Drug Intercation

Opsumit 10 MG Oral Tablet

Generic Name: MACITENTAN

Brand Name: OPSUMIT

Substance Name(s):
MACITENTAN

DRUG INTERACTIONS

7 Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with OPSUMIT ( 7.1 , 12.3 ).

Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.2 , 12.3 ) .

Moderate dual CYP3A4 and CYP2C9 inhibitors (fluconazole, amiodarone) or use of combined CYP3A4 and CYP2C9 inhibitors may increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.3 , 12.3 ).

7.1 Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure.

Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [see Clinical Pharmacology (12.3) ] .

7.2 Strong CYP3A4 Inhibitors Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure.

Many HIV drugs like ritonavir are strong inhibitors of CYP3A4.

Avoid concomitant use of OPSUMIT with strong CYP3A4 inhibitors [see Clinical Pharmacology (12.3) ] .

Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology (12.3) ] .

7.3 Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modelling.

Avoid concomitant use of OPSUMIT with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3) ] .

Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT should also be avoided [see Clinical Pharmacology (12.3) ].

OVERDOSAGE

10 OPSUMIT has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage).

Adverse reactions of headache, nausea and vomiting were observed.

In the event of an overdose, standard supportive measures should be taken, as required.

Dialysis is unlikely to be effective because macitentan is highly protein-bound.

DESCRIPTION

11 OPSUMIT ® (macitentan) is an endothelin receptor antagonist.

The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide.

It has a molecular formula of C 19 H 20 Br 2 N 6 O 4 S and a molecular weight of 588.27.

Macitentan is achiral and has the following structural formula: Macitentan is a crystalline powder that is insoluble in water.

In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration.

The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A.

The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.

Chemical Structure

CLINICAL STUDIES

14 14.1 Pulmonary Arterial Hypertension The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II–IV] PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily.

Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids.

The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or “other worsening of PAH” during double-blind treatment plus 7 days.

Other worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH.

All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation.

A critical secondary endpoint was time to PAH death or PAH hospitalization.

The mean patient age was 46 years (14% were age 65 or above).

Most patients were white (55%) or Asian (29%) and female (77%).

Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively.

Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)].

At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%).

Study results are described for the placebo and OPSUMIT 10 mg groups.

The median treatment durations were 101 and 118 weeks in the placebo and OPSUMIT 10 mg groups, respectively, up to a maximum of 188 weeks.

Treatment with OPSUMIT 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39–0.76; logrank p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2).

The beneficial effect of OPSUMIT 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment).

Figure 2 Kaplan-Meier Estimates of the Occurrence of the Primary Endpoint Event in the SERAPHIN Study Table 3: Summary of Primary Endpoint Events Placebo N=250 n (%) OPSUMIT 10 mg N=242 n (%) Patients with a primary endpoint event No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT 10 mg treatment groups.

116 (46.4) 76 (31.4) Component as first event Worsening PAH 93 (37.2) 59 (24.4) Death 17 (6.8) 16 (6.6) IV/SC prostanoid 6 (2.4) 1 (0.4) Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3.

Consistent efficacy of OPSUMIT 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC.

Figure 3 Subgroup Analysis of the SERAPHIN Study Eo = Number of events OPSUMIT 10 mg; No = Number of patients randomized to OPSUMIT 10 mg Ep = Number of events placebo; Np = Number of patients randomized to placebo PAH related death or hospitalization for PAH was assessed as a secondary endpoint.

The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving OPSUMIT 10 mg compared to placebo (HR 0.50, 97.5% CI 0.34–0.75; logrank p<0.0001) (Table 4 and Figure 4).

Figure 4 Kaplan-Meier Estimates of the Occurrence of Death due to PAH or Hospitalization for PAH in SERAPHIN Table 4: Summary of Death due to PAH and Hospitalization due to PAH Placebo (N=250) n (%) OPSUMIT 10 mg (N=242) n (%) Death due to PAH or hospitalization for PAH 84 (33.6) 50 (20.7) Component as first event Death due to PAH 5 (2.0) 5 (2.1) Hospitalization for PAH 79 (31.6) 45 (18.6) Treatment with OPSUMIT 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97.5% CI 3–41; p=0.0078), with significant improvement in 6MWD by Month 3.

6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively).

The increase in 6MWD achieved with OPSUMIT was maintained for the duration of the study.

Treatment with OPSUMIT 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo.

Figure 2 Figure 3 Figure 4 Long-Term Treatment of PAH In long-term follow-up of patients who were treated with OPSUMIT 10 mg in the placebo-controlled study (N=242) and the open-label extension study, Kaplan-Meier estimates of survival at 1, 2, 5, and 7 years were 95%, 89%, 73%, and 63% respectively.

The median exposure to OPSUMIT was 4.6 years.

These uncontrolled observations do not allow comparison with a group not given OPSUMIT and cannot be used to determine the long term-effect of OPSUMIT on mortality.

HOW SUPPLIED

16 /STORAGE AND HANDLING OPSUMIT ® (macitentan) tablets are 10 mg white, film-coated, bi-convex debossed with “10” on both sides and supplied as follows: 15 count /PVC/ PE/PVDC aluminum foil blisters in carton (NDC 66215-501-15) 30 count white high-density polyethylene bottle in carton (NDC 66215-501-30) Store at 20ºC to 25ºC (68ºF to 77ºF).

Excursions are permitted between 15°C and 30°C (59°F and 86°F).

[See USP Controlled Room Temperature] .

Keep out of reach of children.

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

DOSAGE FORMS AND STRENGTHS

3 Tablets: 10 mg, bi-convex film-coated, round, white, and debossed with “10” on both sides.

Tablet: 10 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Endothelin (ET)-1 and its receptors (ET A and ET B ) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.

In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.

Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ET A and ET B receptors.

Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells.

One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro .

The clinical impact of dual endothelin blockage is unknown.

INDICATIONS AND USAGE

1 OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH ( 1.1 ).

1.1 Pulmonary Arterial Hypertension OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II–III symptoms treated for an average of 2 years.

Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%) [see Clinical Studies (14.1) ] .

PEDIATRIC USE

8.4 Pediatric Use The safety and efficacy of OPSUMIT in children have not been established.

PREGNANCY

8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, OPSUMIT may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy.

There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy [see Clinical Considerations ] .

There are limited data on OPSUMIT use in pregnant women.

Macitentan was teratogenic in rabbits and rats at all doses tested.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications (4.1) ] .

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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor.

Data Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities.

Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.

BOXED WARNING

WARNING: EMBRYO-FETAL TOXICITY Do not administer OPSUMIT to a pregnant female because it may cause fetal harm [see Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ].

Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment.

Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception [see Pregnancy Testing in Females of Reproductive Potential (2.2) , Use in Specific Populations (8.3) ].

For all female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2) ] .

WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning.

Do not administer OPSUMIT to a pregnant female because it may cause fetal harm ( 4.1 , 5.1 , 8.1 ).

Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment.

Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception ( 2.2 , 8.3 ).

For all female patients, OPSUMIT is available only through a restricted program called the Macitentan – Containing Products Risk Evaluation and Mitigation Strategy (REMS) ( 5.2 ).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS ERAs cause hepatotoxicity and liver failure.

Obtain baseline liver enzymes and monitor as clinically indicated ( 5.3 ).

Fluid retention may require intervention ( 5.4 ) Decreases in hemoglobin ( 5.5 ).

Pulmonary edema in patients with pulmonary veno-occlusive disease.

If confirmed, discontinue treatment ( 5.6 ).

Decreases in sperm count have been observed in patients taking ERAs ( 5.7 ).

5.1 Embryo-fetal Toxicity OPSUMIT may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant.

In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests [see Dosage and Administration (2.2) and Use in Specific Populations (8.1 , 8.3) ] .

OPSUMIT is available for females through the Macitentan-Containing Products REMS, a restricted distribution program [see Warnings and Precautions (5.2) ] .

5.2 Macitentan-Containing Products REMS For all females, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products REMS, because of the risk of embryo-fetal toxicity [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ] .

Notable requirements of the Macitentan-Containing Products REMS include the following: Prescribers must be certified with the Macitentan-Containing Products REMS by enrolling and completing training.

All females, regardless of reproductive potential, must enroll in the Macitentan-Containing Products REMS prior to initiating OPSUMIT.

Male patients are not enrolled in the REMS.

Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] .

Pharmacies must be certified with the Macitentan-Containing Products REMS and must only dispense to patients who are authorized to receive OPSUMIT.

Further information is available at www.MacitentanREMS.com or 1-888-572-2934.

Information on Macitentan-Containing Products REMS certified pharmacies or wholesale distributors is available at 1-888-572-2934.

5.3 Hepatotoxicity ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure.

The incidence of elevated aminotransferases in the study of OPSUMIT in PAH is shown in Table 1.

Table 1: Incidence of Elevated Aminotransferases in the SERAPHIN Study OPSUMIT 10 mg (N=242) Placebo (N=249) >3 × ULN 3.4% 4.5% >8 × ULN 2.1% 0.4% In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group vs.

1.6% for placebo.

Obtain liver enzyme tests prior to initiation of OPSUMIT and repeat during treatment as clinically indicated [see Adverse Reactions (6.2) ] .

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).

If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT.

Consider re-initiation of OPSUMIT when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

5.4 Fluid Retention Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs.

In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.

Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment.

In a small study of OPSUMIT in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the OPSUMIT group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo.

Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported [see Adverse Reactions (6.2) ] .

Monitor for signs of fluid retention after OPSUMIT initiation.

If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSUMIT or underlying heart failure, and the possible need to discontinue OPSUMIT.

5.5 Hemoglobin Decrease Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSUMIT.

These decreases occurred early and stabilized thereafter.

In the placebo-controlled study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group.

A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group.

Decreases in hemoglobin seldom require transfusion.

Initiation of OPSUMIT is not recommended in patients with severe anemia.

Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated [see Adverse Reactions (6.1) ] .

5.6 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD) Should signs of pulmonary edema occur, consider the possibility of associated PVOD.

If confirmed, discontinue OPSUMIT.

5.7 Decreased Sperm Counts OPSUMIT, like other ERAs, may have an adverse effect on spermatogenesis.

Counsel men about potential effects on fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patient to read FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with OPSUMIT and for one month after treatment discontinuation.

Females of reproductive potential must have monthly pregnancy tests and must use reliable methods of contraception while taking OPSUMIT and for one month after discontinuing OPSUMIT [see Use in Specific Populations (8.1) ] .

Macitentan-Containing Products REMS For female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products REMS [see Warnings and Precautions (5.2) ] .

Male patients are not enrolled in the Macitentan-Containing Products REMS.

Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods).

Patients should be instructed to contact their physician if they suspect they may be pregnant.

Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.

Inform female patients (and their guardians, if applicable) of the following notable requirements.

Female patients must sign an enrollment form.

Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] .

Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.

Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.

Review the Medication Guide and REMS educational materials with female patients.

Lactation Advise women not to breastfeed during treatment with OPSUMIT [see Use in Specific Population (8.2) ] .

Hepatotoxicity Some members of this pharmacological class are hepatotoxic.

Educate patients on signs of hepatotoxicity.

Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.

Fluid Retention Educate patients on signs of fluid retention.

Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs.

DOSAGE AND ADMINISTRATION

2 10 mg once daily .

Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended ( 2.1 ).

2.1 Recommended Dosage The recommended dosage of OPSUMIT is 10 mg once daily for oral administration.

Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.

2.2 Pregnancy Testing in Females of Reproductive Potential Obtain a pregnancy test in females of reproductive potential prior to OPSUMIT treatment, monthly during treatment and one month after stopping OPSUMIT.

Initiate treatment with OPSUMIT in females of reproductive potential only after a negative pregnancy test.

[see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ] .

vitamin A 200000 UNT/ML / vitamin D3 10000 UNT/ML / vitamin E 300 UNT/ML Injectable Solution

No Details Found

Ethinyl Estradiol 0.035 MG / Norethindrone 0.5 MG Oral Tablet

WARNINGS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use.

This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

For this reason, combination oral contraceptives, including ORTHO-NOVUM ® and MODICON ® , should not be used by women who are over 35 years of age and smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors.

The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today.

The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies.

Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers.

The relative risk does not provide information on the actual clinical occurrence of a disease.

Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers.

The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs.

2 and 3 with the author’s permission).

For further information, the reader is referred to a text on epidemiological methods.

Thromboembolic Disorders and Other Vascular Problems a.

Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use.

This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes.

The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.

4–10 The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.

11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older, and in nonsmokers over the age of 40 among women who use oral contraceptives.

(See Figure 1 ).

Figure 1.

Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use (Adapted from P.M.

Layde and V.

Beral, ref.

#12.) Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.

13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.

14–18 Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in ).

Similar effects on risk factors have been associated with an increased risk of heart disease.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Table II b.

Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established.

Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.

2,3,19–24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.

25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.

2 A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.

9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.

26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization.

Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed.

Cerebrovascular diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke.

Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.

27–29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.

30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.

30 The attributable risk is also greater in older women.

3 d.

Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.

31–33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.

14–16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.

Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives.

The activity and amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.

For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient.

New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.

Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.

In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.

8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.

34 However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

Estimates of Mortality From Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 2).

These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure.

Each method of contraception has its specific benefits and risks.

The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.

35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors.

In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over.

The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

Table 2: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15–19 20–24 25–29 30–34 35–39 40–44 Adapted from H.W.

Ory, ref.

#35.

No fertility-control methods Deaths are birth-related 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker Deaths are method-related 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker 2.2 3.4 6.6 13.5 51.1 117.2 IUD 0.8 0.8 1.0 1.0 1.4 1.4 Condom 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/ spermicide 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence 2.5 1.6 1.6 1.7 2.9 3.6 3.

Carcinoma of the Reproductive Organs and Breasts Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs.

