to placebo and metformin. There was no difference observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Platelets

Saxagliptin

Saxagliptin did not demonstrate a clinically meaningful or consistent effect on platelet count in the six, double-blind, controlled clinical safety and efficacy trials.

Vitamin B12 Concentrations

Metformin hydrochloride

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on Kombiglyze XR and any apparent abnormalities should be appropriately investigated and managed. [See Warnings and Precautions (5.5).]

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of saxagliptin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. [See Contraindications (4) and Warnings and Precautions (5.13).]


• Acute pancreatitis. [See Indications and Usage (1.1) and Warning and Precautions (5.2).]

Drug Interactions

Strong Inhibitors of CYP3A4/5 Enzymes

Saxagliptin

Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of saxagliptin should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3).]

Cationic Drugs

Metformin hydrochloride

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in healthy volunteers. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Kombiglyze XR and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Use with Other Drugs

Metformin hydrochloride

Some medications can predispose to hyperglycemia and may lead to loss of glycemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving Kombiglyze XR, the patient should be closely observed for loss of glycemic control. When such drugs are withdrawn from a patient receiving Kombiglyze XR, the patient should be observed closely for hypoglycemia.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women with Kombiglyze XR or its individual components. Because animal reproduction studies are not always predictive of human response, Kombiglyze XR, like other antidiabetic medications, should be used during pregnancy only if clearly needed.

Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid.

Saxagliptin

Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to saxagliptin and the active metabolite, respectively, at the MRHD of 5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD.

Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (exposures ≥1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.

Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

No studies in lactating animals have been conducted with the combined components of Kombiglyze XR. In studies performed with the individual components, both saxagliptin and metformin are secreted in the milk of lactating rats. It is not known whether saxagliptin or metformin are secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Kombiglyze XR is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Kombiglyze XR in pediatric patients have not been established.

Geriatric Use

Kombiglyze XR

Elderly patients are more likely to have decreased renal function. Because metformin is contraindicated in patients with renal impairment, carefully monitor renal function in the elderly and use Kombiglyze XR with caution as age increases. [See Warnings and Precautions (5.1, 5.3) and Clinical Pharmacology (12.3).]

Saxagliptin

In the six, double-blind, controlled clinical safety and efficacy trials of saxagliptin, 634 (15.3%) of the 4148 randomized patients were 65 years and over, and 59 (1.4%) patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients ≥65 years old and the younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney. Because the risk of lactic acidosis with metformin is greater in patients with impaired renal function, Kombiglyze XR should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function. [See Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3).]

Overdosage

Saxagliptin

In a controlled clinical trial, once-daily, orally-administered saxagliptin in healthy subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours).

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Kombiglyze XR Description

Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes: saxagliptin and metformin hydrochloride.

Saxagliptin

Saxagliptin is an orally-active inhibitor of the dipeptidyl-peptidase-4 (DPP4) enzyme.

Saxagliptin monohydrate is described chemically as (1S,3S,5S) - 2 - [(2S) - 2 - Amino - 2 - (3 - hydroxytricyclo[3.3.1.13,7]dec - 1 - yl)acetyl] - 2 - azabicyclo[3.1.0]hexane - 3 - carbonitrile, monohydrate or (1S,3S,5S) - 2 - [(2S) - 2 - Amino - 2 - (3 - hydroxyadamantan - 1 - yl)acetyl] - 2 - azabicyclo[3.1.0]hexane - 3 - carbonitrile hydrate. The empirical formula is C18H25N3O2•H2O and the molecular weight is 333.43. The structural formula is:

Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400).

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:

Kombiglyze XR

Kombiglyze XR is available for oral administration as tablets containing either 5.58 mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and 500 mg metformin hydrochloride (Kombiglyze XR 5 mg/500 mg), or 5.58 mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and 1000 mg metformin hydrochloride (Kombiglyze XR 5 mg/1000 mg), or 2.79 mg saxagliptin hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin and 1000 mg metformin hydrochloride (Kombiglyze XR 2.5 mg/1000 mg). Each film-coated tablet of Kombiglyze XR contains the following inactive ingredients: carboxymethylcellulose sodium, hypromellose 2208, and magnesium stearate. The 5 mg/500 mg strength tablet of Kombiglyze XR also contains microcrystalline cellulose and hypromellose 2910. In addition, the film coatings contain the following inactive ingredients: polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, and iron oxides.

The biologically inert components of the tablet may occasionally remain intact during gastrointestinal transit and will be eliminated in the feces as a soft, hydrated mass.

Kombiglyze XR - Clinical Pharmacology

Mechanism of Action

Kombiglyze XR

Kombiglyze XR combines two antihyperglycemic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide.

Saxagliptin

Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.

Metformin hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.9)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamics

Saxagliptin

In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Cardiac Electrophysiology