However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears.

Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid.

Some studies have found a small increase in risk for women who first use COCs before age 20.

Most studies show a similar pattern of risk with COC use regardless of a woman’s reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.

45–48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States.

Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.

49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users.

However, these cancers are extremely rare in the U.S.

and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives.

Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions.

Appropriate diagnostic and therapeutic measures should be undertaken immediately.

Oral Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.

56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, 55,56,58,59 when taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.

Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out.

If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period.

Oral contraceptive use should be discontinued if pregnancy is confirmed.

Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.

60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.

62–64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.

17 This effect has been shown to be directly related to estrogen dose.

65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.

17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.

67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill.

As discussed earlier (see 1a and 1d ), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

Elevated Blood Pressure Women with significant hypertension should not be started on hormonal contraception.

92 An increase in blood pressure has been reported in women taking oral contraceptives 68 and this increase is more likely in older oral contraceptive users 69 and with extended duration of use.

61 Data from the Royal College of General Practitioners 12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.

Women with a history of hypertension or hypertension-related diseases, or renal disease 70 should be encouraged to use another method of contraception.

If these women elect to use oral contraceptives, they should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued.

In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive.

If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy.

Regular monitoring of BP throughout hormonal contraceptive therapy is recommended.

96 For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.

68–71 10.

Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11.

Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use.

Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding.

If pathology has been excluded, time or a change to another formulation may solve the problem.

In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

12.

Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

DRUG INTERACTIONS

Drug Interactions Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Effects of Other Drugs on Combined Hormonal Contraceptives Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding.

Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St.

John’s wort.

Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure.

Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Substances increasing the plasma concentrations of COCs Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20–25%.

Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation.

CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Colesevelam Colesevelam, a bile acid sequestrant, given together with a combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE.

A drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Effects of Combined Hormonal Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.

COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine.

Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation.

This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increases with use of COCs.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children.

Overdosage may cause nausea, and withdrawal bleeding may occur in females.

DESCRIPTION

COMBINED ORAL CONTRACEPTIVES Each of the following products is a combined oral contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol.

ORTHO-NOVUM ® 7/7/7 Tablets Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol.

Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch.

Each light peach tablet contains 0.75 mg of norethindrone and 0.035 mg of ethinyl estradiol.

Inactive ingredients include FD&C Yellow No.

6, lactose, magnesium stearate and pregelatinized corn starch.

Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.

Inactive ingredients include FD&C Yellow No.

6, lactose, magnesium stearate and pregelatinized corn starch.

Each green tablet contains only inert ingredients, as follows: D&C Yellow No.

10 Aluminum Lake, FD&C Blue No.

2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch.

ORTHO-NOVUM ® 1/35 Tablets Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.

Inactive ingredients include FD&C Yellow No.

6, lactose, magnesium stearate and pregelatinized corn starch.

Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM ® 7/7/7.

MODICON ® Tablets Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol.

Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch.

Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM ® 7/7/7.

The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, and for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol.

Their structural formulas are as follows: Chemical Structure

HOW SUPPLIED

Repackaged by A-S Medication Solutions – Libertyville, IL See REPACKAGING INFORMATION for available configurations.

ORTHO-NOVUM ® 7/7/7 Tablets are available in a blister card with a DIALPAK ® Tablet Dispenser (unfilled) (NDC 50458-178-00).

The blister card contains 28 tablets, as follows: 7 white, round, flat-faced, beveled edged tablets imprinted with “Ortho 535” on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol), 7 light peach, round, flat-faced, beveled edged tablets imprinted with “Ortho 75” on both sides (0.75 mg norethindrone and 0.035 mg ethinyl estradiol), 7 peach, round, flat-faced, beveled edged tablets imprinted with “Ortho 135” on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert ingredients.

ORTHO-NOVUM ® 7/7/7 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK ® Tablet Dispensers (NDC 50458-178-15).

ORTHO-NOVUM ® 7/7/7 is available for clinic usage in a VERIDATE ® Tablet Dispenser (unfilled) and VERIDATE ® refills (NDC 50458-178-20).

ORTHO-NOVUM ® 1/35 Tablets are available in a blister card with a DIALPAK ® Tablet Dispenser (unfilled) (NDC 50458-176-00).

The blister card contains 28 tablets, as follows: 21 peach, round, flat-faced, beveled edged tablets imprinted “Ortho 135” on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert ingredients.

ORTHO-NOVUM ® 1/35 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK ® Tablet Dispensers (NDC 50458-176-15).

MODICON ® Tablets are available in a blister card with a DIALPAK ® Tablet Dispenser (unfilled) (NDC 50458-171-00).

The blister card contains 28 tablets, as follows: 21 white, round, flat-faced, beveled edged tablets imprinted “Ortho 535” on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert ingredients.

MODICON ® Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK ® Tablet Dispensers (NDC 50458-171-15).

Store at 25°C (77°F), excursions permitted to 15°–30°C (59°–86°F).

GERIATRIC USE

14.

Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population.

INDICATIONS AND USAGE

ORTHO-NOVUM ® 7/7/7, ORTHO-NOVUM ® 1/35, and MODICON ® Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective.

Table 1 lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception.

The efficacy of these contraceptive methods, except sterilization, the IUD, and the NORPLANT ® System depends upon the reliability with which they are used.

Correct and consistent use of methods can result in lower failure rates.

Table 1: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year.

United States.

% of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

Method (1) Typical Use Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

(2) Perfect Use Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

(3) (4) Adapted from Hatcher et al, 1998, Ref.

# 1.

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.

The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose.

The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral ® (1 dose is 2 white pills), Alesse ® (1 dose is 5 pink pills), Nordette ® or Levlen ® (1 dose is 2 light-orange pills), Lo/Ovral ® (1 dose is 4 white pills), Triphasil ® or Tri-Levlen ® (1 dose is 4 yellow pills).

Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.

However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age.

Source: Trussell J, Contraceptive efficacy.

In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition.

New York, NY: Irvington Publishers, 1998.

Chance The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant.

Among such populations, about 89% become pregnant within one year.

This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

85 85 Spermicides Foams, creams, gels, vaginal suppositories, and vaginal film.

26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.

2 Post-Ovulation 1 Cap With spermicidal cream or jelly.

Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 20 6 56 Withdrawal 19 4 Condom Without spermicides.

Female (Reality ® ) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera ® 0.3 0.3 70 Norplant ® and Norplant-2 ® 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 ORTHO-NOVUM ® 7/7/7, ORTHO-NOVUM ® 1/35 and MODICON ® have not been studied for and are not indicated for use in emergency contraception.

PEDIATRIC USE

13.

Pediatric Use Safety and efficacy of ORTHO-NOVUM ® Tablets and MODICON ® Tablets have been established in women of reproductive age.

Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older.

Use of this product before menarche is not indicated.

PREGNANCY

11.

Pregnancy Pregnancy Category X See CONTRAINDICATIONS and WARNINGS .

NUSRING MOTHERS

12.

Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement.

In addition, combined oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk.

If possible, the nursing mother should be advised not to use combined oral contraceptives but to use other forms of contraception until she has completely weaned her child.

BOXED WARNING

WARNINGS: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use.

This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

For this reason, combination oral contraceptives, including ORTHO-NOVUM ® and MODICON ® , should not be used by women who are over 35 years of age and smoke.

INFORMATION FOR PATIENTS

INFORMATION FOR THE PATIENT See Patient Labeling printed below.

DOSAGE AND ADMINISTRATION

To achieve maximum contraceptive effectiveness, ORTHO-NOVUM ® Tablets and MODICON ® Tablets must be taken exactly as directed and at intervals not exceeding 24 hours.

ORTHO-NOVUM ® Tablets and MODICON ® Tablets are available with the DIALPAK ® Tablet Dispenser which is preset for a Sunday Start.

Day 1 Start is also available.

Sunday Start When taking ORTHO-NOVUM ® 7/7/7, ORTHO-NOVUM ® 1/35, and MODICON ® , the first “active” tablet should be taken on the first Sunday after menstruation begins.

If the period begins on Sunday, the first “active” tablet should be taken that day.

Take one active tablet daily for 21 days followed by one green “reminder” tablet daily for 7 days.

After 28 tablets have been taken, a new course is started the next day (Sunday).

For the first cycle of a Sunday Start regimen, another method of contraception such as a condom or spermicide should be used until after the first 7 consecutive days of administration.

If the patient misses one (1) “active” tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers.

If the patient misses two (2) “active” tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack.

The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills.

If the patient misses two (2) “active” tablets in the third week or misses three (3) or more “active” tablets in a row, the patient should continue taking one tablet every day until Sunday.

On Sunday the patient should throw out the rest of the pack and start a new pack that same day.

The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (“How to Take the Pill” section).

Day 1 Start The dosage of ORTHO-NOVUM ® 7/7/7, ORTHO-NOVUM ® 1/35, and MODICON ® , for the initial cycle of therapy, is one “active” tablet administered daily from the 1st through the 21st day of the menstrual cycle, counting the first day of menstrual flow as “Day 1” followed by one green “reminder” tablet daily for 7 days.

Tablets are taken without interruption for 28 days.

After 28 tablets have been taken, a new course is started the next day.

If the patient misses one (1) “active” tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers.

The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills.

If the patient misses two (2) “active” tablets in the third week or misses three (3) or more “active” tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day.

The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (“How to Take the Pill” section).

The use of ORTHO-NOVUM ® 7/7/7, ORTHO-NOVUM ® 1/35, and MODICON ® for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed.

When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered.

(See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease.

See also PRECAUTIONS: Nursing Mothers .) The possibility of ovulation and conception prior to initiation of medication should be considered.

(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives .)

Riluzole 50 MG Oral Tablet [Rilutek]

DRUG INTERACTIONS

7 • Strong to moderate CYP1A2 inhibitors: Coadministration may increase RILUTEK-associated adverse reactions ( 7.1 ) • Strong to moderate CYP1A2 inducers: Coadministration may result in decreased efficacy ( 7.2 ) • Hepatotoxic drugs: RILUTEK-treated patients that take other hepatotoxic drugs may be at increased risk for hepatotoxicity ( 7.3 ) 7.1 Agents that may Increase Riluzole Blood Concentrations CYP1A2 inhibitors Co-administration of RILUTEK (a CYP1A substrate) with CYP1A2 inhibitors was not evaluated in a clinical trial; however, in vitro findings suggest an increase in riluzole exposure is likely.

The concomitant use of strong or moderate CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, mexiletine, oral contraceptives, thiabendazole, vemurafenib, zileuton) with RILUTEK may increase the risk of RILUTEK-associated adverse reactions [see Clinical Pharmacology ( 12.3 )] .

7.2 Agents that may Decrease Riluzole Plasma Concentrations CYP1A2 inducers Co-administration of RILUTEK (a CYP1A substrate) with CYP1A2 inducers was not evaluated in a clinical trial; however, in vitro findings suggest a decrease in riluzole exposure is likely.

Lower exposures may result in decreased efficacy [see Clinical Pharmacology ( 12.3 )] .

7.3 Hepatotoxic Drugs Clinical trials in ALS patients excluded patients on concomitant medications which were potentially hepatotoxic (e.g., allopurinol, methyldopa, sulfasalazine).

RILUTEK-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see Warnings and Precautions ( 5.1 )] .

OVERDOSAGE

10 Reported symptoms of overdose following ingestion of RILUTEK ranging from 1.5 to 3 grams (30 to 60 times the recommended dose) included acute toxic encephalopathy, coma, drowsiness, memory loss, and methemoglobinemia.

No specific antidote for the treatment of RILUTEK overdose is available.

For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

DESCRIPTION

11 RILUTEK (riluzole) is a member of the benzothiazole class.

The chemical designation for riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole.

Its molecular formula is C 8 H 5 F 3 N 2 OS, and its molecular weight is 234.2.

The chemical structure is: RILUTEK is a white to slightly yellow powder that is very soluble in dimethylformamide, dimethylsulfoxide, and methanol; freely soluble in dichloromethane; sparingly soluble in 0.1 N HCl; and very slightly soluble in water and in 0.1 N NaOH.

Each film-coated tablet for oral use contains 50 mg of riluzole and the following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.

Chemical Structure

CLINICAL STUDIES

14 The efficacy of RILUTEK was demonstrated in two studies (Study 1 and 2) that evaluated RILUTEK 50 mg twice daily in patients with amyotrophic lateral sclerosis (ALS).

Both studies included patients with either familial or sporadic ALS, a disease duration of less than 5 years, and a baseline forced vital capacity greater than or equal to 60% of normal.

Study 1 was a randomized, double-blind, placebo-controlled clinical study that enrolled 155 patients with ALS.

Patients were randomized to receive RILUTEK 50 mg twice daily (n=77) or placebo (n=78) and were followed for at least 13 months (up to a maximum duration of 18 months).

The clinical outcome measure was time to tracheostomy or death.

The time to tracheostomy or death was longer for patients receiving RILUTEK compared to placebo.

There was an early increase in survival in patients receiving RILUTEK compared to placebo.

Figure 1 displays the survival curves for time to death or tracheostomy.

The vertical axis represents the proportion of individuals alive without tracheostomy at various times following treatment initiation (horizontal axis).

Although these survival curves were not statistically significantly different when evaluated by the analysis specified in the study protocol (Logrank test p=0.12), the difference was found to be significant by another appropriate analysis (Wilcoxon test p=0.05).

As seen in Figure 1 , the study showed an early increase in survival in patients given RILUTEK.

Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the RILUTEK 50 mg twice daily and placebo groups was approximately 90 days.

Figure 1.

Time to Tracheostomy or Death in ALS Patients in Study 1 (Kaplan-Meier Curves) Study 2 was a randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS.

Patients were randomized to RILUTEK 50 mg twice daily (n=236) or placebo (n=242) and were followed for at least 12 months (up to a maximum duration of 18 months).

The clinical outcome measure was time to tracheostomy or death.

The time to tracheostomy or death was longer for patients receiving RILUTEK compared to placebo.

Figure 2 displays the survival curves for time to death or tracheostomy for patients randomized to either RILUTEK 100 mg per day or placebo.

Although these survival curves were not statistically significantly different when evaluated by the analysis specified in the study protocol (Logrank test p=0.076), the difference was found to be significant by another appropriate analysis (Wilcoxon test p=0.05).

Not displayed in Figure 2 are the results of RILUTEK 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of RILUTEK 200 mg per day (two times the recommended daily dose), which were not distinguishable from the 100 mg per day results.

Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between RILUTEK and placebo was approximately 60 days.

Although RILUTEK improved survival in both studies, measures of muscle strength and neurological function did not show a benefit.

Figure 2.

Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-Meier Curves) Figure 1 Figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING RILUTEK 50 mg tablets are white, capsule-shaped, film-coated, and engraved with “RPR 202” on one side.

RILUTEK is supplied in bottles of 60 tablets, NDC 24987-700-60.

Store at controlled room temperature, 20°C to 25°C (68°F to77°F), and protect from bright light.

GERIATRIC USE

8.5 Geriatric Use In clinical studies of RILUTEK, 30% of patients were 65 years and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Tablets: 50 mg film-coated, capsule-shaped, white, with “RPR 202” on one side.

Tablets: 50 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.

INDICATIONS AND USAGE

1 RILUTEK is indicated for the treatment of amyotrophic lateral sclerosis (ALS).

RILUTEK is indicated for the treatment of amyotrophic lateral sclerosis (ALS) ( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of RILUTEK in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Risk Summary There are no studies of RILUTEK in pregnant women, and case reports have been inadequate to inform the drug-associated risk.

The background risk for major birth defects and miscarriage in patients with amyotrophic lateral sclerosis is unknown.

In the U.S.

general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In studies in which riluzole was administered orally to pregnant animals, developmental toxicity (decreased embryofetal/offspring viability, growth, and functional development) was observed at clinically relevant doses [see Data ] .

Based on these results, women should be advised of a possible risk to the fetus associated with use of RILUTEK during pregnancy.

Data Animal Data Oral administration of riluzole (3, 9, or 27 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreases in fetal growth (body weight and length) at the high dose.

The mid dose, a no-effect dose for embryofetal developmental toxicity, is approximately equal to the recommended human daily dose (RHDD, 100 mg) on a mg/m 2 basis.

When riluzole was administered orally (3, 10, or 60 mg/kg/day) to pregnant rabbits during the period of organogenesis, embryofetal mortality was increased at the high dose and fetal body weight was decreased and morphological variations increased at all but the lowest dose tested.

The no-effect dose (3 mg/kg/day) for embryofetal developmental toxicity is less than the RHDD on a mg/m 2 basis.

Maternal toxicity was observed at the highest dose tested in rat and rabbit.

When riluzole was orally administered (3, 8, or 15 mg/kg/day) to male and female rats prior to and during mating and to female rats throughout gestation and lactation, increased embryofetal mortality and decreased postnatal offspring viability, growth, and functional development were observed at the high dose.

The mid dose, a no-effect dose for pre- and postnatal developmental toxicity, is approximately equal to the RHDD on a mg/m 2 basis.

NUSRING MOTHERS

8.3 Females and Males of Reproductive Potential In rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality [see Nonclinical Toxicology ( 13.1 )] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Hepatic injury: Use of RILUTEK is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal; discontinue RILUTEK if there is evidence of liver dysfunction ( 5.1 ) • Neutropenia: Advise patients to report any febrile illness ( 5.2 ) • Interstitial lung disease: Discontinue RILUTEK if interstitial lung disease develops ( 5.3 ) 5.1 Hepatic Injury Cases of drug-induced liver injury, some of which were fatal, have been reported in patients taking RILUTEK.

Asymptomatic elevations of hepatic transaminases have also been reported, and in some patients have recurred upon rechallenge with RILUTEK.

In clinical studies, the incidence of elevations in hepatic transaminases was greater in RILUTEK-treated patients than placebo-treated patients.

The incidence of elevations of ALT above 5 times the upper limit of normal (ULN) was 2% in RILUTEK-treated patients.

Maximum increases in ALT occurred within 3 months after starting RILUTEK.

About 50% and 8% of RILUTEK-treated patients in pooled Studies 1 and 2, had at least one elevated ALT level above ULN and above 3 times ULN, respectively [see Clinical Studies ( 14 )] .

Monitor patients for signs and symptoms of hepatic injury, every month for the first 3 months of treatment, and periodically thereafter.

The use of RILUTEK is not recommended if patients develop hepatic transaminases levels greater than 5 times the ULN.

Discontinue RILUTEK if there is evidence of liver dysfunction (e.g., elevated bilirubin).

5.2 Neutropenia Cases of severe neutropenia (absolute neutrophil count less than 500 per mm 3 ) within the first 2 months of RILUTEK treatment have been reported.

Advise patients to report febrile illnesses.

5.3 Interstitial Lung Disease Interstitial lung disease, including hypersensitivity pneumonitis, has occurred in patients taking RILUTEK.

Discontinue RILUTEK immediately if interstitial lung disease develops.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patients to inform their healthcare provider if they experience: • Yellowing of the whites of the eyes [see Warnings and Precautions ( 5.1 )] • Fever [see Warnings and Precautions ( 5.2 )] • Respiratory symptoms—for example, dry cough and difficult or labored breathing [see Warnings and Precautions ( 5.3 )] Manufactured for: Covis Pharmaceuticals, Inc.

Logo

DOSAGE AND ADMINISTRATION

2 The recommended dosage for RILUTEK is 50 mg taken orally twice daily.

RILUTEK should be taken at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology ( 12.3 )] .

Measure serum aminotransferases before and during treatment with RILUTEK [see Warnings and Precautions ( 5.1 )] .

• Recommended dosage: 50 mg twice daily, taken at least 1 hour before or 2 hours after a meal ( 2 ) • Measure serum aminotransferases before and during treatment ( 2 , 5.1 )

mango blossom pollen extract 10000 UNT/ML Injectable Solution

WARNINGS

DO NOT INJECT INTRAVENOUSLY.

Epinephrine 1:1000 should be available.

Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing.

All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death.

(4) (See Adverse Reactions) An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection.

When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.

OVERDOSAGE

Overdose can cause both local and systemic reactions.

An overdose may be prevented by careful observation and questioning of the patient about the previous injection.

If systemic or anaphylactic reaction, does occur, apply a tourniquet above the site of injection and inject intramuscularly or subcutaneously 0.3 to 0.5ml of 1:1000 Epinephrine Hydrochloride into the opposite arm.

The dose may be repeated in 5-10 minutes if necessary.

Loosen the tourniquet at least every 10 minutes.

The Epinephrine Hydrochloride 1:1000 dose for infants to 2 years is 0.05 to 0.1 ml, for children 2 to 6 years it is 0.15 ml, for children 6-12 years it is 0.2 ml.

Patients unresponsive to Epinephrine may be treated with Theophylline.

Studies on asthmatic subjects reveal that plasma concentrations of Theophylline of 5 to 20 µg/ml are associated with therapeutic effects.

Toxicity is particularly apparent at concentrations greater than 20 µg/ml.

A loading dose of Aminophylline of 5.8 mg/kg intravenously followed by 0.9 mg/kg per hour results in plasma concentrations of approximately 10 µg/ml for patients not previously receiving theophylline.

(Mitenko and Ogilive, Nicholoson and Chick,1973) Other beta-adrenergic drugs such as Isoproterenol, Isoetharine, or Albuterol may be used by inhalation.

The usual dose to relieve broncho-constriction in asthma is 0.5 ml of the 0.5% solution for Isoproterenol HCl.

The Albuterol inhaler delivers approximately 90 mcg of Albuterol from the mouthpiece.

The usual dosage for adults and children would be two inhalations repeated every 4-6 hours.

Isoetharine supplied in the Bronkometer unit delivers approximately 340 mcg Isoetharine.

The average dose is one to two inhalations.

Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require oxygen, intubation and the use of life support systems.

DESCRIPTION

Allergenic extracts are sterile solutions consisting of the extractable components from various biological sources including pollens, inhalants, molds, animal epidermals and insects.

Aqueous extracts are prepared using cocas fluid containing NaCl 0.5%, NaHCO3 0.0275%, WFI, preservative 0.4% Phenol.

Glycerinated allergenic extracts are prepared with cocas fluid and glycerin to produce a 50% (v/v) allergenic extract.

Allergenic Extracts are supplied as concentrations designated as protein nitrogen units (PNU) or weight/volume (w/v) ratio.

Standardized extracts are designated in Bioequivalent Allergy Units (BAU) or Allergy Units (AU).

(See product insert for standardized extracts) For diagnostic purposes, allergenic extracts are to be administered by prick-puncture or intradermal routes.

Allergenic extracts are administered subcutaneously for immunotherapy injections.

HOW SUPPLIED

Allergenic extracts are supplied with units listed as: Weight/volume (W/V), Protein Nitrogen Units (PNU/ml), Allergy Units (AU/ml) or Bioequivalent Allergy Units (BAU/ml).

Sizes: Diagnostic Scratch: 5 ml dropper application vials Diagnostic Intradermal: 5 ml or 10 ml vials.

Therapeutic Allergens: 5 ml, 10 ml, 50 ml multiple dose vials.

INDICATIONS AND USAGE

Allergenic extracts are indicated for use in diagnostic testing and as part of a treatment regime for allergic disease, as established by allergy history and skin test reactivity.

Allergenic extracts are indicated for the treatment of allergen specific allergic disease for use as hyposensitization or immunotherapy when avoidance of specific allergens can not be attained.

The use of allergenic extracts for therapeutic purpose has been established by well-controlled clinical studies.

Allergenic extracts may be used as adjunctive therapy along with pharmacotherapy which includes antihistamines, corticosteroids, and cromoglycate, and avoidance measures.

Allergenic extracts for therapeutic use should be given using only the allergen selection to which the patient is allergic, has a history of exposure and are likely to be exposed to again.

BOXED WARNING

WARNING Diagnostic and therapeutic allergenic extracts are intended to be administered by a physician who is an allergy specialist and experienced in allergenic diagnostic testing and immunotherapy and the emergency care of anaphylaxis.

This product should not be injected intravenously.

Deep subcutaneous routes have been safe.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death.

(See Adverse Reactions) Serious adverse reactions should be reported to Nelco Laboratories immediately and a report filed to: MedWatch, The FDA Medical Product Problem Reporting Program, at 5600 Fishers Lane, Rockville, Md.

20852-9787, call 1-800-FDA-1088.

Extreme caution should be taken when using allergenic extracts for patients who are taking beta-blocker medications.

In the event of a serious adverse reaction associated with the use of allergenic extracts, patients receiving beta-blockers may not be responsive to epinephrine or inhaled brochodialators.

(1) (See Precautions) Allergenic extracts should be used with caution for patients with unstable or steroid-dependent asthma or underlying cardiovascular disease.

(See Contraindications)

DOSAGE AND ADMINISTRATION

General Precautions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permits.

The dosage of allergenic extracts is dependent upon the purpose of the administration.

Allergenic extracts can be administered for diagnostic use or for therapeutic use.

When allergenic extracts are administered for diagnostic use, the dosage is dependent upon the method used.

Two methods commonly used are scratch testing and intradermal testing.

Both types of tests result in a wheal and flare response at the site of the test which usually develops rapidly and may be read in 20-30 minutes.

Diagnostic Use : Scratch Testing Method Scratch testing is considered a simple and safe method although less sensitive than the intradermal test.

Scratch testing can be used to determine the degree of sensitivity to a suspected allergen before using the intradermal test.

This combination lessens the severity of response to an allergen which can occur in a very sensitive patient.

The most satisfactory testing site is the patient’s back or volar surface of the arms from the axilla to 2.5 or 5cm above the wrist, skipping the anti-cubital space.

If using the back as a testing site, the most satisfactory area are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins.

Allergenic extracts for diagnostic use are to be administered in the following manner: To scratch surface of skin, use a circular scarifier.

Do not draw blood.

Tests sites should be 4 cm apart to allow for wheal and flare reaction.

1-30 scratch tests may be done at a time.

A separate sterile scratch instrument is to be used on each patient to prevent transmission of homologous serum hepatitis or other infectious agents from one patient to another.

The recommended usual dosage for Scratch testing is one drop of allergen applied to each scratch site.

Do not let dropper touch skin.

Always apply a control scratch with each test set.

Sterile Diluent (for a negative control) is used in exactly the same way as an active test extract.

Histamine may be used as a positive control.

Scratch or prick test sites should be examined at 15 and 30 minutes.

To prevent excessive absorption, wipe off antigens producing large reactions as soon as the wheal appears.

Record the size of the reaction.

Interpretation of Scratch Test Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes.

Wheal and erythema size may be recorded by actual measurement as compared with positive and negative controls.

A positive reaction consists of an area of erythema surrounding the scarification that is larger than the control site.

For uniformity in reporting reactions, the following system is recommended.

(6) REACTION SYMBOL CRITERIA Negative – No wheal.

Erythema absent or very slight (not more than 1 mm diameter) .

One Plus + Wheal absent or very slight erythema present (not more than 3 mm diameter) .

Two Plus ++ Wheal not more than 3mm or erythema not more than 5mm diameter.

Three Plus +++ Wheal between 3mm and 5mm diameter, with erythema.

Possible pseudopodia and itching.

Four Plus ++++ A larger reaction with itching and pain.

Diagnostic Use: Intradermal Skin Testing Method Do not perform intradermal test with allergens which have evoked a 2+ or greater response to a Scratch test.

Clean test area with alcohol, place sites 5 cm apart using separate sterile tuberculin syringe and a 25 gauge needle for each allergen.

Insert needle tip, bevel up, into intracutaneous space.

Avoid injecting into blood vessel, pull back gently on syringe plunger, if blood enters syringe change position of needle.

The recommended dosage and range for intradermal testing is 0.05 ml of not more than 100 pnu/ml or 1:1000 w/v (only if puncture test is negative) of allergenic extract.

Inject slowly until a small bleb is raised.

It is important to make each bleb the same size.

Interpretation of Intradermal Test: The patient’s reaction is graded on the basis of size of wheal and flare as compared to control.

Use 0.05 ml sterile diluent as a negative control to give accurate interpretation.

The tests may be accurately interpreted only when the saline control site has shown a negative response.

Observe patient for at least 30 minutes.

Tests can be read in 15-20 minutes.

Edema, erythema and presence of pseudopods, pain and itching may be observed in 4 plus reactions.

For uniformity in reporting reactions the following system is recommended.

(6) REACTION SYMBOL CRITERIA Negative – No increase in size of bleb since injection.

No erythema.

One Plus + An increase in size of bleb to a wheal not more than 5mm diameter, with associated erythema.

Two Plus ++ Wheal between 5mm and 8mm diameter with erythema.

Three Plus +++ Wheal between 8mm and 12mm diameter with erythema and possible pseudopodia and itching or pain.

Four Plus ++++ Any larger reaction with itch and pain, and possible diffuse blush of the skin surrounding the reaction area.

Therapeutic Use: Recommended dosage & range Check the listed ingredients to verify that it matches the prescription ordered.

When using a prescription set, verify the patient’s name and the ingredients listed with the prescription order.

Assess the patient’s physical and emotional status prior to giving as injection.

Do not give injections to patients who are in acute distress.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response and tolerance to the extract administered during the early phases of an injection regimen.

The dosage must be reduced when transferring a patient from non-standardized or modified extract to standardized extract.

Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy as well as during maintenance therapy.

After therapeutic injections patients should be observed for at least 20 minutes for reaction symptoms.

SUGGESTED DOSAGE SCHEDULE The following schedule may act as a guide.

This schedule has not been proven to be safe or effective.

Sensitive patients may begin with smaller doses of weaker solutions and the dosage increments can be less.

STRENGTH DOSE VOLUME Vial #1 1 0.05 1:100,000 w/v 2 0.10 10 pnu/ml 3 0.15 1 AU/ml 4 0.20 1 BAU/ml 5 0.30 6 0.40 7 0.50 Vial #2 8 0.05 1:10,000 w/v 9 0.10 100 pnu/ml 10 0.15 10 AU/ml 11 0.20 10 BAU/ml 12 0.30 13 0.40 14 0.50 Vial #3 15 0.05 1:1,000 w/v 16 0.10 1,000 pnu/ml 17 0.15 100 AU/ml 18 0.20 100 BAU/ml 19 0.30 20 0.40 21 0.50 Vial #4 22 0.05 1:100 w/v 23 0.07 10,000 pnu/ml 24 0.10 1,000 AU/ml 25 0.15 1,000 BAU/ml 26 0.20 27 0.25 Maintenance Refill 28 0.25 1:100 w/v 29 0.25 10,000 pnu/ml 30 0.25 1,000 AU/ml 31 0.25 1,000 BAU/ml 32 0.25 subsequent doses 33 0.25 Preparation Instructions: All dilutions may be made using sterile buffered diluent.

The calculation may be based on the following ratio: Volume desired x Concentration desired = Volume needed x Concentration available.

Example 1 : If a 1:10 w/v extract is available and it is desired to use a 1:1,000 w/v extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 0.001 = Vn x 0.1 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 1:10 vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting ratio will be a 10 ml vial of 1:1,000 w/v.

Example 2 : If a 10,000 pnu/ml extract is available and it is desired to use a 100 pnu/ml extract substitute as follows: 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 pnu/ml vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting concentration will be a 10 ml vial of 100 pnu/ml.

Example 3: If a 10,000 AU/ml or BAU/ml extract is available and it is desired to use a 100 AU/ml or BAU/ml extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 AU/ml or BAU/ml vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting concentration will be 10ml vial of 100 AU/ml or BAU/ml.

Intervals between doses: The optimal interval between doses of allergenic extract has not been definitely established.

The amount of allergenic extract is increased at each injection by not more than 50%-100% of the previous amount and the next increment is governed by the response to the last injection.

There are three generally accepted methods of pollen hyposensitizing therapy.

PRESEASONAL Treatment starts each year 6 to 8 weeks before onset of seasonal symptoms.

Maximal dose reached just before symptoms are expected.

Injections discontinued during and following season until next year.

CO-SEASONAL Patient is first treated during season with symptoms.

Low initial doses are employed to prevent worsening of condition.

This is followed by an intensive schedule of therapy (i.e.

injections given 2 to 3 times per week).

Fewer Allergists are resorting to this Co-seasonal therapy because of the availability of more effective, symptomatic medications that allow the patient to go through a season relatively symptom free.

PERENNIAL Initially this is the same as pre seasonal.

The allergen is administered twice weekly or weekly for about 20 injections to achieve the maximum tolerated dose.

Then, maintenance therapy may be administered once a week or less frequently.

Duration of Treatment: The usual duration of treatment has not been established.

A period of two or three years of injection therapy constitutes an average minimum course of treatment.

Sudafed PE Children’s Cold & Cough 5 MG / 2.5 MG per 5 ML Oral Solution

Generic Name: DEXTROMETHORPHAN HYDROBROMIDE AND PHENYLEPHRINE HYDROCHLORIDE

Brand Name: Childrens SUDAFED PE Cold plus Cough

Substance Name(s):
DEXTROMETHORPHAN HYDROBROMIDE
PHENYLEPHRINE HYDROCHLORIDE

WARNINGS

Warnings Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Ask a doctor before use if the child has heart disease high blood pressure thyroid disease diabetes persistent or chronic cough such as occurs with asthma cough that occurs with too much phlegm (mucus) a sodium-restricted diet When using this product do not exceed recommended dose Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms due to the common cold, hay fever, or other upper respiratory allergies: cough nasal congestion sinus congestion and pressure

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, carboxymethylcellulose sodium, edetate disodium, FD&C blue no.

1, FD&C red no.

40, flavors, glycerin, purified water, sodium benzoate, sodium citrate, sorbitol solution, sucralose

PURPOSE

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

ASK DOCTOR

DOSAGE AND ADMINISTRATION

Directions find right dose on chart below mL = milliliters repeat dose every 4 hours do not give more than 6 times in 24 hours Age (yr) Dose (mL) under 4 years do not use 4 to 5 years 5 mL 6 to 11 years 10 mL Attention: use only enclosed dosing cup specifically designed for use with this product.

Do not use any other dosing device.

DO NOT USE

Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

STOP USE

Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant

empagliflozin 5 MG / Metformin hydrochloride 1000 MG Oral Tablet

Generic Name: EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

Brand Name: Synjardy

Substance Name(s):
EMPAGLIFLOZIN
METFORMIN HYDROCHLORIDE

DRUG INTERACTIONS

7 See Table 4 for clinically relevant interactions with SYNJARDY or SYNJARDY XR.

Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY XR Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.

Concomitant use of these drugs with SYNJARDY or SYNJARDY XR may increase the risk of lactic acidosis.

Intervention Consider more frequent monitoring of these patients.

Drugs that Reduce Metformin Clearance Clinical Impact Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ] .

Intervention Consider the benefits and risks of concomitant use.

Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism.

Intervention Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

Diuretics Clinical Impact Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.

Intervention Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function.

In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR.

Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.

Intervention Coadministration of SYNJARDY or SYNJARDY XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Drugs Affecting Glycemic Control Clinical Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.

These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

Intervention When such drugs are administered to a patient receiving SYNJARDY or SYNJARDY XR, the patient should be closely observed to maintain adequate glycemic control.

When such drugs are withdrawn from a patient receiving SYNJARDY or SYNJARDY XR, the patient should be observed closely for hypoglycemia.

Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Intervention Monitor serum lithium concentration more frequently during SYNJARDY or SYNJARDY XR initiation and dosage changes.

Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors.

Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention Monitoring glycemic control with 1,5-AG assay is not recommended.

Use alternative methods to monitor glycemic control.

Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis.

Consider more frequent monitoring.

( 7 ) Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis.

Consider benefits and risks of concomitant use.

( 7 ) See full prescribing information for additional drug interactions and information on interference of SYNJARDY or SYNJARDY XR with laboratory tests.

( 7 )

OVERDOSAGE

10 In the event of an overdose with SYNJARDY or SYNJARDY XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams.

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.

Removal of empagliflozin by hemodialysis has not been studied.

DESCRIPTION

11 SYNJARDY and SYNJARDY XR tablets for oral use contain: empagliflozin and metformin HCl.

Empagliflozin Empagliflozin is an inhibitor of the SGLT2.

The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).

Its molecular formula is C 23 H 27 ClO 7 and the molecular weight is 450.91.

The structural formula is: Empagliflozin is a white to yellowish, non-hygroscopic powder.

It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene.

Chemical Structure Metformin HCl Metformin HCl ( N,N -dimethylimidodicarbonimidic diamide HCl) is a biguanide.

Metformin HCl is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 ∙HCl and a molecular weight of 165.63.

Metformin HCl is freely soluble in water 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 HCl is 6.68.

The structural formula is: Chemical Structure SYNJARDY SYNJARDY tablets for oral administration are available in four dosage strengths containing: 5 mg empagliflozin and 500 mg metformin HCl (equivalent to 389.93 mg of metformin) 5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 12.5 mg empagliflozin and 500 mg metformin HCl (equivalent to 389.93 mg of metformin) 12.5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) Each film-coated tablet of SYNJARDY contains the following inactive ingredients: colloidal silicon dioxide, copovidone, corn starch, and magnesium stearate.

Film-coating: black ferrosoferric oxide and ferric oxide red (12.5 mg/500 mg, 12.5 mg/1,000 mg) or ferric oxide yellow (5 mg/500 mg, 5 mg/1,000 mg), hypromellose, polyethylene glycol 400, talc and titanium dioxide.

SYNJARDY XR Each film-coated tablet of SYNJARDY XR consists of an extended-release metformin HCl core tablet that is coated with the immediate-release drug substance empagliflozin.

SYNJARDY XR tablets for oral administration are available in four dosage strengths containing: 5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 10 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 12.5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 25 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) Each film-coated tablet of SYNJARDY XR contains the following inactive ingredients: Tablet Core: hypromellose, magnesium stearate, and polyethylene oxide.

Film-coatings and Printing Ink: carnauba wax, FD&C blue#2/indigo carmine aluminum lake (12.5 mg/1,000 mg, 25 mg/1,000 mg), ferric oxide red (10 mg/1,000 mg), ferric oxide yellow (5 mg/1,000 mg, 10 mg/1,000 mg, 25 mg/1,000 mg), ferrosoferric oxide, hypromellose, isopropyl alcohol, polydextrose, polyethylene glycol, propylene glycol, purified water, talc, and titanium dioxide.

CLINICAL STUDIES

14 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus In adult patients with type 2 diabetes mellitus, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo and metformin.

Reductions in HbA1c were observed across subgroups including age, sex, race, and baseline BMI.

Empagliflozin Add-On Combination Therapy with Metformin in Adult Patients with Type 2 Diabetes Mellitus A total of 637 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin.

Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin HCl per day entered an open-label 2-week placebo run-in.

At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 7 ).

Table 7 Results at Week 24 From a Placebo-Controlled Trial for Empagliflozin used in Combination with Metformin Empagliflozin 10 mg N=217 Empagliflozin 25 mg N=213 Placebo N=207 a Modified intent-to-treat population.

Last observation on trial (LOCF) was used to impute missing data at Week 24.

At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.

b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region.

Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207 HbA1c (%) a Baseline (mean) 7.9 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.8 -0.1 Difference from placebo + metformin (adjusted mean) (95% CI) -0.6 b (-0.7, -0.4) -0.6 b (-0.8, -0.5) — Patients [n (%)] achieving HbA1c <7% 75 (38%) 74 (39%) 23 (13%) FPG (mg/dL) c Baseline (mean) 155 149 156 Change from baseline (adjusted mean) -20 -22 6 Difference from placebo + metformin (adjusted mean) -26 -29 — Body Weight Baseline mean in kg 82 82 80 % change from baseline (adjusted mean) -2.5 -2.9 -0.5 Difference from placebo (adjusted mean) (95% CI) -2.0 b (-2.6, -1.4) -2.5 b (-3.1, -1.9) — At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 25 mg.

Empagliflozin Initial Combination Therapy with Metformin A total of 1,364 patients with type 2 diabetes mellitus participated in a double-blind, randomized, active-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin as initial therapy compared to the corresponding individual components.

Treatment-naïve patients with inadequately controlled type 2 diabetes mellitus entered an open-label placebo run-in for 2 weeks.

At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized to one of 8 active-treatment arms: empagliflozin 10 mg or 25 mg; metformin HCl 1,000 mg, or 2,000 mg; empagliflozin 10 mg in combination with 1,000 mg or 2,000 mg metformin HCl; or empagliflozin 25 mg in combination with 1,000 mg or 2,000 mg metformin HCl.

At Week 24, initial therapy of empagliflozin in combination with metformin provided statistically significant reductions in HbA1c (p-value <0.01) compared to the individual components (see Table 8 ).

Table 8 Glycemic Parameters at 24 Weeks in a Trial Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy Empagliflozin 10 mg + Metformin 1,000 mg a N=161 Empagliflozin 10 mg + Metformin 2,000 mg a N=167 Empagliflozin 25 mg + Metformin 1,000 mg a N=165 Empagliflozin 25 mg + Metformin 2,000 mg a N=169 Empagliflozin 10 mg N=169 Empagliflozin 25 mg N=163 Metformin 1,000 mg a N=167 Metformin 2,000 mg a N=162 a Metformin HCl total daily dose, administered in two equally divided doses per day.

b p-value ≤0.0062 (modified intent-to-treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).

c p-value ≤0.0056 (modified intent-to-treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).

HbA1c (%) Baseline (mean) 8.7 8.7 8.8 8.7 8.6 8.9 8.7 8.6 Change from baseline (adjusted mean) -2.0 -2.1 -1.9 -2.1 -1.4 -1.4 -1.2 -1.8 Comparison vs empagliflozin (adjusted mean) (95% CI) -0.6 b (-0.9, -0.4) -0.7 b (-1.0, -0.5) -0.6 c (-0.8, -0.3) -0.7 c (-1.0, -0.5) — — — — Comparison vs metformin (adjusted mean) (95% CI) -0.8 b (-1.0, -0.6) -0.3 b (-0.6, -0.1) -0.8 c (-1.0, -0.5) -0.3 c (-0.6, -0.1) — — — — Patients [n (%)] achieving HbA1c <7% 96 (63%) 112 (70%) 91 (57%) 111 (68%) 69 (43%) 51 (32%) 63 (38%) 92 (58%) Empagliflozin Add-On Combination Therapy with Metformin and Sulfonylurea A total of 666 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes mellitus on at least 1,500 mg per day of metformin HCl and on a sulfonylurea, entered a 2-week open-label placebo run-in.

At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

Treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 9 ).

Table 9 Results at Week 24 from a Placebo-Controlled Trial for Empagliflozin in Combination with Metformin and Sulfonylurea Empagliflozin 10 mg N=225 Empagliflozin 25 mg N=216 Placebo N=225 a Modified intent-to-treat population.

Last observation on trial (LOCF) was used to impute missing data at Week 24.

At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.

b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region.

Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=225, for empagliflozin 25 mg, n=215, for placebo, n=224 HbA1c (%) a Baseline (mean) 8.1 8.1 8.2 Change from baseline (adjusted mean) -0.8 -0.8 -0.2 Difference from placebo (adjusted mean) (95% CI) -0.6 b (-0.8, -0.5) -0.6 b (-0.7, -0.4) — Patients [n (%)] achieving HbA1c <7% 55 (26%) 65 (32%) 20 (9%) FPG (mg/dL) c Baseline (mean) 151 156 152 Change from baseline (adjusted mean) -23 -23 6 Difference from placebo (adjusted mean) -29 -29 — Body Weight Baseline mean in kg 77 78 76 % change from baseline (adjusted mean) -2.9 -3.2 -0.5 Difference from placebo (adjusted mean) (95% CI) -2.4 b (-3.0, -1.8) -2.7 b (-3.3, -2.1) — Active-Controlled Trial vs Glimepiride in Combination with Metformin The efficacy of empagliflozin was evaluated in a double-blind, glimepiride-controlled, trial in 1,545 patients with type 2 diabetes mellitus with insufficient glycemic control despite metformin therapy.

Patients with inadequate glycemic control and an HbA1c between 7% and 10% after a 2-week run-in period were randomized to glimepiride or empagliflozin 25 mg.

At Week 52, empagliflozin 25 mg and glimepiride lowered HbA1c and FPG (see Table 10 , Figure 3 ).

The difference in observed effect size between empagliflozin 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%.

The mean daily dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day.

Table 10 Results at Week 52 from an Active-Controlled Trial Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin Empagliflozin 25 mg N=765 Glimepiride N=780 a Modified intent-to-treat population.

Last observation on trial (LOCF) was used to impute data missing at Week 52.

At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to empagliflozin 25 mg and glimepiride, respectively.

b Non-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region) c ANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) d FPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779 HbA1c (%) a Baseline (mean) 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.7 Difference from glimepiride (adjusted mean) (97.5% CI) -0.07 b (-0.15, 0.01) — FPG (mg/dL) d Baseline (mean) 150 150 Change from baseline (adjusted mean) -19 -9 Difference from glimepiride (adjusted mean) -11 — Body Weight Baseline mean in kg 82.5 83 % change from baseline (adjusted mean) -3.9 2.0 Difference from glimepiride (adjusted mean) (95% CI) -5.9 c (-6.3, -5.5) — Figure 3 Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population) – LOCF At Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg for glimepiride.

The differences between treatment groups for systolic blood pressure was statistically significant (p-value <0.0001).

At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for empagliflozin 25 mg and -0.66% for glimepiride.

The adjusted mean treatment difference was -0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%.

The mean daily dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day.

The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data.

Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data.

In this multiple imputation analysis, 13.9% of the data were imputed for empagliflozin 25 mg and 12.9% for glimepiride.

At Week 104, empagliflozin 25 mg daily resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for empagliflozin 25 mg vs.

+1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).

Figure 3 14.2 Glycemic Control Trials in Pediatric Patients with Type 2 Diabetes Mellitus Glycemic Control Trial of Empagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus DINAMO (NCT03429543) was a 26-week, double-blind, randomized, placebo-controlled, parallel group trial, with a double-blind active treatment safety extension period up to 52 weeks to assess the efficacy of empagliflozin.

The trial enrolled pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1c 6.5 to 10.5%).

Patients treated with metformin (at least 1,000 mg daily or maximally tolerated dose), with or without insulin therapy, and those with a history of intolerance to metformin therapy were enrolled.

Patients were randomized to 3 treatment arms (empagliflozin 10 mg, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or placebo) over 26 weeks.

Patients in the empagliflozin 10 mg group who failed to achieve HbA1c <7.0% at Week 12 underwent a second randomization at Week 14 to remain on the 10 mg dose or increase to 25 mg.

Patients on placebo were re-randomized at Week 26 to one of the empagliflozin doses (10 mg or 25 mg) or a DPP-4 inhibitor.

A total of 157 patients were treated with either empagliflozin (10 mg or 25 mg; N=52), a DPP-4 inhibitor (N=52), or placebo (N=53).

Background therapies as adjunct to diet and exercise included metformin (51%), a combination of metformin and insulin (40.1%), insulin (3.2%), or none (5.7%).

The mean HbA1c at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2.1 years.

The mean age was 14.5 years (range: 10-17 years) and 51.6% were aged 15 years and older.

Approximately, 50% were White, 6% were Asian, 31% were Black or African American, and 38% were of Hispanic or Latino ethnicity.

The mean BMI was 36.0 kg/m 2 and mean BMI Z-score was 3.0.

Patients with an eGFR less than 60 mL/min/1.73 m 2 were not enrolled in the trial.

Approximately 25% of the trial population had microalbuminuria or macroalbuminuria.

At Week 26, treatment with empagliflozin was superior in reducing HbA1c from baseline versus placebo (see Table 11 ).

Table 11 Results at Week 26 for a Placebo-Controlled Trial for Empagliflozin in Combination with Metformin and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus a Empagliflozin 10 mg and 25 mg Placebo a Modified intent-to-treat set (All randomized and treated patients with baseline measurement).

b Multiple imputations using placebo wash-out approach with 500 iterations for missing data.

Imputed for HbA1c (empagliflozin N=5 (9.6%), placebo N=3 (5.7%)), for FPG (empagliflozin N=4 (8.3%), placebo N=2 (3.8%)).

c Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value and baseline age stratum (< 15 years vs 15 to < 18 years).

d Not evaluated for statistical significance, not part of sequential testing procedure.

e p-value=0.0116 (two-sided) HbA1c (%) b Number of patients n=52 n=53 Baseline (mean) 8.0 8.1 Change from baseline c -0.2 0.7 Difference from placebo c (95% CI) -0.8 e (-1.5, -0.2) — FPG (mg/dL) b,d Number of patients n=48 n=52 Baseline (mean) 154 159 Change from baseline c -19 17 Difference from placebo c (95% CI) -36 (-60.7, -10.7) — Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus: A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks).

The results are displayed in Table 12.

Table 12 Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl vs.

Placebo in Pediatric Patients a with Type 2 Diabetes Mellitus Metformin HCl Placebo p-value a Pediatric patients mean age 13.8 years (range 10-16 years) FPG (mg/dL) (n=37) (n=36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 <0.001 Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively.

Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively.

14.3 Empagliflozin Cardiovascular Outcome Trial in Adult Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease EMPA-REG OUTCOME was a multicenter, multinational, randomized, double-blind parallel group trial that compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes mellitus and atherosclerotic cardiovascular (CV) disease.

Concomitant antidiabetic medications were kept stable for the first 12 weeks of the trial.

Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7,020 patients were treated (empagliflozin 10 mg = 2,345; empagliflozin 25 mg = 2,342; placebo = 2,333) and followed for a median of 3.1 years.

Approximately 72% of the trial population was White, 22% was Asian, and 5% was Black or African American.

The mean age was 63 years and approximately 72% were male.

All patients in the trial had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%).

The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes mellitus for more than 10 years.

Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators, respectively and the mean eGFR was 74 mL/min/1.73 m 2 .

At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%).

All patients had established atherosclerotic CV disease at baseline including one (82%) or more (18%) of the following: a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%).

At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g.

At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE).

A major adverse cardiac event was defined as occurrence of either a CV death or a non-fatal myocardial infarction (MI) or a non-fatal stroke.

The statistical analysis plan had pre-specified that the 10 and 25 mg dosages would be combined.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated.

Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99).

The treatment effect was due to a significant reduction in the risk of CV death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 13 and Figures 4 and 5 ).

Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dosage groups.

Table 13 Treatment Effect for the Primary Composite Endpoint and its Components a Placebo N=2,333 Empagliflozin N=4,687 Hazard ratio vs placebo (95% CI) a Treated set (patients who had received at least one dose of trial drug) b p-value for superiority (2-sided) 0.04 c Total number of events Composite of CV death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) b 282 (12.1%) 490 (10.5%) 0.86 (0.74, 0.99) Non-fatal myocardial infarction c 121 (5.2%) 213 (4.5%) 0.87 (0.70, 1.09) Non-fatal stroke c 60 (2.6%) 150 (3.2%) 1.24 (0.92, 1.67) CV death c 137 (5.9%) 172 (3.7%) 0.62 (0.49, 0.77) Figure 4 Estimated Cumulative Incidence of First MACE Figure 5 Estimated Cumulative Incidence of CV Death The efficacy of empagliflozin on CV death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial.

A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial.

Most of these deaths were categorized as CV deaths.

The non-CV deaths were only a small proportion of deaths and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).

Figure 4 Figure 5 14.4 Empagliflozin Heart Failure Trials, Including Adult Patients with Type 2 Diabetes Mellitus EMPEROR-Reduced Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction ≤ 40%) EMPEROR-Reduced (NCT03057977) was a double-blind trial conducted in adults with chronic heart failure (New York Heart Association [NYHA] functional class II-IV) with left ventricular ejection fraction (LVEF) ≤40% to evaluate the efficacy of empagliflozin as adjunct to standard of care heart failure therapy.

Of 3,730 patients, 1,863 were randomized to empagliflozin 10 mg once daily and 1,867 to placebo once daily and were followed for a median of 16 months.

Baseline Disease Characteristics and Demographics EMPEROR-Reduced included patients with type 2 diabetes mellitus (n=1,856) and patients without type 2 diabetes mellitus (n=1,874).

The mean age of the trial population was 67 years (range: 25 to 94 years) and 76% were males, 24% were women, and 27% were 75 years of age or older.

Approximately 71% of the trial population were White, 18% Asian and 7% Black or African American.

At randomization, 75% of patients were NYHA class II, 24% were class III and 0.5% were class IV.

The mean LVEF was 28%.

At baseline, the mean eGFR was 62 mL/min/1.73 m 2 and the median urinary albumin to creatinine ratio (UACR) was 22 mg/g.

Approximately half of the patients (52%) had eGFR equal to or above 60 mL/min/1.73 m 2 , 24% had eGFR 45 to less than 60 mL/min/1.73 m 2 , and 19% had eGFR 30 to less than 45 mL/min/1.73 m 2 .

At baseline, 88% of patients were treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or angiotensin receptor-neprilysin inhibitors (ARNI), 95% with beta-blockers, 71% with mineralocorticoid receptor antagonists (MRA), and 95% with diuretics.

In EMPEROR-Reduced, history of type 2 diabetes mellitus was present in 50% of the patients, and 46% of these patients were treated with metformin (444 patients in the empagliflozin group and 418 in the placebo group) and 25% were treated with insulin.

In the type 2 diabetes mellitus subpopulation, the mean age was 67 years; 77% were males; 69% White, 19% Asian and 7% Black or African American; 32% were Hispanic/Latino.

In the type 2 diabetes mellitus subpopulation, at baseline, 71% of patients were classified as NYHA class II, 28% class III and 0.7% class IV; the mean LVEF was 27%; the mean baseline eGFR was 61 mL/min/1.73 m 2 .

In this subpopulation, at baseline, 88% of patients were treated with ACE inhibitors, ARB, or ARNI, 95% with beta-blockers, 70% with MRA, and 96% with diuretics.

Results In EMPEROR-Reduced, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint of CV death or hospitalization for heart failure (HHF) mostly through a reduction in HHF (HR 0.75 [95% CI 0.65, 0.86]).

Empagliflozin reduced the risk of first and recurrent HHF, a key secondary endpoint.

Because of the metformin component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with heart failure without type 2 diabetes mellitus [see Indications and Usage (1) ] .

The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.73 [95% CI 0.60, 0.87]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.65 [95% CI 0.49, 0.86]).

EMPEROR-Preserved Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction > 40%) EMPEROR-Preserved (NCT03057951) was a double-blind trial conducted in patients with chronic heart failure NYHA Class II-IV with LVEF >40% to evaluate the efficacy of empagliflozin as adjunct to standard of care therapy.

Of 5,988 patients, 2,997 patients were randomized to empagliflozin 10 mg once daily and 2,991 patients to placebo once daily and were followed for a median of 26 months.

Baseline Disease Characteristics and Demographics EMPEROR-Preserved included patients with type 2 diabetes mellitus (n=2,928) and patients without type 2 diabetes mellitus (n=3,060).

The mean age of the trial population was 72 years (range: 22 to 100 years) and 55% were males, 45% were women, and 43% were 75 years of age or older.

Approximately 76% of the trial population were White, 14% Asian and 4% Black or African American.

At randomization, 82% of patients were NYHA class II, 18% were class III and 0.3% were class IV.

This trial included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60% (34.4%) and a LVEF ≥60% (32.5%).

At baseline, the mean eGFR was 61 mL/min/1.73 m 2 and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g.

Approximately half of the patients (50%) had eGFR equal to or above 60 mL/min/1.73 m 2 , 26% had eGFR 45 to less than 60 mL/min/1.73 m 2 , and 19% had eGFR 30 to less than 45 mL/min/1.73 m 2 .

At baseline, 81% of patients were treated with ACE inhibitors, ARBs, or ARNI, 86% with beta-blockers, 38% with MRAs, and 86% with diuretics.

In EMPEROR-Preserved, history of type 2 diabetes mellitus was present in 49% of the patients, and 54% of these patients were treated with metformin (773 patients in the empagliflozin group and 803 in the placebo group) and 29% were treated with insulin.

In the type 2 diabetes mellitus subpopulation, the mean age was 71 years, 57% were males, 75% White, 13% Asian and 5% Black or African American.

In the type 2 diabetes mellitus subpopulation, at baseline, 79% of patients were classified as NYHA class II, 20% class III and 0.2% class IV; the trial also included type 2 diabetics with LVEF <50% (35%), with a LVEF 50 to <60% (34%) and a LVEF ≥60% (31%).

For this subpopulation, the mean baseline eGFR was 60 mL/min/1.73 m 2 ; and at baseline, 83% of patients were treated with ACE inhibitors, ARB, or ARNI, 88% with beta-blockers, 39% with MRA, and 89% with diuretics.

Results In EMPEROR-Preserved, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint (time to first event of either CV death or HHF) mostly through a reduction in hospitalization for heart failure (HR 0.79 [95% CI 0.69, 0.90]).

Empagliflozin reduced the risk of first and recurrent HHF, a key secondary endpoint.

Because of the metformin component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with heart failure without type 2 diabetes mellitus [see Indications and Usage (1) ] .

The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.80 [95% CI 0.67, 0.95]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.79 [95% CI 0.61, 1.02]).

HOW SUPPLIED

16 /STORAGE AND HANDLING SYNJARDY tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 500 mg Metformin HCl orange yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “500”.

Bottles of 60 Bottles of 180 0597-0159-60 0597-0159-18 5 mg Empagliflozin 1,000 mg Metformin HCl brownish yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “1000”.

Bottles of 60 Bottles of 180 0597-0175-60 0597-0175-18 12.5 mg Empagliflozin 500 mg Metformin HCl pale brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “500”.

Bottles of 60 Bottles of 180 0597-0180-60 0597-0180-18 12.5 mg Empagliflozin 1,000 mg Metformin HCl dark brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “1000”.

Bottles of 60 Bottles of 180 0597-0168-60 0597-0168-18 SYNJARDY XR extended-release tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 1,000 mg Metformin HCl olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S5” on the top line and “1000 M” on the bottom line.

Bottles of 60 Bottles of 180 0597-0290-74 0597-0290-59 10 mg Empagliflozin 1,000 mg Metformin HCl orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S10” on the top line and “1000 M” on the bottom line.

Bottles of 30 Bottles of 90 0597-0280-73 0597-0280-90 12.5 mg Empagliflozin 1,000 mg Metformin HCl blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S12” on the top line and “1000 M” on the bottom line.

Bottles of 60 Bottles of 180 0597-0300-45 0597-0300-93 25 mg Empagliflozin 1,000 mg Metformin HCl light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S25” on the top line and “1000 M” on the bottom line.

Bottles of 30 Bottles of 90 0597-0295-88 0597-0295-78 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Indications and Usage ( 1 ) 6/2023 Dosage and Administration ( 2.2 ) 2/2023 Dosage and Administration ( 2.3 , 2.7 ) 6/2023 Dosage and Administration ( 2.6 ) 10/2023 Warnings and Precautions ( 5.2 , 5.8 ) 10/2023 Warnings and Precautions ( 5.5 ) 6/2023

GERIATRIC USE

8.5 Geriatric Use Assess renal function more frequently in SYNJARDY or SYNJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients [see Warnings and Precautions (5.1 , 5.3) ].

The recommended dosage for the metformin component of SYNJARDY or SYNJARDY XR in geriatric patients should usually start at the lower end of the dosage range.

Empagliflozin In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older.

In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.

In heart failure trials, EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older.

EMPEROR-Preserved included 2,402 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older.

No overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients.

Metformin Clinical studies of metformin did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients .

DOSAGE FORMS AND STRENGTHS

3 SYNJARDY Tablets: 5 mg empagliflozin/500 mg metformin HCl ( 3 ) 5 mg empagliflozin/1,000 mg metformin HCl ( 3 ) 12.5 mg empagliflozin/500 mg metformin HCl ( 3 ) 12.5 mg empagliflozin/1,000 mg metformin HCl ( 3 ) SYNJARDY XR Tablets: 5 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 10 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 25 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) SYNJARDY Tablets: Empagliflozin Strength Metformin HCl Strength Color/Shape Tablet Markings 5 mg 500 mg orange yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “500”.

5 mg 1,000 mg brownish yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “1000”.

12.5 mg 500 mg pale brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “500”.

12.5 mg 1,000 mg dark brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “1000”.

SYNJARDY XR Tablets: Empagliflozin Strength Metformin HCl Extended – Release Strength Color/Shape Tablet Markings 5 mg 1,000 mg olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S5” on the top line and “1000 M” on the bottom line.

10 mg 1,000 mg orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S10” on the top line and “1000 M” on the bottom line.

12.5 mg 1,000 mg blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S12” on the top line and “1000 M” on the bottom line.

25 mg 1,000 mg light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S25” on the top line and “1000 M” on the bottom line.

MECHANISM OF ACTION

12.1 Mechanism of Action SYNJARDY or SYNJARDY XR SYNJARDY and SYNJARDY XR contain: empagliflozin, a SGLT2 inhibitor, and metformin, a biguanide.

Empagliflozin Empagliflozin is an inhibitor of the SGLT2, the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation.

By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule.

This may influence several physiological functions such as lowering both pre- and afterload of the heart and downregulating sympathetic activity.

Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.

It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.5) ] and does not cause hyperinsulinemia.

With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

INDICATIONS AND USAGE

1 SYNJARDY SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

SYNJARDY XR SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus .

Empagliflozin Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Cardiovascular death in adults with established cardiovascular disease.

( 1 ) Cardiovascular death and hospitalization for heart failure in adults with heart failure.

( 1 ) Limitations of Use : Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

It may increase the risk of diabetic ketoacidosis in these patients.

( 1 ) Because of the metformin component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.

( 1 ) SYNJARDY SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus .

SYNJARDY XR SYNJARDY XR is a combination of empagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus .

Cardiovascular death and hospitalization for heart failure in adults with heart failure.

Limitations of Use SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2) ] .

Because of the metformin component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.

PEDIATRIC USE

8.4 Pediatric Use SYNJARDY The safety and effectiveness of SYNJARDY as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older.

Use of SYNJARDY for this indication is supported by evidence from a 26-week double-blind, placebo-controlled clinical trial of empagliflozin, with a double-blind active treatment safety extension period of up to 52 weeks in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] .

The safety profile of pediatric patients treated with empagliflozin was similar to that observed in adults with type 2 diabetes mellitus, with the exception of hypoglycemia risk which was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ].

Use of SYNJARDY for this indication is also supported by evidence from adequate and well-controlled studies of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical study using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus [see Clinical Studies (14) ] .

In this study, adverse reactions were similar to those described in adults.

The safety and effectiveness of SYNJARDY have not been established in pediatric patients less than 10 years of age.

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

PREGNANCY

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects from empagliflozin, SYNJARDY and SYNJARDY XR are not recommended during the second and third trimesters of pregnancy.

The limited available data with SYNJARDY, SYNJARDY XR, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.

Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data ) .

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ) .

In animal studies, empagliflozin, a component of SYNJARDY and SYNJARDY XR, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy.

Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible.

No adverse developmental effects were observed when metformin was administered to pregnant rats or rabbits (see Data ) .

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10.

The estimated background risk of miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy.

However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC.

These findings were not observed after a 13-week drug-free, recovery period.

These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans.

Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects.

In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose.

Empagliflozin crosses the placenta and reaches fetal tissues in rats.

In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity.

Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).

Metformin HCl: Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis.

This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

Empagliflozin and Metformin HCl: No adverse developmental effects were observed when empagliflozin and metformin HCl were coadministered to pregnant rats during the period of organogenesis at exposures of approximately 35- and 14-times the clinical AUC exposure of empagliflozin associated with the 10 mg and 25 mg doses, respectively, and 4-times the clinical AUC exposure of metformin associated with the 2,000 mg dose.

BOXED WARNING

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.

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

Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ] .

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.1) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7) ].

If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting.

Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ].

WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.

Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain.

Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.

( 5.1 ) If lactic acidosis is suspected, discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting.

Prompt hemodialysis is recommended.

( 5.1 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider monitoring in patients at risk of ketoacidosis, as indicated.

Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue SYNJARDY or SYNJARDY XR if ketoacidosis is suspected.

Monitor patients for resolution of ketoacidosis before restarting.

( 5.2 ) Volume Depletion: Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics.

Monitor for signs and symptoms during therapy.

( 5.3 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

( 5.4 ) Hypoglycemia: Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia.

In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher regardless of insulin use.

Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating SYNJARDY or SYNJARDY XR.

( 5.5 ) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males.

Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise.

If suspected, institute prompt treatment.

( 5.6 ) Genital Mycotic Infections: Monitor and treat as appropriate.

( 5.7 ) Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment.

( 5.8 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with empagliflozin.

If hypersensitivity reactions occur, discontinue SYNJARDY or SYNJARDY XR, treat promptly, and monitor until signs and symptoms resolve.

( 5.9 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels.

Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities.

( 5.10 ) 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.

These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis.

Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL.

Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR.

In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions).

Hemodialysis has often resulted in reversal of symptoms and recovery .

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] : Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).

SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications (4) ].

Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR.

In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7) ] .

Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.

Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ] .

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis.

Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.

Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable.

Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.

SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).

Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia.

When such events occur, discontinue SYNJARDY or SYNJARDY XR.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis.

Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.

Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis.

This may be due to impaired lactate clearance resulting in higher lactate blood levels.

Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, empagliflozin, a component of SYNJARDY or SYNJARDY XR, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate.

In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin.

SYNJARDY and SYNJARDY XR are not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis.

There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including SYNJARDY or SYNJARDY XR.

Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath.

Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL).

Ketoacidosis and glucosuria may persist longer than typically expected.

Urinary glucose excretion persists for 3 days after discontinuing SYNJARDY or SYNJARDY XR [see Clinical Pharmacology (12.2) ] ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation.

Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis.

If ketoacidosis is suspected, discontinue SYNJARDY or SYNJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed.

Monitor patients for resolution of ketoacidosis before restarting SYNJARDY or SYNJARDY XR.

Withhold SYNJARDY or SYNJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis.

Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.6) ] .

Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SYNJARDY or SYNJARDY XR and seek medical attention immediately if signs and symptoms occur.

5.3 Volume Depletion Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1) ] .

There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin.

Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension.

Before initiating SYNJARDY or SYNJARDY XR in patients with one or more of these characteristics, assess volume status and renal function.

In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR.

Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

5.4 Urosepsis and Pyelonephritis There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving empagliflozin.

Treatment with empagliflozin increases the risk for urinary tract infections.

Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6) ] .

5.5 Hypoglycemia Insulin and insulin secretagogues are known to cause hypoglycemia.

In adult patients, the risk of hypoglycemia may be increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.

In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use [see Adverse Reactions (6.1) ] .

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin.

Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin.

Cases have been reported in both females and males.

Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with SYNJARDY or SYNJARDY XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis.

If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement.

Discontinue SYNJARDY or SYNJARDY XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.7 Genital Mycotic Infections Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1) ] .

Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections.

Monitor and treat as appropriate.

5.8 Lower Limb Amputation In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed.

Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95% CI) (0.81, 1.36).

In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively.

Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee.

Some patients had multiple amputations.

SYNJARDY and SYNJARDY XR are not indicated for the treatment of chronic kidney disease.

Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation.

The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.

Counsel patients about the importance of routine preventative foot care.

Monitor patients receiving SYNJARDY or SYNJARDY XR for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

5.9 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin.

If a hypersensitivity reaction occurs, discontinue SYNJARDY or SYNJARDY XR; treat promptly per standard of care, and monitor until signs and symptoms resolve.

SYNJARDY and SYNJARDY XR are contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in SYNJARDY or SYNJARDY XR [see Contraindications (4) ] .

5.10 Vitamin B 12 Deficiency In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of metformin-treated patients.

Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation.

Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels.

Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on SYNJARDY or SYNJARDY XR and manage any abnormalities [see Adverse Reactions (6.1) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Lactic Acidosis Inform patients of the risks of lactic acidosis due to metformin, its symptoms, and conditions that predispose to its development.

Advise patients to discontinue SYNJARDY or SYNJARDY XR immediately and to notify their healthcare provider promptly if unexplained hyperventilation, malaise, myalgia, unusual somnolence, or other nonspecific symptoms occur.

Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving SYNJARDY or SYNJARDY XR.

Instruct patients to inform their healthcare provider that they are taking SYNJARDY or SYNJARDY XR prior to any surgical or radiological procedure, as temporary discontinuation may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1) ] .

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that SYNJARDY or SYNJARDY XR can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.

Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing).

Inform patients that blood glucose may be normal even in the presence of ketoacidosis.

Advise patients that they may be asked to monitor ketones.

If symptoms of ketoacidosis occur, instruct patients to discontinue SYNJARDY or SYNJARDY XR and seek medical attention immediately [see Warnings and Precautions (5.2) ] .

Volume Depletion Inform patients that symptomatic hypotension may occur with SYNJARDY or SYNJARDY XR and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.3) ] .

Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.

Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious.

Provide them with information on the symptoms of urinary tract infections.

Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.4) ] .

Hypoglycemia Inform patients that hypoglycemia has been reported when SYNJARDY or SYNJARDY XR is used with insulin secretagogues or insulin.

Hypoglycemia may occur in pediatric patients regardless of concomitant antidiabetic treatment.

Educate patients or caregivers on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5) ] .

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with empagliflozin, a component of SYNJARDY and SYNJARDY XR.

Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.6) ] .

Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections.

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7) ] .

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of the penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections.

Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis).

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7) ] .

Lower Limb Amputation Counsel patients about the importance of routine preventative foot care.

Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.8) ].

Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with empagliflozin, a component of SYNJARDY and SYNJARDY XR.

Advise patients to report immediately any skin reaction or angioedema, and to discontinue the drug until they have consulted prescribing healthcare provider [see Warnings and Precautions (5.9) ] .

Vitamin B 12 Deficiency Inform patients about the importance of regular hematological parameters while receiving SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.10) ] .

Laboratory Tests Inform patients that elevated glucose in urinalysis is expected when taking SYNJARDY or SYNJARDY XR [see Drug Interactions (7) ] .

Pregnancy Advise pregnant patients, and patients of reproductive potential, of the potential risk to a fetus with treatment with SYNJARDY or SYNJARDY XR [see Use in Specific Populations (8.1) ] .

Instruct patients to report pregnancies to their healthcare provider as soon as possible.

Lactation Advise patients that breastfeeding is not recommended during treatment with SYNJARDY or SYNJARDY XR [see Use in Specific Populations (8.2) ] .

Patients of Reproductive Potential Inform patients that treatment with metformin may result in ovulation in some premenopausal anovulatory patients, which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ] .

Administration Instructions Inform patients that SYNJARDY XR tablets must be swallowed whole and never split, crushed, dissolved, or chewed and that incompletely dissolved SYNJARDY XR tablets may be eliminated in the feces.

Missed Dose Instruct patients to take SYNJARDY or SYNJARDY XR only as prescribed.

If a dose is missed, it should be taken as soon as the patient remembers.

Advise patients not to double their next dose [see Dosage and Administration (2.7) ] .

DOSAGE AND ADMINISTRATION

2 Assess renal function before initiating and as clinically indicated.

Assess volume status and correct volume depletion before initiating.

( 2.1 ) Individualize the starting dosage based on the patient’s current regimen and renal function.

( 2.2 , 2.3 , 2.4 ) The maximum recommended dosage is 25 mg/day of empagliflozin and 2,000 mg/day of metformin HCl.

( 2.2 , 2.3 ) Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin component.

( 2.4 ) SYNJARDY: take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal side effects due to metformin.

( 2.2 , 2.3 ) SYNJARDY XR: take orally once daily with a meal in the morning, with gradual dosage escalation to reduce the gastrointestinal side effects due to metformin.

Swallow whole; do not split, crush, dissolve, or chew.

( 2.2 ) SYNJARDY or SYNJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.

( 2.5 ) Withhold SYNJARDY or SYNJARDY XR at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

( 2.6 ) 2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated [see Warnings and Precautions (5.1 , 5.3) ] .

Assess volume status.

In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6) ] .

2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults When switching to SYNJARDY or SYNJARDY XR from: Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg.

Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg.

Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component.

Recommended dosage of SYNJARDY or SYNJARDY XR: The recommended total daily dosage of empagliflozin is 10 mg.

For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1) ].

Take SYNJARDY orally twice daily with meals.

Take SYNJARDY XR orally once daily with a meal in the morning.

Swallow each tablet whole.

Do not split, crush, dissolve, or chew.

2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older Individualize the dosage of SYNJARDY based on the patient’s current regimen.

Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg .

Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1) ].

2.4 Dosage Recommendations in Patients with Renal Impairment Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin component.

SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 or in patients on dialysis [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] .

2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast.

Re-evaluate eGFR 48 hours after the imaging procedure; restart SYNJARDY or SYNJARDY XR if renal function is stable [see Warnings and Precautions (5.1) ] .

2.6 Temporary Interruption for Surgery Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] .

2.7 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible.

Do not double up the next dose.

dorzolamide 20 MG/ML (as dorzolamide HCl 22.26 MG/ML) / timolol 5 MG/ML (as timolol maleate 6.83 MG/ML) Ophthalmic Solution

WARNINGS

Systemic Exposure Dorzolamide hydrochloride – timolol maleate contains dorzolamide, a sulfonamide, and timolol maleate, a beta-adrenergic blocking agent; and although administered topically, is absorbed systemically.

Therefore, the same types of adverse reactions that are attributable to sulfonamides and/or systemic administration of beta-adrenergic blocking agents may occur with topical administration.

For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate ( see CONTRAINDICATIONS ).

Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration.

If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.

In Patients Without a History of Cardiac Failure continued depression of the myocardium with betablocking agents over a period of time can, in some cases, lead to cardiac failure.

At the first sign or symptom of cardiac failure, dorzolamide hydrochloride – timolol maleate should be discontinued.

Obstructive Pulmonary Disease Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which dorzolamide hydrochloride – timolol maleate is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta blockingagents, including dorzolamide hydrochloride – timolol maleate.

Major Surgery The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial.

Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta adrenergicallymediated reflex stimuli.

This may augment the risk of general anesthesia in surgical procedures.

Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia.

Difficulty in restarting and maintaining the heartbeat has also been reported.

For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

Diabetes Mellitus Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents.

Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.

Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

DRUG INTERACTIONS

Drug Interactions Carbonic anhydrase inhibitors: There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and dorzolamide hydrochloride – timolol maleate.

The concomitant administration of dorzolamide hydrochloride – timolol maleate and oral carbonic anhydrase inhibitors is not recommended.

Acid-base disturbances: Although acid-base and electrolyte disturbances were not reported in the clinical trials with dorzolamide hydrochloride ophthalmic solution, these disturbances have been reported with oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy).

Therefore, the potential for such drug interactions should be considered in patients receiving dorzolamide hydrochloride –timolol maleate.

Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and dorzolamide hydrochloride – timolol maleate should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure.

The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking agents, such as dorzolamide hydrochloride – timolol maleate, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension.

In patients with impaired cardiac function, coadministration should be avoided.

Catecholamine-depleting drugs: Close observation of the patient is recommended when a betablocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digital isand calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.

Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

Injectable Epinephrine: ( See PRECAUTIONS, General, Anaphylaxis .) Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose).

Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose.

No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the recommended human ophthalmic dose).

The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class effect of carbonic anhydrase inhibitors in rats.

Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts.

No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (~5 times the recommended human ophthalmic dose) for one year.

In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day(approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose).

Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.

In a lifetime oral study of timolol maleate in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/ kg/day, (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose).

In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day.

An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans.

Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

The following tests for mutagenic potential were negative for dorzolamide: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 μg/mL).

In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 μg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains.

In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2.

A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats with either timolol maleate or dorzolamide hydrochloride demonstrated no adverse effect on male or female fertility at doses up to approximately 100 times the systemic exposure following the maximum recommended human ophthalmic dose.

OVERDOSAGE

There are no human data available on overdosage with dorzolamide hydrochloride – timolol maleate.

Symptoms consistent with systemic administration of beta-blockers or carbonic anhydrase inhibitors may occur, including electrolyte imbalance, development of an acidotic state, dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest and possible central nervous system effects.

Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored ( see also ADVERSE REACTIONS ).

A study of patients with renal failure showed that timolol did not dialyze readily.

DESCRIPTION

Dorzolamide hydrochloride – timolol maleate (dorzolamide hydrochloride-timolol maleate ophthalmic solution) is the combination of a topical carbonic anhydrase inhibitor and a topical beta- adrenergic receptor blocking agent.

Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6- methyl-4H-thieno[2,3-b]thiopyran]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride.

Dorzolamide hydrochloride is optically active.

The speciﬁc rotation is: [a] 25°C (C=1, water) = ~ -17° .405 nm Its empirical formula is C10H16N2O4S3•HCl and its structural formula is: Dorzolamide hydrochloride has a molecular weight of 360.91.

It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.

Timolol maleate is described chemically as: (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt).Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer.The optical rotation of timolol maleate is: [a] 25°C in 1N HCl (C = 5) = -12.2° (-11.7° to -12.5°) .405 nm Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is: Timolol maleate has a molecular weight of 432.50.

It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol.

Timolol maleate is stable at room temperature.

Dorzolamide hydrochloride – timolol maleate is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution.

The pH of the solution is approximately 5.65, and the osmolarity is 242-323 mOsM.

Each mL of dorzolamide hydrochloride – timolol maleate contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (6.83 mg timolol maleate).

Inactive ingredients are sodium citrate, hydroxyethyl cellulose, sodium hydroxide, mannitol, and water for injection.

Benzalkonium chloride 0.0075% is added as a preservative.

HOW SUPPLIED

Dorzolamide hydrochloride – timolol maleate ophthalmic solution is a clear, colorless to nearly colorless, slightly viscous solution.

Dorzolamide Hydrochloride – Timolol Maleate Ophthalmic Solution is supplied in a 10-mL white, round low-density polyethylene (LPDE) bottle, with a natural LPDE dropper tip, and blue colored high-density polyethylene (HPDE) eyedropper cap.

A white tamper evident overcap is provided.

Dorzolamide hydrochloride – timolol maleate ophthalmic solution is available as follows: NDC 47781-136-34, 10 mL Storage Store dorzolamide hydrochloride – timolol maleate ophthalmic solution at 20-25°C (68-77°F).

[see USP Controlled Room Temperature].

Protect from light.

GERIATRIC USE

Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.

INDICATIONS AND USAGE

Dorzolamide hydrochloride – timolol maleate is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers (failed to achieve target IOP determined after multiple measurements over time).

The IOP-lowering of dorzolamide hydrochloride – timolol maleate b.i.d.

was slightly less than that seen with the concomitant administration of 0.5% timolol b.i.d.

and 2.0% dorzolamide t.i.d.

( see CLINICAL PHARMACOLOGY, Clinical Studies ).

PEDIATRIC USE

Pediatric Use The safety and effectiveness of dorzolamide hydrochloride ophthalmic solution and timolol maleate ophthalmic solution have been established when administered individually in pediatric patients aged 2 years and older.

Use of these drug products in these children is supported by evidence from adequate and well-controlled studies in children and adults.

Safety and efficacy in pediatric patients below the age of 2 years have not been established.

PREGNANCY

Pregnancy: Teratogenic Effects: Pregnancy: Category C.

Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥2.5 mg/kg/day (31 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies.

These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights.

No treatment-related malformations were seen at 1.0 mg/kg/day (13 times the recommended human ophthalmic dose).

Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations.

Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring.

Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions.

Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women.

Dorzolamide hydrochloride– timolol maleate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers It is not known whether dorzolamide is excreted in human milk.

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.

Because of the potential for serious adverse reactions from dorzolamide hydrochloride – timolol maleate in nursing infants, 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.

DOSAGE AND ADMINISTRATION

The dose is one drop of dorzolamide hydrochloride – timolol maleate in the affected eye(s) two times daily.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart ( see also PRECAUTIONS, Drug Interactions ).

palonosetron 0.075 MG per 1.5 ML Injection

DRUG INTERACTIONS

7 Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes.

Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and, CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5.

Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [ see Warnings and Precautions (5.2) ].

Coadministration of 0.25 mg I.V.

palonosetron and 20 mg I.V.

dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V.

bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, C max : 15% increase).

A study in healthy volunteers involving single-dose I.V.

palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin, and mitomycin C) in murine tumor models.

The potential for clinically significant drug interactions with palonosetron appears to be low ( 7 )

OVERDOSAGE

10 There is no known antidote to ALOXI.

Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study.

This is approximately 25 times the recommended dose of 0.25 mg.

This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose.

A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice.

The major signs of toxicity were convulsions, gasping, pallor, cyanosis, and collapse.

DESCRIPTION

11 ALOXI (palonosetron hydrochloride) is an antiemetic and antinauseant agent.

It is a serotonin-3 (5-HT 3 ) receptor antagonist with a strong binding affinity for this receptor.

Chemically, palonosetron hydrochloride is: (3a S) -2-[( S )-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1 H benz[ de ]isoquinoline hydrochloride.

The empirical formula is C 19 H 24 N 2 O.HCl, with a molecular weight of 332.87.

Palonosetron hydrochloride exists as a single isomer and has the following structural formula: Palonosetron hydrochloride is a white to off-white crystalline powder.

It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

ALOXI injection is a sterile, clear, colorless, nonpyrogenic, isotonic, buffered solution for intravenous administration.

ALOXI injection is available as 5 mL single use vial or 1.5 mL single use vial.

Each 5 mL vial contains 0.25 mg palonosetron base as 0.28 mg palonosetron hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.

Each 1.5 mL vial contains 0.075 mg palonosetron base as 0.084 mg palonosetron hydrochloride, 62.25 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.

The pH of the solution in the 5 mL and 1.5 mL vials is 4.5 to 5.5.

The structural formula for serotonin-3 (5-HT3) is a receptor antagonist with a strong binding affinity for this receptor.

Chemically, palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride.

The empirical formula is C19H24N2O.HCl, with a molecular weight of 332.87.

CLINICAL STUDIES

14 97.5% Confidence Interval ALOXI minus Comparator c 97.5% Confidence Interval ALOXI minus Comparator c 97.5% Confidence Interval ALOXI minus Comparator c 14.1 Chemotherapy-Induced Nausea and Vomiting in Adults Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting induced by both moderately and highly emetogenic chemotherapy was studied in three Phase 3 trials and one Phase 2 trial.

In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy.

The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed.

Moderately Emetogenic Chemotherapy Two Phase 3, double-blind trials involving 1132 patients compared single-dose I.V.

ALOXI with either single-dose I.V.

ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m², cyclophosphamide 25 mg/m², epirubicin, irinotecan, and methotrexate > 250 mg/m².

Concomitant corticosteroids were not administered prophylactically in study 1 and were only used by 4-6% of patients in study 2.

The majority of patients in these studies were women (77%), White (65%) and naïve to previous chemotherapy (54%).

The mean age was 55 years.

Highly Emetogenic Chemotherapy A Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose I.V.

palonosetron from 0.3 to 90 mcg/kg (equivalent to 1100 mg/m²).

Concomitant corticosteroids were not administered prophylactically.

Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.

A Phase 3, double-blind trial involving 667 patients compared single-dose I.V.

ALOXI with single-dose I.V.

ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥ 60 mg/m², cyclophosphamide > 1500 mg/m², and dacarbazine.

Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients.

Of the 667 patients, 51% were women, 60% White, and 59% naïve to previous chemotherapy.

The mean age was 52 years.

Efficacy Results The antiemetic activity of ALOXI was evaluated during the acute phase (0-24 hours) [Table 4], delayed phase (24-120 hours) [Table 5], and overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase 3 trials.

Table 4: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 81 0.009 Ondansetron 32 mg I.V.

185 69 2 ALOXI 0.25 mg 189 63 NS Dolasetron 100 mg I.V.

191 53 Highly Emetogenic 3 ALOXI 0.25 mg 223 59 NS Difference in Complete Response Rates Ondansetron 32 mg I.V.

221 57 a Intent-to-treat cohort b 2-sided Fisher’s exact test.

Significance level at α=0.025.

c These studies were designed to show non-inferiority.

A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

These studies show that ALOXI was effective in the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy.

In study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly.

Clinical superiority over other 5-HT 3 receptor antagonists has not been adequately demonstrated in the acute phase.

Table 5: Prevention of Delayed Nausea and Vomiting (24-120 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 74 <0.001 Ondansetron 32 mg I.V.

185 55 2 ALOXI 0.25 mg 189 54 0.004 Dolasetron 100 mg I.V.

191 39 Difference in Complete Response Rates a Intent-to-treat cohort b 2-sided Fisher’s exact test.

Significance level at α=0.025.

c These studies were designed to show non-inferiority.

A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

These studies show that ALOXI was effective in the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy.

Table 6: Prevention of Overall Nausea and Vomiting (0-120 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 69 <0.001 Ondansetron 32 mg I.V.

185 50 2 ALOXI 0.25 mg 189 46 0.021 Dolasetron 100 mg I.V.

191 34 Difference in Complete Response Rates a Intent-to-treat cohort b 2-sided Fisher’s exact test.

Significance level at α=0.025.

c These studies were designed to show non-inferiority.

A lower bound greater than –15% demonstrates non inferiority between ALOXI and comparator.

These studies show that ALOXI was effective in the prevention of nausea and vomiting throughout the 120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy.

14.2 Chemotherapy-Induced Nausea and Vomiting in Pediatrics One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients.

The total population (N = 327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white.

Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of ALOXI 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hours after the first dose of ondansetron, with a maximum total dose of 32 mg).

Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m 2 ), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin.

Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.

Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy.

Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron.

Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%.

The non-inferiority margin was 15%.

Efficacy Results As shown in Table 7, intravenous ALOXI 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval.

Table 7: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates I.V.

ALOXI 20 mcg/kg (N=165) I.V.

Ondansetron 0.15 mg/kg x 3 (N=162) Difference [97.5% Confidence Interval]*: I.V.

ALOXI minus I.V.

Ondansetron Comparator 59.4% 58.6% 0.36% [-11.7%, 12.4%] * To adjust for multiplicity of treatment groups, a lower-bound of a 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.

In patients that received ALOXI at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.

14.3 Postoperative Nausea and Vomiting In one multicenter, randomized, stratified, double-blind, parallel-group, phase 3 clinical study (Study 1), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery.

All patients received general anesthesia.

Study 1 was a pivotal study conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of post operative nausea and vomiting and/or motion sickness.

In Study 1 patients were randomized to receive palonosetron 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia.

The antiemetic activity of palonosetron was evaluated during the 0 to 72 hour time period after surgery.

Of the 138 patients treated with 0.075 mg palonosetron in Study 1 and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers.

As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian.

The age of patients ranged from 21 to 74 years, with a mean age of 37.9 years.

Three patients were greater than 65 years of age.

Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 and in the 24-72 hours postoperatively.

Secondary efficacy endpoints included: Complete Response (CR) 0-48 and 0-72 hours Complete Control (CC) defined as CR and no more than mild nausea Severity of nausea (none, mild, moderate, severe) The primary hypothesis in Study 1 was that at least one of the three palonosetron doses were superior to placebo.

Results for Complete Response in Study 1 for 0.075 mg palonosetron versus placebo are described in the following table.

Table 8: Prevention of Postoperative Nausea and Vomiting: Complete Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo Treatment n/N (%) Palonosetron Vs Placebo Δ p-value* Co-primary Endpoints CR 0-24 hours Palonosetron 59/138 (42.8%) 16.8% 0.004 Placebo 35/135 (25.9%) CR 24-72 hours Palonosetron 67/138 (48.6%) 7.8% 0.188 Placebo 55/135 (40.7%) * To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p<0.017.

Δ Difference (%): palonosetron 0.075 mg minus placebo Palonosetron 0.075 mg reduced the severity of nausea compared to placebo.

Analyses of other secondary endpoints indicate that palonosetron 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.

A phase 2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate I.V.

palonosetron for the prevention of post-operative nausea and vomiting following abdominal or vaginal hysterectomy.

Five I.V.

palonosetron doses (0.1, 0.3, 1.0, 3.0, and 30 µg/kg) were evaluated in a total of 381 intent-to-treat patients.

The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery.

The lowest effective dose was palonosetron 1 µg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004.

Palonosetron 1 µg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC # 62856-797-01, ALOXI Injection 0.25 mg/5 mL (free base) single-use vial individually packaged in a carton.

NDC # 62856-798-01, ALOXI Injection 0.075 mg/1.5 mL (free base) single-use vial packaged in a carton containing 5 vials.

Storage Store at controlled temperature of 20–25°C (68°F–77°F).

Excursions permitted to 15–30°C (59-86°F).

Protect from freezing.

Protect from light.

RECENT MAJOR CHANGES

Indication ( 1.2 ) Dosage and Administration, Pediatric Cancer Patients ( 2.1 ) Warnings and Precautions, Serotonin Syndrome ( 5.2 ) 05/2014 05/2014 09/2014

GERIATRIC USE

8.5 Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years).

Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old.

No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out.

No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old.

No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded.

No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients.

However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

DOSAGE FORMS AND STRENGTHS

3 ALOXI is supplied as a single-use sterile, clear, colorless solution in glass vials that provide: 0.25 mg (free base) per 5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.075 mg (free base) per 1.5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.25 mg/5mL (free base) single-use vial ( 3 ) 0.075 mg/1.5mL (free base) single-use vial ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Palonosetron is a 5-HT 3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used.

5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema.

It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT 3 receptors located on vagal afferents to initiate the vomiting reflex.

Postoperative nausea and vomiting is influenced by multiple patient, surgical, and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract.

The 5-HT 3 receptor has been demonstrated to selectively participate in the emetic response.

INDICATIONS AND USAGE

1 ALOXI is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in adults for: Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses ( 1.1 ) Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses ( 1.1 ) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.

Efficacy beyond 24 hours has not been demonstrated ( 1.3 ) ALOXI is indicated in pediatric patients aged 1 month to less than 17 years for: Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy ( 1.2 ) 1.1 Chemotherapy -Induced Nausea and Vomiting in Adults ALOXI is indicated for: Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 M onth to Less than 17 Years ALOXI is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

1.3 Postoperative Nausea and Vo miting in Adults ALOXI is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.

Efficacy beyond 24 hours has not been demonstrated.

As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.

In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low.

PEDIATRIC USE

8.4 Pediatric Use Chemotherapy-Induced Nausea and Vomiting Safety and effectiveness of ALOXI have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

Use is supported by a clinical trial where 165 pediatric patients aged 2 months to <17 years were randomized to receive a single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [ see Clinical Studies (14.2) ] .

While this study demonstrated that pediatric patients require a higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [ see Adverse Reactions (6.1) ] .

Safety and effectiveness of ALOXI in neonates (less than 1 month of age) have not been established.

Postoperative Nausea and Vomiting Studies Safety and efficacy have not been established in pediatric patients for prevention of postoperative nausea and vomiting.

Two pediatric trials were performed.

Pediatric Study 1, a dose finding study, was conducted to compare two doses of palonosetron, 1 mcg/kg (max 0.075 mg) versus 3 mcg/kg (max 0.25 mg).

A total of 150 pediatric surgical patients participated, age range 1 month to <17 years.

No dose response was observed.

Pediatric Study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared I.V.

palonosetron (1 mcg/kg, max 0.075 mg) versus I.V.

ondansetron.

A total of 670 pediatric surgical patients participated, age 30 days to <17 years.

The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group.

Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated.

Adverse reactions to palonosetron were similar to those reported in adults (Table 2).

PREGNANCY

8.1 Pregnancy Pregnancy Category B Risk Summary Adequate and well controlled studies with ALOXI have not been conducted in pregnant women.

In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively.

Because animal reproduction studies are not always predictive of human response, ALOXI should be used during pregnancy only if clearly needed.

Animal Data In animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether ALOXI is present in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study [ see Nonclinical Toxicology (13.1) ] , 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other selective 5-HT 3 receptor antagonists ( 5.1 ) Serotonin syndrome has been reported with 5-HT 3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs ( 5.2 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT 3 receptor antagonists.

5.2 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists.

Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue).

Some of the reported cases were fatal.

Serotonin syndrome occurring with overdose of another 5-HT 3 receptor antagonist alone has also been reported.

The majority of reports of serotonin syndrome related to 5-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ALOXI and other serotonergic drugs.

If symptoms of serotonin syndrome occur, discontinue ALOXI and initiate supportive treatment.

Patients should be informed of the increased risk of serotonin syndrome, especially if ALOXI is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labelling ( Patient Information ).

Instructions for Patients Patients should be advised to report to their physician all of their medical conditions, including any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6.3) ].

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of ALOXI and another serotonergic agent such as medications to treat depression and migraines.

Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [ see Warnings and Precautions (5.2) ].

Patients should be instructed to read the Patient Information.

DOSAGE AND ADMINISTRATION

2 Chemotherapy-Induced Nausea and Vomiting ( 2.1 ) Age Dose* Infusion Time Adults 0 .

2 5 m g x 1 Infuse over 3 0 s e c o nd s beginning approx.

30 min before the start of chemo Pediatrics (1 month to less than 17 years) 2 0 m icr o g r a m s p er k il o g r a m (max 1.5 mg) x 1 Infuse over 1 5 m i nut es beginning approx.

30 min before the start of chemo *Note different dosing units in pediatrics Postoperative Nausea and Vomiting ( 2.1 ) Adult Dosage: a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

2.1 Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Age Dose* Infusion Time Adults 0 .

2 5 m g x 1 Infuse over 3 0 s e c o nd s beginning approx.

30 min before the start of chemo Pediatrics (1 month to less than 17 years) 2 0 m icr o g r a m s p er k il o g r a m (max 1.5 mg) x 1 Infuse over 1 5 m i nut es beginning approx.

30 min before the start of chemo *Note different dosing units in pediatrics Postoperative Nausea and Vomiting Dosage for Adults – a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

2.2 Instructions for I ntravenous Administration ALOXI is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/ mL).

ALOXI should not be mixed with other drugs.

The infusion line should be flushed with normal saline before and after administration of ALOXI.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

Sudafed PE Children’s Cold & Cough 5 MG / 2.5 MG per 5 ML Oral Solution

Generic Name: DEXTROMETHORPHAN HYDROBROMIDE AND PHENYLEPHRINE HYDROCHLORIDE

Brand Name: Childrens SUDAFED PE Cold plus Cough

Substance Name(s):
DEXTROMETHORPHAN HYDROBROMIDE
PHENYLEPHRINE HYDROCHLORIDE

WARNINGS

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms due to the common cold, hay fever, or other upper respiratory allergies: cough nasal congestion sinus congestion and pressure

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, carboxymethylcellulose sodium, edetate disodium, FD&C blue no.

1, FD&C red no.

40, flavors, glycerin, purified water, sodium benzoate, sodium citrate, sorbitol solution, sucralose

PURPOSE

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

ASK DOCTOR

DOSAGE AND ADMINISTRATION

Do not use any other dosing device.

DO NOT USE

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

STOP USE

ACTIVE INGREDIENTS

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant