Author: druginteractionchecker_lgaiz4

Esomeprazole 20 MG Injection

DRUG INTERACTIONS

7 Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.

In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4.

No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.

Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.

Postmarketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy.

Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme.

Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Increased plasma levels of diazepam were observed 12 hours after dosing and onwards.

However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance.

Clopidogrel is metabolized to its active metabolite in part by CYP2C19.

Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

Avoid concomitant administration of esomeprazole sodium with clopidogrel.

When using esomeprazole sodium, consider use of alternative anti-platelet therapy [ see Clinical Pharmacology (12.3) ].

Omeprazole acts as an inhibitor of CYP2C19.

Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max and AUC of cilostazol by 18% and 26%, respectively.

C max and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69%, respectively.

Coadministration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite.

Therefore, a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered.

Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.

Dose adjustment of esomeprazole is not normally required for the recommended doses.

However, in patients who may require higher doses, dose adjustment may be considered.

Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased esomeprazole serum levels.

Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St.

John’s Wort, an inducer of CYP3A4.

In a cross-over study in 12 healthy male subjects, St.

John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C max and AUC decreased by 49.6% and 43.9%, respectively).

Avoid concomitant use of St.

John’s Wort or rifampin with esomeprazole sodium.

Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole.

Concomitant use of atazanavir and proton pump inhibitors is not recommended.

Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.

Omeprazole has been reported to interact with some antiretroviral drugs.

The clinical importance and the mechanisms behind these interactions are not always known.

Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug.

Other possible interaction mechanisms are via CYP2C19.

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole.

Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75%, respectively, for nelfinavir and M8.

Following multiple doses of atazanavir (400 mg daily) and omeprazole (40 mg daily, 2 hr before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95%.

Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in C max by 75% and in C min by 106% following multiple dosing of saquinavir/ritonavir (1,000 mg/100 mg) twice daily for 15 days with omeprazole 40 mg daily coadministered days 11 to 15.

Dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these NSAIDs.

Esomeprazole inhibits gastric acid secretion.

Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability.

Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole.

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects).

Esomeprazole is an enantiomer of omeprazole.

Coadministration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin.

Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole.

Esomeprazole inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g.

ketoconazole, iron salts, erlotinib, and digoxin).

Patients treated with esomeprazole and digoxin may need to be monitored for digoxin toxicity.

( 7 ) Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

( 7 ) Esomeprazole may reduce the plasma levels of atazanavir, nelfinavir, and saquinavir.

( 7 ) Concomitant treatment with a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.

( 7 ) May increase systemic exposure of cilostazol and an active metabolite.

Consider dose reduction.

( 7 ) Clopidogrel: Esomeprazole decreases exposure to the active metabolite of clopidogrel.

( 7 ) Tacrolimus: Esomeprazole may increase serum levels of tacrolimus ( 7.2 ) Methotrexate: Esomeprazole may increase serum levels of methotrexate ( 7.3 ) 7.1 Interactions with Investigations of Neuroendocrine Tumors Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors [ see Warnings and Precautions (5.8) , Clinical Pharmacology (12.2) ].

7.2 Tacrolimus Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.

7.3 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate.

However, no formal drug interaction studies of methotrexate with PPIs have been conducted [ see Warnings and Precautions (5.9) ].

OVERDOSAGE

10 The minimum lethal dose of esomeprazole sodium in rats after bolus administration was 310 mg/kg (about 62 times the human dose on a body surface area basis).

The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia and intermittent clonic convulsions.

The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient.

Single oral doses of 80 mg and intravenous doses of 308 mg of esomeprazole over 24 hours were uneventful.

Reports of overdosage with omeprazole in humans may also be relevant.

Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose).

Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert – ADVERSE REACTIONS ).

No specific antidote for esomeprazole is known.

Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis.

In the event of overdosage, treatment should be symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be considered.

For current information on treatment of any drug overdose, a certified Regional Poison Control Center should be contacted.

Telephone numbers are listed in the Physicians’ Desk Reference (PDR) or local telephone book.

DESCRIPTION

11 The active ingredient in esomeprazole sodium for injection is ( S )-5-methoxy-2[[(4-methoxy-3,5­-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H -benzimidazole sodium, a proton pump inhibitor that inhibits gastric acid secretion.

Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers.

Its molecular formula is C 17 H 18 N 3 O 3 SNa with molecular weight of 367.4 g/mol (sodium salt) and 345.4 g/mol (parent compound).

Esomeprazole sodium is freely soluble in water.

The structural formula is: Esomeprazole sodium for injection is supplied as sterile, freeze-dried, white to off-white, porous cake or powder in a 5 mL vial, intended for intravenous administration after reconstitution with 0.9% Sodium Chloride Injection, USP; Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP.

Esomeprazole sodium for injection contains esomeprazole sodium 21.3 mg or 42.5 mg equivalent to esomeprazole 20 mg or 40 mg, edetate disodium 1.5 mg and sodium hydroxide q.s.

for pH adjustment.

The pH of reconstituted solution of esomeprazole sodium for injection depends on the reconstitution volume and is in the pH range of 9 to 11.

The stability of esomeprazole sodium in aqueous solution is strongly pH dependent.

The rate of degradation increases with decreasing pH.

chemical-structure

CLINICAL STUDIES

14 14.1 Acid Suppression in Gastroesophageal Reflux Disease (GERD) Four multicenter, open-label, two-period crossover studies were conducted to compare the pharmacodynamic efficacy of the intravenous formulation of esomeprazole (20 mg and 40 mg) to that of esomeprazole magnesium delayed-release capsules at corresponding doses in patients with symptoms of GERD, with or without erosive esophagitis.

The patients (n=206, 18 to 72 years old; 112 female; 110 Caucasian, 50 Black, 10 Asian, and 36 Other Race) were randomized to receive either 20 mg or 40 mg of intravenous or oral esomeprazole once daily for 10 days (Period 1), and then were switched in Period 2 to the other formulation for 10 days, matching their respective dose level from Period 1.

The intravenous formulation was administered as a 3-minute injection in two of the studies, and as a 15-minute infusion in the other two studies.

Basal acid output (BAO) and maximal acid output (MAO) were determined 22 to 24 hours post-dose on Period 1, Day 11; on Period 2, Day 3; and on Period 2, Day 11.

BAO and MAO were estimated from 1-hour continuous collections of gastric contents prior to and following (respectively) subcutaneous injection of 6 mcg/kg of pentagastrin.

In these studies, after 10 days of once daily administration, the intravenous dosage forms of esomeprazole sodium 20 mg and 40 mg were similar to the corresponding oral dosage forms in their ability to suppress BAO and MAO in these GERD patients (see table below).

There were no major changes in acid suppression when switching between intravenous and oral dosage forms.

Table 5: Mean (SD) BAO and MAO measured 22 to 24 hours post-dose following once daily oral and intravenous administration of esomeprazole for 10 days in GERD patients with or without a history of erosive esophagitis Study Dose in mg Intravenous Administration Method BAO in mmol H+/h MAO in mmol H+/h Intravenous Oral Intravenous Oral 1 (N=42) 20 3-minute injection 0.71 (1.24) 0.69 (1.24) 5.96 (5.41) 5.27 (5.39) 2 (N=44) 20 15-minute infusion 0.78 (1.38) 0.82 (1.34) 5.95 (4) 5.26 (4.12) 3 (N=50) 40 3-minute injection 0.36 (0.61) 0.31 (0.55) 5.06 (3.9) 4.41 (3.11) 4 (N=47) 40 15-minute infusion 0.36 (0.79) 0.22 (0.39) 4.74 (3.65) 3.52 (2.86)

HOW SUPPLIED

16 /STORAGE AND HANDLING Esomeprazole sodium for injection is supplied as a white to off-white, freeze-dried cake containing 20 mg or 40 mg of esomeprazole per single-use vial.

NDC 47335-508-44 one carton containing 10 vials of esomeprazole sodium for injection (each vial contains 20 mg of esomeprazole).

NDC 47335-509-44 one carton containing 10 vials of esomeprazole sodium for injection (each vial contains 40 mg of esomeprazole).

Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature].

Protect from light.

Store in carton until time of use.

Following reconstitution and administration, discard any unused portion of esomeprazole solution.

RECENT MAJOR CHANGES

Dosage and Administration, Preparation and Administration Instructions ( 2.3 ) 03/2014 Warnings and Precautions, Interactions with Diagnostic Investigations for Neuroendocrine Tumors ( 5.8 ) 03/2014

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients who received oral esomeprazole magnesium in clinical trials, 1,459 were 65 to 74 years of age and 354 patients were ≥ 75 years of age.

No overall differences in safety and efficacy were observed between the elderly and younger individuals, 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 Esomeprazole sodium for injection is supplied as a white to off-white, freeze-dried cake containing 20 mg or 40 mg of esomeprazole per single-use vial.

Esomeprazole sodium for injection is supplied as a freeze-dried cake containing 20 mg or 40 mg of esomeprazole per single-use vial.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H + /K + ­-ATPase in the gastric parietal cell.

The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide.

By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity.

This effect is dose-related up to a daily dose of 20 mg to 40 mg and leads to inhibition of gastric acid secretion.

INDICATIONS AND USAGE

1 Esomeprazole sodium for injection is a proton pump inhibitor indicated for the treatment of: Gastroesophageal Reflux Disease (GERD) with erosive esophagitis (EE) in adults and pediatric patients greater than one month of age, when oral therapy is not possible or appropriate.

( 1.1 ) 1.1 Treatment of Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis Esomeprazole sodium for injection is indicated for the short-term treatment of GERD with erosive esophagitis in adults and pediatric patients 1 month to 17 years, inclusively as an alternative to oral therapy when oral esomeprazole is not possible or appropriate.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of esomeprazole sodium for injection have been established in pediatric patients 1 month to 17 years of age for short-term treatment of GERD with Erosive Esophagitis [ see Clinical Pharmacology, Pharmacokinetics (12.3) ].

However, effectiveness has not been established in patients less than 1 month of age.

1 month to 17 years of age Use of esomeprazole sodium for injection in pediatric patients 1 month to 17 years of age for short-term treatment of GERD with Erosive Esophagitis is supported by: a) results observed from a pharmacokinetic (PK) study on esomeprazole sodium for injection performed in pediatric patients, b) predictions from a population PK model comparing I.V.

PK data between adult and pediatric patients, and c) relationship between exposure and pharmacodynamic results obtained from adult I.V.

and pediatric oral data and d) PK results already included in the current approved labeling and from adequate and well-controlled studies that supported the approval of esomeprazole sodium for injection for adults.

Neonates 0 to 1 month of age Following administration of esomeprazole sodium for injection in neonates the geometric mean (range) for CL was 0.17 L/h/kg (0.04 L/h/kg to 0.32 L/h/kg).

The safety and effectiveness of esomeprazole sodium for injection in neonates have not been established.

Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 57 times a daily human dose of 40 mg based on body surface area.

Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology ( 13.2 )].

PREGNANCY

8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with esomeprazole sodium for injection in pregnant women.

Esomeprazole is the s-isomer of omeprazole.

Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use.

Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 57 times and 35 times, respectively, an oral human dose of 40 mg.

However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 33.6 times an oral human dose of 40 mg (see Animal Data) .

Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, esomeprazole sodium for injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data Esomeprazole is the S-isomer of omeprazole.

Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2 receptor antagonists or other controls.

A population based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy.

The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population.

The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population.

A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor.

The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester.

A retrospective cohort study reported on 689 pregnant women exposed to either H2 blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester.

The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively.

A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures).

The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease paired controls.

Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.

Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.

Animal Data Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium.

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis).

Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33 times an oral human dose of 40 mg on a body surface area basis).

Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis).

In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis).

Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).

Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis).

When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).

A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.

NUSRING MOTHERS

8.3 Nursing Mothers Esomeprazole is likely present in human milk.

Esomeprazole is the S-isomer of omeprazole and limited data indicate that maternal doses of omeprazole 20 mg daily produce low levels in human milk.

Caution should be exercised when esomeprazole sodium for injection is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Symptomatic response to therapy with esomeprazole sodium does not preclude the presence of gastric malignancy.

( 5.1 ) Atrophic gastritis has been noted with long-term omeprazole therapy.

( 5.2 ) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea.

( 5.3 ) Avoid concomitant use of esomeprazole with clopidogrel.

( 5.4 ) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.

( 5.5 ) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs ( 5.6 ) Avoid concomitant use of esomeprazole sodium with St.

John’s Wort or rifampin due to the potential reduction in esomeprazole levels ( 5.7 , 7.2 ) Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors.

( 5.8 , 12.2 ) 5.1 Risk of Concomitant Gastric Malignancy Symptomatic response to therapy with esomeprazole sodium does not preclude the presence of gastric malignancy.

5.2 Atrophic Gastritis Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.

5.3 Clostridium difficile Associated Diarrhea Published observational studies suggest that PPI therapy like esomeprazole sodium may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients.

This diagnosis should be considered for diarrhea that does not improve [ see Adverse Reactions ( 6.2 ) ].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

5.4 Interaction with Clopidogrel Avoid concomitant use of esomeprazole sodium with clopidogrel.

Clopidogrel is a prodrug.

Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite.

The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity.

Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel.

When using esomeprazole sodium consider alternative anti-platelet therapy.

[see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] 5.5 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.

The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer).

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.

[ see Dosage and Administration ( 2 ), Adverse Reactions ( 6.2 ) ] 5.6 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy.

Serious adverse events include tetany, arrhythmias, and seizures.

In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.

[ See Adverse Reactions ( 6.2 ) ] 5.7 Concomitant use of Esomeprazole Sodium with St.

John’s Wort or Rifampin Drugs which induce CYP2C19 or CYP3A4 (such as St.

John’s Wort or rifampin) can substantially decrease esomeprazole concentrations [ see Drug Interactions (7) ].

Avoid concomitant use of esomeprazole sodium with St.

John’s Wort or rifampin.

5.8 Interactions with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.

If serial tests are performed (e.g.

for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [ see Clinical Pharmacology ( 12.2 )].

5.9 Concomitant use of Esomeprazole Sodium with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.

In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients [ see Drug Interactions (7.3) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patients to let their healthcare provider know if they are taking, or begin taking other medications, because esomeprazole can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes [ see Drug Interactions (7) ].

Let patients know that antacids may be used while taking esomeprazole sodium for injection.

Advise patients to immediately report and seek care for diarrhea that does not improve.

This may be a sign of Clostridium difficile associated diarrhea [ see Warnings and Precautions (5.3) ].

Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [ see Warnings and Precautions (5.6) ].

Distributed by: Caraco Pharmaceutical Laboratories, Ltd.

1150 Elijah McCoy Drive, Detroit, MI 48202 Manufactured by: Sun Pharmaceutical Ind.

Ltd.

Halol-Baroda Highway, Halol-389 350, Gujarat, India.

ISS.

04/2014 PJPI0275A

DOSAGE AND ADMINISTRATION

2 General Information Esomeprazole sodium for injection should not be administered concomitantly with any other medications through the same intravenous site and/or tubing.

The intravenous line should always be flushed with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection.

The admixture should be stored at room temperature up to 30°C (86°F) and should be administered within the designated time period as listed in Table 1 below.

No refrigeration is required.

Table 1 Storage Time for Final (diluted) Product Diluent Administer within: 0.9% Sodium Chloride Injection, USP 12 hours Lactated Ringer’s Injection, USP 12 hours 5% Dextrose Injection, USP 6 hours Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

As soon as oral therapy is possible or appropriate, intravenous therapy with esomeprazole sodium for injection should be discontinued and the therapy should be continued orally.

GERD – with Erosive Esophagitis ( 2.1 ): Adults: Dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes).

Pediatric: Give the following doses once daily as an intravenous infusion over 10 minutes to 30 minutes.

( 2.1 ) 1 year to 17 years: Body weight less than 55 kg: 10 mg Body weight 55 kg or greater: 20 mg 1 month to less than 1 year of age: 0.5 mg/kg For patients with severe liver impairment (Child Pugh Class C), a maximum dose of 20 mg once daily of esomeprazole should not be exceeded.

( 2.1 , 8.6 , 12.3 ) 2.1 GERD with Erosive Esophagitis Adult Patients The recommended adult dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes).

Safety and efficacy of esomeprazole sodium for injection as a treatment of GERD patients with erosive esophagitis for more than 10 days have not been demonstrated.

Dosage adjustment is not required in patients with mild to moderate liver impairment (Child Pugh Classes A and B).

For patients with severe liver impairment (Child Pugh Class C), a maximum dose of 20 mg once daily of esomeprazole sodium for injection should not be exceeded [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology, ( 12.3 )] .

Pediatric Patients The recommended doses for children ages 1 month to 17 years, inclusive, are provided below.

Dose should be infused over 10 minutes to 30 minutes.

1 year to 17 years: Body weight less than 55 kg: 10 mg Body weight 55 kg or greater: 20 mg 1 month to less than 1 year of age: 0.5 mg/kg 2.3 Preparations and Administration Instructions General Information The reconstituted solution of esomeprazole sodium for injection should be stored at room temperature up to 30°C (86°F) and administered within 12 hours after reconstitution.

(Administer within 6 hours if 5% Dextrose Injection is used after reconstitution).

No refrigeration is required [see Dosage and Administration ( 2 ), Table 1 ].

Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis Preparation Instructions for Adult Patients Intravenous Injection (20 mg or 40 mg vial) over no less than 3 minutes The freeze-dried powder should be reconstituted with 5 mL of 0.9% Sodium Chloride Injection, USP.

Withdraw 5 mL of the reconstituted solution and administer as an intravenous injection over no less than 3 minutes.

Preparation Instructions for Pediatric Patients Intravenous Infusion (20 mg or 40 mg) over 10 minutes to 30 minutes A solution for intravenous infusion is prepared by first reconstituting the contents of one vial * with 5 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP and further diluting the resulting solution to a final volume of 50 mL.

The resultant concentration after diluting to a final volume of 50 mL is 0.8 mg/mL (for 40 mg vial) and 0.4 mg/mL (for 20 mg vial).

The solution (admixture) should be administered as an intravenous infusion over a period of 10 minutes to 30 minutes.

*For patients 1 month to less than 1 year of age, first calculate the dose (0.5 mg/kg) to determine the vial size needed.

Colchicine 0.6 MG Oral Tablet [Colcrys]

DRUG INTERACTIONS

7 COLCRYS (colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp).

Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine.

If COLCRYS is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely.

Fatal drug interactions have been reported.

Physicians should ensure that patients are suitable candidates for treatment with COLCRYS and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction.

Signs and symptoms of COLCRYS toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS should be discontinued immediately.

Table 4 provides recommendations as a result of other potentially significant drug interactions.

Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.

Table 4.

Other Potentially Significant Drug Interactions Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.

Other Lipid-Lowering Drugs: fibrates, gemfibrozil Digitalis Glycosides: digoxin Coadministration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine.

The potential for drug-drug interactions must be considered prior to and during therapy.

See full prescribing information for a complete list of reported and potential interactions ( 2.4 , 5.3 , 7 ).

OVERDOSAGE

10 The exact dose of colchicine that produces significant toxicity is unknown.

Fatalities have occurred after ingestion of a dose as low as 7 mg over a four-day period, while other patients have survived after ingesting more than 60 mg.

A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions such as myelosuppression.

There was 100% mortality in those who ingested more than 0.8 mg/kg.

The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea and significant fluid loss, leading to volume depletion.

Peripheral leukocytosis may also be seen.

Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multiorgan failure and its consequences.

Death is usually a result of respiratory depression and cardiovascular collapse.

If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one week after the initial ingestion.

Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock.

Otherwise, treatment is symptomatic and supportive.

No specific antidote is known.

Colchicine is not effectively removed by dialysis [ see Pharmacokinetics (12.3) ] .

DESCRIPTION

11 Colchicine is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3, 10-tetramethoxy-9-oxobenzo [alpha] heptalen-7-yl) acetamide with a molecular formula of C 22 H 25 NO 6 and a molecular weight of 399.4.

The structural formula of colchicine is given below.

Colchicine occurs as a pale yellow powder that is soluble in water.

COLCRYS (colchicine, USP) tablets are supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575″ × 0.3030″), debossed with “AR 374” on one side and scored on the other, containing 0.6 mg of the active ingredient colchicine USP.

Inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide and triacetin.

Structural Formula of Colchicine

CLINICAL STUDIES

14 The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature.

Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate-lowering therapy.

In both trials, treatment with colchicine decreased the frequency of gout flares.

The efficacy of a low-dosage regimen of oral colchicine (COLCRYS total dose 1.8 mg over one hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, one-week, dose-comparison study.

Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours [4.8 mg total]); low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total] followed by five placebo doses hourly); or placebo (two capsules, then one capsule hourly × 6 hours).

Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours.

The efficacy of colchicine was measured based on response to treatment in the target joint, using patient self-assessment of pain at 24 hours following the time of first dose as recorded in the diary.

A responder was one who achieved at least a 50% reduction in pain score at the 24 hour post-dose assessment relative to the pretreatment score and did not use rescue medication prior to the actual time of 24 hour post-dose assessment.

Rates of response were similar for the recommended low-dose treatment group (38%) and the nonrecommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.

Table 8.

Number (%) of Responders Based on Target Joint Pain Score at 24 Hours Post First Dose COLCRYS Dose Responders n (%) Placebo n (%) (n=58) % Differences in Proportion Low-Dose (n=74) High-Dose (n=52) Low-Dose vs Placebo (95% CI) High-Dose vs Placebo (95% CI) 28 (38%) 17 (33%) 9 (16%) 22 (8, 37) 17 (1, 33) Figure 1 shows the percentage of patients achieving varying degrees of improvement in pain from baseline at 24 hours.

Figure 1 Pain Relief on Low and High Doses of COLCRYS and Placebo (Cumulative) Figure1 The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature.

Three randomized, placebo-controlled studies were identified.

The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.

One of the studies randomized 15 patients with FMF to a six-month crossover study during which five patients discontinued due to study noncompliance.

The 10 patients completing the study experienced five attacks over the course of 90 days while treated with colchicine compared to 59 attacks over the course of 90 days while treated with placebo.

Similarly, the second study randomized 22 patients with FMF to a four-month crossover study during which nine patients discontinued due to lack of efficacy while receiving placebo or study noncompliance.

The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo.

The third study was discontinued after an interim analysis of six of the 11 patients enrolled had completed the study; results could not be confirmed.

Open-label experience with colchicine in adults and children with FMF is consistent with the randomized, controlled trial experience and was utilized to support information on the safety profile of colchicine and for dosing recommendations.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied COLCRYS (colchicine, USP) tablets 0.6 mg are purple, film-coated, capsule-shaped tablets debossed with “AR 374” on one side and scored on the other side.

Bottles of 30 NDC 64764-119-07 Bottles of 60 NDC 64764-119-06 Bottles of 100 NDC 64764-119-01 Bottles of 250 NDC 64764-119-03 Bottles of 500 NDC 64764-119-05 Bottles of 1000 NDC 64764-119-10 NDC 69189-0119-1 single dose pack with 1 tablet as repackaged by Avera McKennan Hospital 16.2 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from light.

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

GERIATRIC USE

8.5 Geriatric Use Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see Dose Modification for Coadministration of Interacting Drugs (2.4) and Pharmacokinetics (12.3) ] .

DOSAGE FORMS AND STRENGTHS

3 0.6 mg tablets — purple capsule-shaped, film-coated with “AR 374” debossed on one side and scored on the other side.

0.6 mg tablets ( 3 ).

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism by which COLCRYS exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β.

Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation and migration of neutrophils thought to mediate some gout symptoms.

INDICATIONS AND USAGE

1 COLCRYS (colchicine, USP) tablets are an alkaloid indicated for: Prophylaxis and treatment of gout flares in adults ( 1.1 ).

Familial Mediterranean fever (FMF) in adults and children 4 years or older ( 1.2 ).

COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

1.1 Gout Flares COLCRYS (colchicine, USP) tablets are indicated for prophylaxis and the treatment of acute gout flares.

Prophylaxis of Gout Flares: COLCRYS is indicated for prophylaxis of gout flares.

Treatment of Gout Flares: COLCRYS tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

1.2 Familial Mediterranean Fever (FMF) COLCRYS (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).

PEDIATRIC USE

8.4 Pediatric Use The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies.

There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine.

Gout is rare in pediatric patients; safety and effectiveness of colchicine in pediatric patients has not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with colchicine in pregnant women.

Colchicine crosses the human placenta.

While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF).

Although animal reproductive and developmental studies were not conducted with COLCRYS, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity and altered postnatal development at exposures within or above the clinical therapeutic range.

COLCRYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

8.3 Nursing Mothers Colchicine is excreted into human milk.

Limited information suggests that exclusively breastfed infants receive less than 10 percent of the maternal weight-adjusted dose.

While there are no published reports of adverse effects in breastfeeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability.

Caution should be exercised, and breastfeeding infants should be observed for adverse effects when COLCRYS is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Fatal overdoses have been reported with colchicine in adults and children.

Keep COLCRYS out of the reach of children ( 5.1 , 10 ).

Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported ( 5.2 ).

Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ).

Drug interaction P-gp and/or CYP3A4 inhibitors: Coadministration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death ( 5.3 , 7 ).

Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect.

Consider temporary interruption or discontinuation of COLCRYS ( 5.4 , 7 ).

5.1 Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see Overdosage (10) ] .

COLCRYS should be kept out of the reach of children.

5.2 Blood Dyscrasias Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been reported with colchicine used in therapeutic doses.

5.3 Drug Interactions Colchicine is a P-gp and CYP3A4 substrate.

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors.

If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted [see Drug Interactions (7) ] .

Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir) is contraindicated in patients with renal or hepatic impairment [see Contraindications (4) ].

5.4 Neuromuscular Toxicity Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses.

Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk.

Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid or benzafibrate (themselves associated with myotoxicity) or cyclosporine with COLCRYS may potentiate the development of myopathy [ see Drug Interactions (7) ].

Once colchicine is stopped, the symptoms generally resolve within one week to several months.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Dosing Instructions Patients should be advised to take COLCRYS as prescribed, even if they are feeling better.

Patients should not alter the dose or discontinue treatment without consulting with their doctor.

If a dose of COLCRYS is missed: For treatment of a gout flare when the patient is not being dosed for prophylaxis, take the missed dose as soon as possible.

For treatment of a gout flare during prophylaxis, take the missed dose immediately, wait 12 hours, then resume the previous dosing schedule.

For prophylaxis without treatment for a gout flare, or FMF, take the dose as soon as possible and then return to the normal dosing schedule.

However, if a dose is skipped the patient should not double the next dose.

Fatal Overdose Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine.

COLCRYS should be kept out of the reach of children.

Blood Dyscrasias Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia and thrombocytopenia may occur with COLCRYS.

Drug and Food Interactions Patients should be advised that many drugs or other substances may interact with COLCRYS and some interactions could be fatal.

Therefore, patients should report to their healthcare provider all of the current medications they are taking and check with their healthcare provider before starting any new medications, particularly antibiotics.

Patients should also be advised to report the use of nonprescription medication or herbal products.

Grapefruit and grapefruit juice may also interact and should not be consumed during COLCRYS treatment.

Neuromuscular Toxicity Patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with COLCRYS alone or when it is used with certain other drugs.

Patients developing any of these signs or symptoms must discontinue COLCRYS and seek medical evaluation immediately.

DOSAGE AND ADMINISTRATION

2 The long-term use of colchicine is established for FMF and the prophylaxis of gout flares, but the safety and efficacy of repeat treatment for gout flares has not been evaluated.

The dosing regimens for COLCRYS are different for each indication and must be individualized.

The recommended dosage of COLCRYS depends on the patient’s age, renal function, hepatic function and use of coadministered drugs [see Dose Modification for Coadministration of Interacting Drugs (2.4) ] .

COLCRYS tablets are administered orally without regard to meals.

COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

Gout Flares: Prophylaxis of Gout Flares: 0.6 mg once or twice daily in adults and adolescents older than 16 years of age ( 2.1 ).

Maximum dose 1.2 mg/day.

Treatment of Gout Flares: 1.2 mg (two tablets) at the first sign of a gout flare followed by 0.6 mg (one tablet) one hour later ( 2.1 ).

FMF: Adults and children older than 12 years 1.2 – 2.4 mg; children 6 to 12 years 0.9 – 1.8 mg; children 4 to 6 years 0.3 – 1.8 mg ( 2.2 , 2.3 ).

Give total daily dose in one or two divided doses ( 2.2 ).

Increase or decrease the dose as indicated and as tolerated in increments of 0.3 mg/day, not to exceed the maximum recommended daily dose ( 2.2 ).

Colchicine tablets are administered orally without regard to meals.

See full prescribing information for dose adjustment regarding patients with impaired renal function ( 2.5 ), impaired hepatic function ( 2.6 ), the patient’s age ( 2.3 , 8.5 ) or use of coadministered drugs ( 2.4 ).

2.1 Gout Flares Prophylaxis of Gout Flares The recommended dosage of COLCRYS for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily.

The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.

An increase in gout flares may occur after initiation of uric acid-lowering therapy, including pegloticase, febuxostat and allopurinol, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits.

COLCRYS is recommended upon initiation of gout flare prophylaxis with uric acid-lowering therapy.

Prophylactic therapy may be beneficial for at least the first six months of uric acid-lowering therapy.

Treatment of Gout Flares The recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later.

Higher doses have not been found to be more effective.

The maximum recommended dose for treatment of gout flares is 1.8 mg over a one-hour period.

COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later.

Wait 12 hours and then resume the prophylactic dose.

2.2 FMF The recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily.

COLCRYS should be increased as needed to control disease and as tolerated in increments of 0.3 mg/day to a maximum recommended daily dose.

If intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day.

The total daily COLCRYS dose may be administered in one to two divided doses.

2.3 Recommended Pediatric Dosage Prophylaxis and Treatment of Gout Flares COLCRYS is not recommended for pediatric use in prophylaxis or treatment of gout flares.

FMF The recommended dosage of COLCRYS for FMF in pediatric patients 4 years of age and older is based on age.

The following daily doses may be given as a single or divided dose twice daily: Children 4 to 6 years: 0.3 mg to 1.8 mg daily Children 6 to 12 years: 0.9 mg to 1.8 mg daily Adolescents older than 12 years: 1.2 mg to 2.4 mg daily 2.4 Dose Modification for Coadministration of Interacting Drugs Concomitant Therapy Coadministration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) increases the risk of colchicine-induced toxic effects ( Table 1 ).

If patients are taking or have recently completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as shown in the table below [see Drug Interactions (7) ] .

Table 1.

COLCRYS Dose Adjustment for Coadministration with Interacting Drugs if no Alternative Available For magnitude of effect on colchicine plasma concentrations [see Pharmacokinetics (12.3)] Strong CYP3A4 Inhibitors When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [see Contraindications (4)] Drug Noted or Anticipated Outcome Gout Flares FMF Prophylaxis of Gout Flares Treatment of Gout Flares Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Atazanavir Clarithromycin Darunavir/ Ritonavir Indinavir Itraconazole Ketoconazole Lopinavir/ Ritonavir Nefazodone Nelfinavir Ritonavir Saquinavir Telithromycin Tipranavir/ Ritonavir Significant increase in colchicine plasma levels ; fatal colchicine toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor.

Similarly, significant increase in colchicine plasma levels is anticipated with other strong CYP3A4 inhibitors.

0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day 1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 – 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Moderate CYP3A4 Inhibitors Drug Noted or Anticipated Outcome Gout Flares FMF Prophylaxis of Gout Flares Treatment of Gout Flares Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Amprenavir Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir (pro-drug of Amprenavir) Grapefruit juice Verapamil Significant increase in colchicine plasma concentration is anticipated.

Neuromuscular toxicity has been reported with diltiazem and verapamil interactions.

0.6 mg twice a day 0.6 mg once a day 0.3 mg twice a day or 0.6 mg once a day 0.3 mg once a day 1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

1.2 mg (2 tablets) × 1 dose.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 – 2.4 mg.

Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) P-gp Inhibitors Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications (4)] Drug Noted or Anticipated Outcome Gout Flares FMF Prophylaxis of Gout Flares Treatment of Gout Flares Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Cyclosporine Ranolazine Significant increase in colchicine plasma levels ; fatal colchicine toxicity has been reported with cyclosporine, a P-gp inhibitor.

Similarly, significant increase in colchicine plasma levels is anticipated with other P-gp inhibitors.

0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day 1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

0.6 mg (1 tablet) × 1 dose.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 – 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Table 2.

COLCRYS Dose Adjustment for Coadministration with Protease Inhibitors Protease Inhibitor Clinical Comment w/Colchicine – Prophylaxis of Gout Flares w/Colchicine – Treatment of Gout Flares w/Colchicine – Treatment of FMF Atazanavir sulfate (Reyataz) Patients with renal or hepatic impairment should not be given colchicine with Reyataz.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Darunavir (Prezista) Patients with renal or hepatic impairment should not be given colchicine with Prezista/ritonavir.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Fosamprenavir (Lexiva) with Ritonavir Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Fosamprenavir (Lexiva) Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.

Original dose Adjusted dose 1.2 mg (2 tablets) × 1 dose.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg twice a day or 0.6 mg once a day 0.3 mg once a day Indinavir (Crixivan) Patients with renal or hepatic impairment should not be given colchicine with Crixivan.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Lopinavir/Ritonavir (Kaletra) Patients with renal or hepatic impairment should not be given colchicine with Kaletra.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Nelfinavir mesylate (Viracept) Patients with renal or hepatic impairment should not be given colchicine with Viracept.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Ritonavir (Norvir) Patients with renal or hepatic impairment should not be given colchicine with Norvir.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Saquinavir mesylate (Invirase) Patients with renal or hepatic impairment should not be given colchicine with Invirase/ritonavir.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Tipranavir (Aptivus) Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ritonavir.

Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) 0.6 mg twice a day 0.6 mg once a day 0.3 mg once a day 0.3 mg once every other day Treatment of gout flares with COLCRYS is not recommended in patients receiving prophylactic dose of COLCRYS and CYP3A4 inhibitors.

2.5 Dose Modification in Renal Impairment Colchicine dosing must be individualized according to the patient’s renal function [see Renal Impairment (8.6) ] .

Cl cr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula: [140-age (years) × weight (kg)] Cl cr = ————————————— 72 × serum creatinine (mg/dL) × 0.85 for female patients Gout Flares Prophylaxis of Gout Flares For prophylaxis of gout flares in patients with mild (estimated creatinine clearance [Cl cr ] 50 to 80 mL/min) to moderate (Cl cr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine.

However, in patients with severe impairment, the starting dose should be 0.3 mg/day and any increase in dose should be done with close monitoring.

For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ] .

Treatment of Gout Flares For treatment of gout flares in patients with mild (Cl cr 50 to 80 mL/min) to moderate (Cl cr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine.

However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks.

For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy.

For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet).

For these patients, the treatment course should not be repeated more than once every two weeks [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ] .

Treatment of gout flares with COLCRYS is not recommended in patients with renal impairment who are receiving COLCRYS for prophylaxis.

FMF Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis.

For these patients, the dosage should be reduced [see Clinical Pharmacology (12.3) ] .

Patients with mild (Cl cr 50 to 80 mL/min) and moderate (Cl cr 30 to 50 mL/min) renal impairment should be monitored closely for adverse effects of COLCRYS.

Dose reduction may be necessary.

For patients with severe renal failure (Cl cr less than 30 mL/min), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see Renal Impairment (8.6) ] .

For patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day.

Dosing can be increased with close monitoring.

Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ] .

2.6 Dose Modification in Hepatic Impairment Gout Flares Prophylaxis of Gout Flares For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine.

Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment [see Hepatic Impairment (8.7) ] .

Treatment of Gout Flares For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine.

However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, a treatment course should be repeated no more than once every two weeks.

For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Hepatic Impairment (8.7) ] .

Treatment of gout flares with COLCRYS is not recommended in patients with hepatic impairment who are receiving COLCRYS for prophylaxis.

FMF Patients with mild to moderate hepatic impairment should be monitored closely for adverse effects of colchicine.

Dose reduction should be considered in patients with severe hepatic impairment [see Hepatic Impairment (8.7) ].

Exelon 9.5 MG/Day 24 HR Transdermal Patch

Generic Name: RIVASTIGMINE
Brand Name: Exelon
  • Substance Name(s):
  • RIVASTIGMINE

DRUG INTERACTIONS

7 Concomitant use with metoclopramide, beta-blockers, or cholinomimetics and anticholinergic medications is not recommended.

( 7.1 , 7.2 , 7.3 ) 7.1 Metoclopramide Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and EXELON PATCH is not recommended.

7.2 Cholinomimetic and Anticholinergic Medications EXELON PATCH may increase the cholinergic effects of other cholinomimetic medications and may also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine).

Concomitant use of EXELON PATCH with medications having these pharmacologic effects is not recommended unless deemed clinically necessary [see Warnings and Precautions (5.4)] .

7.3 Beta-blockers Additive bradycardic effects resulting in syncope may occur when EXELON is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol).

Concomitant use is not recommended when signs of bradycardia, including syncope are present.

OVERDOSAGE

10 Overdose with EXELON PATCH has been reported in the postmarketing setting [see Warnings and Precautions (5.1)] .

Overdoses have occurred from application of more than one patch at one time and not removing the previous day’s patch before applying a new patch.

The symptoms reported in these overdose cases are similar to those seen in cases of overdose associated with rivastigmine oral formulations.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.

As rivastigmine has a plasma half-life of about 3.4 hours after patch administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose the patch should be immediately removed and no further patch should be applied for the next 24 hours.

As in any case of overdose, general supportive measures should be utilized.

Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, and convulsions.

Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

Atypical responses in blood pressure and heart rate have been reported with other drugs that increase cholinergic activity when coadministered with quaternary anticholinergics, such as glycopyrrolate.

Additional symptoms associated with rivastigmine overdose are diarrhea, abdominal pain, dizziness, tremor, headache, somnolence, confusional state, hyperhidrosis, hypertension, hallucinations and malaise.

Due to the short plasma elimination half-life of rivastigmine after patch administration, dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) would not be clinically indicated in the event of an overdose.

In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered.

A fatal outcome has rarely been reported with rivastigmine overdose.

DESCRIPTION

11 EXELON PATCH (rivastigmine transdermal system) contains rivastigmine, a reversible cholinesterase inhibitor known chemically as (S)-3-[1-(dimethylamino) ethyl]phenyl ethylmethylcarbamate.

It has an empirical formula of C 14 H 22 N 2 O 2 as the base and a molecular weight of 250.34 g/mol (as the base).

Rivastigmine is a viscous, clear, and colorless to yellow to very slightly brown liquid that is sparingly soluble in water and very soluble in ethanol, acetonitrile, n-octanol and ethyl acetate.

The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 4.27.

EXELON PATCH is for transdermal administration.

The patch is a 4-layer laminate containing the backing layer, drug matrix, adhesive matrix and overlapping release liner (see Figure 1).

The release liner is removed and discarded prior to use.

Figure 1: Cross Section of the EXELON PATCH Layer 1: Backing Film Layer 2: Drug Product (Acrylic) Matrix Layer 3: Adhesive (Silicone) Matrix Layer 4: Release Liner (removed at time of use) Excipients within the formulation include acrylic copolymer, poly (butylmethacrylate, methylmethacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil, and vitamin E.

rivastigmine chemical structure Figure 1: Cross Section of the EXELON PATCH

CLINICAL STUDIES

14 The effectiveness of the EXELON PATCH in dementia of the Alzheimer’s type and dementia associated with Parkinson’s disease was based on the results of 3 controlled trials of EXELON PATCH in patients with Alzheimer’s disease (Studies 1, 2, and 3) (see below); 3 controlled trials of oral rivastigmine in patients with dementia of the Alzheimer’s type; and 1 controlled trial of oral rivastigmine in patients with dementia associated with Parkinson’s disease.

See the prescribing information for oral rivastigmine for details of the four studies of oral rivastigmine.

Mild-to-Moderate Alzheimer’s Disease International 24-Week Study of EXELON PATCH in Dementia of the Alzheimer’s Type (Study 1) This study was a randomized double-blind, double dummy clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score greater than or equal to 10 and less than or equal to 20] (Study 1).

The mean age of patients participating in this trial was 74 years with a range of 50 to 90 years.

Approximately 67% of patients were women, and 33% were men.

The racial distribution was Caucasian 75%, black 1%, Asian 9%, and other races 15%.

The effectiveness of the EXELON PATCH was evaluated in Study 1 using a dual outcome assessment strategy, evaluating for changes in both cognitive performance and overall clinical effect.

The ability of the EXELON PATCH to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s-disease patients.

The ADAS-Cog examines selected aspects of cognitive performance, including elements of memory, orientation, attention, reasoning, language, and praxis.

The ADAS-Cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment.

Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The ability of the EXELON PATCH to produce an overall clinical effect was assessed using the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC).

The ADCS-CGIC is a more standardized form of the Clinician’s Interview-Based Impression of Change-Plus (CIBIC-Plus) and is also scored as a 7-point categorical rating; scores range from 1, indicating “markedly improved,” to 4, indicating “no change,” to 7, indicating “marked worsening.” In Study 1, 1195 patients were randomized to 1 of the following 4 treatments: EXELON PATCH 9.5 mg/24 hours, EXELON PATCH 17.4 mg/24 hours, EXELON Capsules in a dose of 6 mg twice daily, or placebo.

This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase.

In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.

Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study.

At 24 weeks, the mean differences in the ADAS-Cog change scores for the EXELON-treated patients compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the EXELON PATCH 9.5 mg/24 hours, EXELON PATCH 17.4 mg/24 hours, and EXELON Capsule 6 mg twice daily groups, respectively.

The difference between each of these groups and placebo was statistically significant.

Although a slight improvement was observed with the 17.4 mg/24 hours patch compared to the 9.5 mg/24 hours patch on this outcome measure, no meaningful difference between the two was seen on the global evaluation (see Figure 4).

Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 1 Figure 4 presents the distribution of patients’ scores on the ADCS-CGIC for all 4 treatment groups.

At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the EXELON-treated groups with the patients on placebo was 0.2 units.

The difference between each of these groups and placebo was statistically significant.

Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing Study 1 International 48-Week Study of EXELON PATCH in Dementia of the Alzheimer’s Type (Study 2) This study was a randomized double-blind clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 10 and less than or equal to 24] (Study 2).

The mean age of patients participating in this trial was 76 years with a range of 50 to 85 years.

Approximately 65% of patients were women and 35% were men.

The racial distribution was approximately Caucasian 97%, black 2%, Asian 0.5%, and other races 1%.

Approximately 27% of the patients were taking memantine throughout the entire duration of the study.

Alzheimer’s disease patients who received 24 to 48 weeks open-label treatment with EXELON PATCH 9.5 mg/24 hours and who demonstrated functional and cognitive decline were randomized into treatment with either EXELON PATCH 9.5 mg/24 hours or EXELON PATCH 13.3 mg/24 hours in a 48-week, double-blind treatment phase.

Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of greater than or equal to 2 points from the previous visit or a decrease of greater than or equal to 3 points from baseline.

Study 2 was designed to compare the efficacy of EXELON PATCH 13.3 mg/24 hours versus that of EXELON PATCH 9.5 mg/24 hours during the 48-week, double-blind treatment phase.

The ability of the EXELON PATCH 13.3 mg/24 hours to improve cognitive performance over that provided by the EXELON PATCH 9.5 mg/24 hours was assessed by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) [see Clinical Studies (14)] .

The ability of the EXELON PATCH 13.3 mg/24 hours to improve overall function versus that provided by EXELON PATCH 9.5 mg/24 hours was assessed by the instrumental subscale of the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-IADL).

The ADCS-IADL subscale is composed of items 7 to 23 of the caregiver-based ADCS-ADL scale.

The ADCS-IADL assesses activities, such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests.

A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment.

Out of a total of 1584 patients enrolled in the initial open-label phase of the study, 567 patients were classified as decliners and were randomized into the 48-week double-blind treatment phase of the study.

Two hundred eighty-seven (287) patients entered the 9.5 mg/24 hours EXELON PATCH treatment group and 280 patients entered the 13.3 mg/24 hours EXELON PATCH treatment group.

Figure 5 illustrates the time course for the mean change from double-blind baseline in ADCS-IADL scores for each treatment group over the course of the 48-week treatment phase of the study.

Decline in the mean ADCS-IADL score from the double-blind baseline for the Intent to Treat–Last Observation Carried Forward (ITT-LOCF) analysis was less at each timepoint in the 13.3 mg/24 hour EXELON PATCH treatment group than in the 9.5 mg/24 hours EXELON PATCH treatment group.

The 13.3 mg/24 hours dose was statistically significantly superior to the 9.5mg/24 hours dose at weeks 16, 24, 32, and 48 (primary endpoint).

Figure 6 illustrates the time course for the mean change from double-blind baseline in ADAS-Cog scores for both treatment groups over the 48-week treatment phase.

The between-treatment group difference for EXELON PATCH 13.3 mg/24 hours versus EXELON PATCH 9.5 mg/24 hours was nominally statistically significant at week 24 (p = 0.027), but not at week 48 (p = 0.227), which was the primary endpoint.

Figure 5: Time Course of the Change From Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2 Figure 6: Time Course of the Change From Double-Blind Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 2 Severe Alzheimer’s Disease 24-Week United States Study With EXELON PATCH in Severe Alzheimer’s Disease (Study 3) This was a 24-week randomized double-blind, clinical investigation in patients with severe Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 3 and less than or equal to 12].

The mean age of patients participating in this trial was 78 years with a range of 51 to 96 years with 62% aged greater than 75 years.

Approximately 65% of patients were women and 35% were men.

The racial distribution was approximately Caucasian 87%, black 7%, Asian 1%, and other races 5%.

Patients on a stable dose of memantine were permitted to enter the study.

Approximately 61% of the patients in each treatment group were taking memantine throughout the entire duration of the study.

The study was designed to compare the efficacy of EXELON PATCH 13.3 mg/24 hours versus that of EXELON PATCH 4.6 mg/24 hours during the 24-week double-blind treatment phase.

The ability of the 13.3 mg/24 hours EXELON PATCH to improve cognitive performance versus that provided by the 4.6 mg/24 hours EXELON PATCH was assessed with the Severe Impairment Battery (SIB) which uses a validated 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced AD patients.

The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuospatial ability, construction, and orienting to name.

The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability.

The ability of the 13.3 mg/24 hours EXELON PATCH to improve overall function versus that provided by the 4.6 mg/24 hours EXELON PATCH was assessed with the Alzheimer’s Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) which is a caregiver-based ADL scale composed of 19 items developed for use in clinical studies of dementia.

It is designed to assess the patient’s performance of both basic and instrumental activities of daily living, such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions.

A sum score is calculated by adding the scores of the individual items and can range from 0 to 54, with higher scores indicating less functional impairment.

In this study, 716 patients were randomized into one of the following treatments: EXELON PATCH 13.3 mg/24 hours or EXELON PATCH 4.6 mg/24 hours in a 1:1 ratio.

This 24-week study was divided into an 8-week titration phase followed by a 16-week maintenance phase.

In the active treatment arms of this study, temporary dose adjustments below the target dose were permitted during the titration and maintenance phase in the event of poor tolerability.

Figure 7 illustrates the time course for the mean change from baseline SIB scores for each treatment group over the course of the 24-week treatment phase of the study.

Decline in the mean SIB score from the baseline for the Modified Full Analysis Set (MFAS)-Last Observation Carried Forward (LOCF) analysis was less at each timepoint in the 13.3 mg/24 hours EXELON PATCH treatment group than in the 4.6 mg/24 hours EXELON PATCH treatment group.

The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 8 illustrates the time course for the mean change from baseline in ADCS-ADL-SIV scores for each treatment group over the course of the 24-week treatment phase of the study.

Decline in the mean ADCS-ADL-SIV score from baseline for the MFAS-LOCF analysis was less at each timepoint in the 13.3 mg/24 hours EXELON PATCH treatment group than in the 4.6 mg/24 hours EXELON PATCH treatment group.

The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 7: Time Course of the Change From Baseline in SIB Score for Patients Observed at Each Time Point (Modified Full Analysis Set-LOCF) Figure 8: Time Course of the Change From Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified Full Analysis Set-LOCF) Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing the Study Figure 5 Time Course of the Change from Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2 Figure 6 Time Course of the Change from Double-Blind Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 2 Figure 7 Time Course of the Change from Baseline in SIB Score for Patients Observed at Each Time Point (Modified full analysis set–LOCF) Figure 8 Time Course of the Change from Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified full analysis set – LOCF)

HOW SUPPLIED

16 /STORAGE AND HANDLING EXELON PATCH: 4.6 mg/24 hours Each patch of 5 cm 2 contains 9 mg rivastigmine base with in vivo release rate of 4.6 mg/24 hours.

Carton of 30………………………NDC 0078-0501-15 EXELON PATCH: 9.5 mg/24 hours Each patch of 10 cm 2 contains 18 mg rivastigmine base with in vivo release rate of 9.5 mg/24 hours.

Carton of 30………………………..NDC 0078-0502-15 EXELON PATCH: 13.3 mg/24 hours Each patch of 15 cm 2 contains 27 mg rivastigmine base with in vivo release rate of 13.3 mg/24 hours.

Carton of 30………………………NDC 0078-0503-15 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Keep EXELON PATCH in the individual sealed pouch until use.

Each pouch contains 1 patch.

Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients in clinical studies of EXELON PATCH, 88% were 65 years and over, while 55% were 75 years.

No overall differences in safety or effectiveness were observed between these patients and younger patients, 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 EXELON PATCH is available in 3 strengths.

Each patch has a beige backing layer labeled as either: EXELON ® PATCH 4.6 mg/24 hours, AMCX EXELON ® PATCH 9.5 mg/24 hours, BHDI EXELON ® PATCH 13.3 mg/24 hours, CNFU Patch: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Although the precise mechanism of action of rivastigmine is unknown, it is thought to exert its therapeutic effect by enhancing cholinergic function.

This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase.

The effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact.

There is no evidence that rivastigmine alters the course of the underlying dementing process.

INDICATIONS AND USAGE

1 EXELON PATCH is an acetylcholinesterase inhibitor indicated for treatment of: Mild, moderate, and severe dementia of the Alzheimer’s type (AD).

( 1.1 ) Mild-to-moderate dementia associated with Parkinson’s disease (PD).

( 1.2 ) 1.1 Alzheimer’s Disease EXELON PATCH is indicated for the treatment of dementia of the Alzheimer’s type (AD).

Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease.

1.2 Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).

PEDIATRIC USE

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

The use of EXELON PATCH in pediatric patients (below 18 years of age) is not recommended.

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of EXELON in pregnant women.

In animals, no adverse effects on embryo-fetal development were observed at oral doses 2-4 times the maximum recommended human dose (MRHD) (see Data) .

The background risk of major birth defects and 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%-4% and 15%-20%, respectively.

Data Animal Data Oral administration of rivastigmine to pregnant rats and rabbits throughout organogenesis produced no adverse effects on embryo-fetal development up to the highest dose tested (2.3 mg/kg/day), which is 2 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2 ) basis.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hospitalization and, rarely, death have been reported due to application of multiple patches at same time.

Ensure patients or caregivers receive instruction on proper dosing and administration.

( 5.1 ) Gastrointestinal Adverse Reactions: May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption.

Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes.

( 5.2 ) Application-site reactions may occur with the patch form of rivastigmine.

Discontinue treatment if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal.

( 5.3 ) 5.1 Medication Errors Resulting in Overdose Medication errors with EXELON PATCH have resulted in serious adverse reactions; some cases have required hospitalization, and rarely, led to death.

The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time.

Instruct patients and their caregivers on important administration instructions for EXELON PATCH [see Dosage and Administration (2.4)] .

5.2 Gastrointestinal Adverse Reactions EXELON PATCH can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss.

Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes.

The incidence and severity of these reactions are dose-related [see Adverse Reactions (6.1)] .

For this reason, initiate treatment with EXELON PATCH at a dose of 4.6 mg/24 hours, and titrate to a dose of 9.5 mg/24 hours and then to a dose of 13.3 mg/24 hours, if appropriate [see Dosage and Administration (2.1)] .

If treatment is interrupted for more than 3 days because of intolerance, reinitiate EXELON PATCH with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae.

A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of rivastigmine without retitration after 8 weeks of treatment interruption.

Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur.

It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration.

5.3 Skin Reactions Skin application-site reactions may occur with EXELON PATCH.

These reactions are not in themselves an indication of sensitization.

However, use of rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal.

In these cases, treatment should be discontinued [see Contraindications (4)] .

In patients who develop application-site reactions to EXELON PATCH, suggestive of allergic contact dermatitis and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision.

It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form.

There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal).

In these cases, treatment should be discontinued [see Contraindications (4)] .

Patients and caregivers should be instructed accordingly.

5.4 Other Adverse Reactions From Increased Cholinergic Activity Neurologic Effects Extrapyramidal Symptoms : Cholinomimetics, including rivastigmine, may exacerbate or induce extrapyramidal symptoms.

Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson’s disease who were treated with EXELON Capsules.

Seizures : Drugs that increase cholinergic activity are believed to have some potential for causing seizures.

However, seizure activity also may be a manifestation of Alzheimer’s disease.

Peptic Ulcers/Gastrointestinal Bleeding Cholinesterase inhibitors, including rivastigmine, may increase gastric acid secretion due to increased cholinergic activity.

Monitor patients using EXELON PATCH for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs).

Clinical studies of rivastigmine have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Use with Anesthesia Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Cardiac Conduction Effects Because rivastigmine increases cholinergic activity, use of the EXELON PATCH may have vagotonic effects on heart rate (e.g., bradycardia).

The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions.

In clinical trials, rivastigmine was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or electrocardiogram (ECG) abnormalities.

Genitourinary Effects Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.

Pulmonary Effects Drugs that increase cholinergic activity, including EXELON PATCH, should be used with care in patients with a history of asthma or obstructive pulmonary disease.

5.5 Impairment in Driving or Use of Machinery Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery.

The administration of rivastigmine may also result in adverse reactions that are detrimental to these functions.

During treatment with EXELON PATCH, routinely evaluate the patient’s ability to continue driving or operating machinery.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Importance of Correct Usage Inform patients or caregivers of the importance of applying the correct dose on the correct part of the body.

They should be instructed to rotate the application site in order to minimize skin irritation.

The same site should not be used within 14 days.

The previous day’s patch must be removed before applying a new patch to a different skin location.

EXELON PATCH should be replaced every 24 hours and the time of day should be consistent.

It may be helpful for this to be part of a daily routine, such as the daily bath or shower.

Only 1 patch should be worn at a time [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] .

Instruct patients or caregivers to avoid exposure of the patch to external heat sources (excessive sunlight, saunas, solariums) for long periods of time.

Instruct patients who have missed a dose to apply a new patch immediately.

They may apply the next patch at the usual time the next day.

Instruct patients to not apply 2 patches to make up for 1 missed.

Inform the patient or caregiver to contact the physician for retitration instructions if treatment has been interrupted.

Discarding Used Patches Instruct patients or caregivers to fold the patch in half after use, return the used patch to its original pouch, and discard it out of the reach and sight of children and pets.

They should also be informed that drug still remains in the patch after 24-hour usage.

They should be instructed to avoid eye contact and to wash their hands after handling the patch.

In case of accidental contact with the eyes, or if their eyes become red after handling the patch, they should be instructed to rinse immediately with plenty of water and to seek medical advice if symptoms do not resolve [see Dosage and Administration (2.4)] .

Gastrointestinal Adverse Reactions Inform patients or caregivers of the potential gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, including the possibility of dehydration due to these symptoms.

Explain that EXELON PATCH may affect the patient’s appetite and/or the patient’s weight.

Patients and caregivers should be instructed to look for these adverse reactions, in particular when treatment is initiated or the dose is increased.

Instruct patients and caregivers to inform a physician if these adverse reactions persist [see Warnings and Precautions (5.2)] .

Skin Reactions Inform patients or caregivers about the potential for allergic contact dermatitis reactions to occur.

Patients or caregivers should be instructed to inform a physician if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal [see Warnings and Precautions (5.3)] .

Concomitant Use of Drugs With Cholinergic Action Inform patients or caregivers that while wearing EXELON PATCH, patients should not be taking EXELON Capsules or EXELON Oral Solution or other drugs with cholinergic effects [see Warnings and Precautions (5.4)] .

Pregnancy Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 T2020-95

DOSAGE AND ADMINISTRATION

2 Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours.

( 2.1 , 2.4 ) Initial Dose: Initiate treatment with 4.6 mg/24 hours EXELON PATCH.

( 2.1 ) Dose Titration ( 2.1 ): After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose.

Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours.

Mild-to-Moderate Alzheimer’s Disease and Parkinson’s Disease Dementia: EXELON PATCH 9.5 mg/24 hours or 13.3 mg/24 hours once daily.

( 2.1 ) Severe Alzheimer’s Disease: EXELON PATCH 13.3 mg/24 hours once daily.

( 2.1 ) For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours.

( 2.1 ) Consider dose adjustments in patients with ( 2.2 ): Mild-to-moderate hepatic impairment ( 8.6 ) Low (less than 50 kg) body weight ( 8.7 ) 2.1 Recommended Dosing Initial Dose Initiate treatment with one 4.6 mg/24 hours EXELON PATCH applied to the skin once daily [see Dosage and Administration (2.4)] .

Dose Titration Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been tolerated.

For mild-to-moderate AD and PDD patients, continue the effective dose of 9.5 mg/24 hours for as long as therapeutic benefit persists.

Patients can then be increased to the maximum effective dose of 13.3 mg/24 hours dose.

For patients with severe AD, 13.3 mg/24 hours is the effective dose.

Doses higher than 13.3 mg/24 hours confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse reactions [see Warnings and Precautions (5.2), Adverse Reactions (6.1)] .

Mild-to-Moderate Alzheimer’s Disease and Mild-to-Moderate Parkinson’s Disease Dementia The effective dosage of EXELON PATCH is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Severe Alzheimer’s Disease The effective dosage of EXELON PATCH in patients with severe Alzheimer’s disease is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Interruption of Treatment If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength EXELON PATCH.

If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours EXELON PATCH and titrate as described above.

2.2 Dosing in Specific Populations Dosing Modifications in Patients with Hepatic Impairment Consider using the 4.6 mg/24 hours EXELON PATCH as both the initial and maintenance dose in patients with mild (Child-Pugh score 5 to 6) to moderate (Child-Pugh score 7 to 9) hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .

Dosing Modifications in Patients with Low Body Weight Carefully titrate and monitor patients with low body weight (less than 50 kg) for toxicities (e.g., excessive nausea, vomiting), and consider reducing the maintenance dose to the 4.6 mg/24 hours EXELON PATCH if such toxicities develop.

2.3 Switching to EXELON PATCH from EXELON Capsules or EXELON Oral Solution Patients treated with EXELON Capsules or Oral Solution may be switched to EXELON PATCH as follows: A patient who is on a total daily dose of less than 6 mg of oral rivastigmine can be switched to the 4.6 mg/24 hours EXELON PATCH.

A patient who is on a total daily dose of 6 mg to 12 mg of oral rivastigmine can be switched to the 9.5 mg/24 hours EXELON PATCH.

Instruct patients or caregivers to apply the first patch on the day following the last oral dose.

2.4 Important Administration Instructions EXELON PATCH is for transdermal use on intact skin.

(a) Do not use the patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

(b) Apply the EXELON PATCH once a day.

Press down firmly for 30 seconds until the edges stick well when applying to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing.

Use the upper or lower back as the site of application because the patch is less likely to be removed by the patient.

If sites on the back are not accessible, apply the patch to the upper arm or chest.

Do not apply to a skin area where cream, lotion, or powder has recently been applied.

(c) Do not apply to skin that is red, irritated, or cut.

(d) Replace the EXELON PATCH with a new patch every 24 hours.

Instruct patients to only wear 1 patch at a time (remove the previous day’s patch before applying a new patch) [see Warnings and Precautions (5.1), Overdosage (10)] .

If a patch falls off or if a dose is missed, apply a new patch immediately, and then replace this patch the following day at the usual application time.

(e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days.

Do not apply a new patch to the same location for at least 14 days.

(f) May wear the patch during bathing and in hot weather.

Avoid long exposure to external heat sources (excessive sunlight, saunas, solariums).

(g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children.

(h) Wash hands with soap and water after removing the patch.

In case of contact with eyes or if the eyes become red after handling the patch, rinse immediately with plenty of water, and seek medical advice if symptoms do not resolve.

Timolol 5 MG/ML Ophthalmic Solution

WARNINGS

As with other topically applied ophthalmic drugs, Betimol ® is absorbed systemically.

The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration.

For example, severe respiratory 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 topical administration of beta-adrenergic blocking agents.

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 cardiac failure.

In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure.

Betimol ® should be discontinued at the first sign or symptom of cardiac failure.

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 which are contraindications) should in general not receive beta-blocking agents.

Major Surgery The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to a major surgery is controversial.

Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli.

This may augment the risk of general anesthesia in surgical procedures.

Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia.

Difficulty in restarting and maintaining the heartbeat has also been reported.

For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic receptor blocking agents is recommended.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of beta-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 which might precipitate a thyroid storm.

DRUG INTERACTIONS

Drug Interactions Beta-adrenergic blocking agents Patients who are receiving a beta-adrenergic blocking agent orally and Betimol ® should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade.

Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently.

Catecholamine-depleting drugs Close observation of the patient is recommended when a beta-blocker 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 produce vertigo, syncope, or postural hypotension.

Calcium antagonists Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension.

In patients with impaired cardiac function, co-administration should be avoided.

Digitalis and calcium antagonists The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

Injectable Epinephrine (See PRECAUTIONS, General, Anaphylaxis .)

OVERDOSAGE

No information is available on overdosage with Betimol ® .

Symptoms that might be expected with an overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia, and acute cardiac failure.

DESCRIPTION

Betimol ® (timolol ophthalmic solution), 0.25% and 0.5%, is a non-selective beta-adrenergic antagonist for ophthalmic use.

The chemical name of the active ingredient is (S)-1-[(1,1-dimethylethyl)amino]-3-[(4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol.

Timolol hemihydrate is the levo isomer.

Specific rotation is [α] 25 405nm =-16° (C=10% as the hemihydrate form in 1N HCl).

The molecular formula of timolol is Formula C 13 H 24 N 4 O 3 S and its structural formula is: Timolol (as the hemihydrate) is a white, odorless, crystalline powder which is slightly soluble in water and freely soluble in ethanol.

Timolol hemihydrate is stable at room temperature.

Betimol ® is a clear, colorless, isotonic, sterile, microbiologically preserved phosphate buffered aqueous solution.

It is supplied in two dosage strengths, 0.25% and 0.5%.

Each mL of Betimol ® 0.25% contains 2.56 mg of timolol hemihydrate equivalent to 2.5 mg Timolol.

Each mL of Betimol ® 0.5% contains 5.12 mg of timolol hemihydrate equivalent to 5.0 mg timolol.

Inactive ingredients: monosodium and disodium phosphate dihydrate to adjust pH (6.5 – 7.5) and water for injection, benzalkonium chloride 0.01% added as preservative.

The osmolality of Betimol ® is 260 to 320 mOsmol/kg.

Chemical Structure

CLINICAL STUDIES

Clinical Studies In two controlled multicenter studies in the U.S., Betimol ® 0.25% and 0.5% were compared with respective timolol maleate eyedrops.

In these studies, the efficacy and safety profile of Betimol ® was similar to that of timolol maleate.

HOW SUPPLIED

Betimol ® (timolol ophthalmic solution) is a clear, colorless solution.

Betimol ® 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows: NDC 68669-522-05 5.0mL fill in 5 cc container NDC 68669-522-10 10mL fill in 11 cc container NDC 68669-522-15 15mL fill in 15 cc container Betimol ® 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows: NDC 68669-525-05 5.0mL fill in 5 cc container NDC 68669-525-10 10mL fill in 11 cc contalner NDC 68669-525-15 15mL fill in 15 cc container Rx Only STORAGE Store between 15-25°C (59-77°F).

Do not freeze.

Protect from light.

INDICATIONS AND USAGE

Betimol ® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

PEDIATRIC USE

Pediatric use Safety and efficacy in pediatric patients have not been established.

PREGNANCY

Pregnancy Teratogenic effects Category C Teratogenicity of timolol (as the maleate) after oral administration was studied in mice and rabbits.

No fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose).

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.

Betimol ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing mothers Because of the potential for serious adverse reactions in nursing infants from timolol, 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.

INFORMATION FOR PATIENTS

Information for Patients Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions can become contaminated by common bacteria known to cause ocular infections.

Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

(See PRECAUTIONS, General .) Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 5 minutes apart.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or cardiac failure should be advised not to take this product (See CONTRAINDICATIONS .)

DOSAGE AND ADMINISTRATION

Betimol ® Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent.

The usual starting dose is one drop of 0.25 percent Betimol ® in the affected eye(s) twice a day.

If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s).

Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Since in some patients the pressure-lowering response to Betimol ® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Betimol ® .

Dosages above one drop of 0.5 percent Betimol ® twice a day generally have not been shown to produce further reduction in intraocular pressure.

If the patient’s intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with pilocarpine and other miotics, and/or epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted.

Fexofenadine hydrochloride 60 MG Oral Tablet

WARNINGS

Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients.

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: runny nose sneezing itchy, watery eyes itching of the nose or throat

INACTIVE INGREDIENTS

Inactive ingredients crospovidone, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, titanium dioxide

PURPOSE

Purpose Antihistamine

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.

ASK DOCTOR

Ask a doctor before use if you have kidney disease.

Your doctor should determine if you need a different dose.

DOSAGE AND ADMINISTRATION

Directions For 30mg: adults and children 12 years of age and over take two 30 mg tablets with water every 12 hours; do not take more than 4 tablets in 24 hours children 6 to under 12 years of age take one 30 mg tablet with water every 12 hours; do not take more than 2 tablets in 24 hours children under 6 years of age do not use adults 65 years of age and older ask a doctor consumers with kidney disease ask a doctor For 60mg: adults and children 12 years of age and over take one 60 mg tablet with water every 12 hours; do not take more than 2 tablets in 24 hours children under 12 years of age do not use adults 65 years of age and older ask a doctor consumers with kidney disease ask a doctor For 180mg: adults and children 12 years of age and over take one 180 mg tablet with water once a day; do not take more than 1 tablet in 24 hours children under 12 years of age do not use adults 65 years of age and older ask a doctor consumers with kidney disease ask a doctor

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding ask a health professional before use.

STOP USE

Stop use and ask doctor if an allergic reaction to this product occurs.

Seek medical help right away.

ACTIVE INGREDIENTS

Active ingredient (in each tablet) For 30 mg: Fexofenadine HCl, USP 30 mg For 60 mg: Fexofenadine HCl, USP 60 mg For 180 mg: Fexofenadine HCl, USP 180 mg

ZOSTRIX Joint & Arthritis Pain Relief 0.025 % / 2 % Topical Cream

WARNINGS

Warnings For external use only.

Do not apply to wounds or to damaged or irritated skin.

When using this product • you may experience a burning sensation which is normal and related to the way the product works.

With regular use, this sensation generally diminishes.

• avoid contact with eyes.

Do not get it on mucous membranes, into eyes, or on contact lenses.

If this occurs, rinse the affected area thoroughly with water.

• do not apply immediately before or after activities such as bathing, swimming, sun bathing, or strenuous exercise • do not apply heat to the treated areas immediately before or after use • do not tightly wrap or bandage the treated area • avoid inhaling airborne material from dried residue.

This can result in coughing, sneezing, tearing, throat or respiratory irritation.

Stop use and ask a doctor • conditions worsens, or if symptoms persist for more than 7 days or clear up and occur again within a few days • blisters occurs • difficulty breathing or swallowing occurs • severe burning persists

INDICATIONS AND USAGE

Uses For the temporary relief of minor aches and pains of the muscle joints associated with • strains • sprains • bruises • arthritis

INACTIVE INGREDIENTS

Inactive Ingredients Benzyl alcohol, cetearyl alcohol, ceteareth-20, cetyl alcohol, glyceryl stearate, isopropyl myristate, PEG-100 stearate, petrolatum, sorbitol & water.

PURPOSE

Purposes Topical Analgesic Topical Analgesic

KEEP OUT OF REACH OF CHILDREN

Keep Out of Reach of Children

DOSAGE AND ADMINISTRATION

Directions • for persons under 18 years of age, ask a doctor before using • apply a thin film of cream to the affected area and gently rub in until fully absorbed • for optimum relief, apply 3 to 4 times daily • best results typically occur after 2 to 4 weeks of continuous use • unless treating hands, wash hands thoroughly with soap and water immediately after use • see package insert for more information

ACTIVE INGREDIENTS

Active ingredients Capsaicin 0.025% Menthol 2.0%

Insulin analog, Glargine 300 UNT Pen Injector

Generic Name: INSULIN GLARGINE
Brand Name: BASAGLAR KwikPen
  • Substance Name(s):
  • INSULIN GLARGINE

DRUG INTERACTIONS

7 Table 6 includes clinically significant drug interactions with BASAGLAR Table 6: Clinically Significant Drug Interactions with BASAGLAR Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.

Intervention: Dose reductions and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.

Drugs That May Decrease the Blood Glucose Lowering Effect of BASAGLAR Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones Intervention: Dose increases and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.

Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of BASAGLAR Drugs: Alcohol, beta-blockers, clonidine, and lithium salts.

Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.

Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.

Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics ( 7 ).

Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones ( 7 ).

Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine ( 7 ).

Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine ( 7 ).

OVERDOSAGE

10 Excess insulin administration relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 )] .

Mild episodes of hypoglycemia can be treated with oral glucose.

Adjustments in drug dosage, meal patterns, or physical activity level may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose.

Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery.

Hypokalemia must be corrected appropriately.

DESCRIPTION

11 Insulin glargine is a long-acting human insulin analog produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism.

Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain.

Chemically, insulin glargine is 21 A -Gly-30 B -a-L-Arg-30 B b-L-Arg-human insulin and has the empirical formula C 267 H 404 N 72 O 78 S 6 and a molecular weight of 6.063 kDa.

Insulin glargine has the following structural formula: BASAGLAR (insulin glargine) injection is a sterile clear and colorless aqueous solution for subcutaneous use.

Each mL contains 100 units of insulin glargine (3.6378 mg).

The 3 mL BASAGLAR prefilled pen presentations contain the following inactive ingredients per mL: glycerin (17 mg), metacresol (2.7 mg), zinc oxide (content adjusted to provide 30 mcg zinc ion), and Water for Injection, USP.

The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%.

BASAGLAR has a pH of approximately 4.

Structural Formula

CLINICAL STUDIES

14 14.1 Overview of Clinical Studies The safety and effectiveness of another insulin glargine product, 100 units/mL, given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adults and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus ( see Tables 8 , 9 , 11 , and 12 ).

In general, the reduction in glycated hemoglobin (HbA 1c ) with this other insulin glargine product was similar to that with NPH insulin.

14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes Patients with inadequately controlled type 1 diabetes participated in a 24-week open-label, active-controlled study with a 28 week extension to evaluate the glucose lowering effect of once-daily BASAGLAR compared to that of once-daily administration of another insulin glargine product, 100 units/mL, or a non-U.S.-licensed insulin glargine, 100 units/mL, (comparator insulin glargine products, 100 units/mL) both in combination with mealtime insulin lispro.

Randomized were 535 adults with type 1 diabetes.

Mean age was 41.2 years and mean duration of diabetes was 16.39 years.

57.9% were male.

74.5% were Caucasian, 2.1% Black or African American and 4.3% American Indian or Alaskan native.

3.9% were Hispanic.

73.5 percent of patients had GFR>90 mL/min/1.73m 2 .

The mean BMI was approximately 25.54 kg/m 2 .

At week 24, treatment with BASAGLAR provided a mean reduction in HbA 1c that was non-inferior to that achieved with comparator insulin glargine products, 100 units/mL ( see Table 7 ).

Table 7: Type 1 Diabetes Mellitus – Adult (BASAGLAR plus Mealtime insulin versus Comparator Insulin Glargine Products, 100 units/mL, plus Mealtime Insulin) a One patient randomized to the BASAGLAR group was not included in the Full Analysis Set.

b “Comparator insulin glargine products, 100 units/mL” refers to another insulin glargine product, 100 units/mL, and a non-U.S.-licensed insulin glargine, 100 units/mL, used in this study.

c ANCOVA Model includes treatment, country and time of baseline basal insulin injection (daytime or evening/bedtime) as fixed effects and baseline HbA 1c as covariate.

d The results were calculated based on the number of patients in the Full Analysis Set using their last observed post-baseline value of HbA 1c .

Observed HbA 1c data at 24 weeks were available from 256 (95.5%) and 258 (96.6%) subjects randomized to the BASAGLAR and comparator insulin glargine products, 100 units/mL, groups, respectively.

Efficacy Parameter BASAGLAR + insulin lispro (N=268 a ) Comparator Insulin Glargine Products, 100 units/mL b + insulin lispro (N=267) HbA 1c (%) Baseline (mean) 7.75 7.79 Change from baseline (adjusted mean c,d ) -0.35 -0.46 Difference from comparator (adjusted mean c,d ) (95% CI) 0.11 (-0.002, 0.219) Proportion of patients achieving HbA 1c <7% d 34.5% 32.2% In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534) were randomized to 28 weeks of basal-bolus treatment with another insulin glargine product, 100 units/mL, or NPH insulin.

Regular human insulin was administered before each meal.

This other insulin glargine product was administered at bedtime.

NPH insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily.

In Study A, the average age was 39.2 years.

The majority of patients were Caucasian (99%) and 55.7% were male.

The mean BMI was approximately 24.9 kg/m 2 .

The mean duration of diabetes was 15.5 years.

In Study B, the average age was 38.5 years.

The majority of patients were Caucasian (95.3%) and 50.6% were male.

The mean BMI was approximately 25.8 kg/m 2 .

The mean duration of diabetes was 17.4 years.

In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with another insulin glargine product, 100 units/mL, or NPH insulin.

Insulin lispro was used before each meal.

This other insulin glargine product was administered once daily at bedtime and NPH insulin was administered once or twice daily.

The average age was 39.2 years.

The majority of patients were Caucasian (96.9%) and 50.6% were male.

The mean BMI was approximately 25.6 kg/m 2 .

The mean duration of diabetes was 18.5 years.

In these 3 studies, another insulin glargine product, 100 units/mL, and NPH insulin had similar effects on HbA 1c ( see Table 8 ) with a similar overall rate of hypoglycemia [see Adverse Reactions ( 6.1 )] .

Table 8: Type 1 Diabetes Mellitus – Adult (Another Insulin Glargine Product, 100 units/mL, versus NPH) Treatment duration Treatment in combination with Study A 28 weeks Regular insulin Study B 28 weeks Regular insulin Study C 16 weeks Insulin lispro Another Insulin Glargine Product NPH Another Insulin Glargine Product NPH Another Insulin Glargine Product NPH Number of subject treated 292 293 264 270 310 309 HbA 1c (%) Baseline (mean) 8.0 8.0 7.7 7.7 7.6 7.7 Adjusted mean change at trial end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1 Treatment Difference (95% CI) +0.1 (0.0; + 0.2) +0.1(-0.1; + 0.2) 0.0 (+0.1; + 0.1) Fasting blood glucose (mg/dL) Baseline (mean) 167 166 166 175 175 173 Adjusted mean change at trial end -21 -16 -20 -17 -29 -12 Type 1 Diabetes – Pediatric ( see Table 9) The efficacy of BASAGLAR to improve glycemic control in pediatric patients with type 1 diabetes mellitus is based on an adequate and well-controlled trial of another insulin glargine product, 100 units/mL, in pediatric patients with type 1 diabetes mellitus (Study D).

In this randomized, active-controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal.

Patients were randomized to either this other insulin glargine product administered once daily at bedtime or NPH insulin administered once or twice daily.

The average age was 11.7 years.

The majority of patients were Caucasian (96.8%) and 51.9% were male.

The mean BMI was approximately 18.9 kg/m 2 .

The mean duration of diabetes was 4.8 years.

Similar effects on HbA 1c ( see Table 9 ) were observed in both treatment groups.

Table 9: Type 1 Diabetes Mellitus – Pediatric (Another Insulin Glargine Product, 100 units/mL, plus Regular Insulin versus NPH plus Regular Insulin) Study D Another Insulin Glargine Product + Regular Insulin NPH + Regular Insulin Number of subjects treated 174 175 HbA 1c Baseline mean 8.5 8.8 Change from baseline (adjusted mean) +0.3 +0.3 Difference from NPH (adjusted mean) (95% CI) 0.0 (-0.2; +0.3) Fasting blood glucose (mg/dL) Baseline mean 194 191 Mean change from baseline -23 -12 14.3 Clinical Studies in Adults with Type 2 Diabetes Patients with type 2 diabetes participated in a double-blind, active-controlled study to evaluate the glucose lowering effect of once-daily BASAGLAR plus oral antidiabetic medication (OAM) compared to that of another insulin glargine product, 100 units/mL, or a non-U.S.-licensed insulin glargine, 100 units/mL (comparator insulin glargine products, 100 units/mL) administered once-daily along with OAMs.

Patients were either insulin naïve (approximately 60%) and had failed to achieve adequate glycemic control on at least 2 OAMs, or were already on another insulin glargine product, 100 units/mL, or a non-U.S.-licensed insulin glargine, 100 units/mL, along with at least 2 OAMs with adequate or inadequate glycemic control (approximately 40%).

A total of 759 patients were randomized.

Three patients randomized to BASAGLAR did not receive study drug and were not included in efficacy analysis.

The average age was approximately 59 years.

The majority of patients were White (78%) and 50% of the patients were male.

Sixty-eight percent of patients had GFR>90 mL/min/1.73m 2 .

The mean BMI was approximately 32 kg/m 2 .

At week 24, treatment with BASAGLAR provided a mean reduction in HbA 1c that was non-inferior to that achieved with comparator insulin glargine products, 100 units/mL ( see Table 10 ).

Table 10: Type 2 Diabetes Mellitus – Adult (BASAGLAR plus Oral Antidiabetic Medications versus Comparator Insulin Glargine Products, 100 units/mL, plus Oral Antidiabetic Medications) a Three patients randomized to BASAGLAR did not receive study drug and were not included in the Full Analysis Set.

b “Comparator insulin glargine products, 100 units/mL” refers to another insulin glargine product, 100 units/mL, and a non-U.S.-licensed insulin glargine, 100 units/mL, used in this study.

c ANCOVA Model includes treatment, country, sulfonylurea use and time of baseline basal insulin injection (daytime or evening/bedtime) as fixed effects and baseline HbA 1c as covariate.

d The results were calculated based on the number of patients in the Full Analysis Set using their last observed post-baseline value of HbA 1c .

Observed HbA 1c data at 24 weeks were available from 331 (88%) and 329 (87%) subjects randomized to the BASAGLAR and comparator insulin glargine products, 100 units/mL, groups, respectively.

BASAGLAR + Oral Antidiabetic Medication (N=376) a Comparator Insulin Glargine Products, 100 units/mL b + Oral Antidiabetic Medication (N=380) HbA 1c (%) Baseline (mean) 8.35 8.31 Change from baseline (adjusted mean c,d ) -1.3 -1.3 Difference from comparator (adjusted mean c,d ) (95% CI) 0.05 (-0.07, 0.17) Proportion of patients achieving HbA 1c <7% d 48.8% 52.5% In a randomized, controlled clinical study (Study E) (n=570), another insulin glargine product, 100 units/mL, was evaluated for 52 weeks in combination with oral anti-diabetic medications (a sulfonylurea, metformin, acarbose, or combination of these drugs).

The average age was 59.5 years.

The majority of patients were Caucasian (92.8%) and 53.7% were male.

The mean BMI was approximately 29.1 kg/m 2 .

The mean duration of diabetes was 10.3 years.

This other insulin glargine product administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA 1c and fasting glucose ( see Table 11 ).

The rate of hypoglycemia was similar in this other insulin glargine product and NPH insulin treated patients [see Adverse Reactions ( 6.1 )] .

In a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral anti-diabetic medications (n=518), a basal-bolus regimen of another insulin glargine product, 100 units/mL, once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks.

Regular human insulin was used before meals, as needed.

The average age was 59.3 years.

The majority of patients were Caucasian (80.7%) and 60% were male.

The mean BMI was approximately 30.5 kg/m 2 .

The mean duration of diabetes was 13.7 years.

This other insulin glargine product had similar effectiveness as either once- or twice daily NPH insulin in reducing HbA 1c and fasting glucose ( see Table 11 ) with a similar incidence of hypoglycemia [see Adverse Reactions ( 6.1 )] .

In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with another insulin glargine product, 100 units/mL, once-daily or twice-daily NPH insulin.

For patients not previously treated with insulin, the starting dose of this other insulin glargine product or NPH insulin was 10 units daily.

Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started this other insulin glargine product at a dose that was 80% of the total previous NPH insulin dose.

The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the ETDRS scale.

HbA 1c change from baseline was a secondary endpoint.

Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data.

Patients or study personnel used an algorithm to adjust this other insulin glargine product and NPH insulin doses to a target fasting plasma glucose ≤100 mg/dL.

After this other insulin glargine product or NPH insulin dose was adjusted, other anti-diabetic agents, including pre-meal insulin were to be adjusted or added.

The average age was 55.1 years.

The majority of patients were Caucasian (85.3%) and 53.9% were male.

The mean BMI was approximately 34.3 kg/m 2 .

The mean duration of diabetes was 10.8 years.

This other insulin glargine product group had a smaller mean reduction from baseline in HbA 1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in this other insulin glargine product group ( see Table 11 ).

Both treatment groups had a similar incidence of reported symptomatic hypoglycemia.

The incidence of severe symptomatic hypoglycemia in the ORIGIN Trial is given in Table 5 [see Adverse Reactions ( 6.1 )] .

Table 11: Type 2 Diabetes Mellitus – Adult (Another Insulin Glargine Product, 100 units/mL, versus NPH) Treatment duration Treatment in combination with Study E 52 weeks Oral agents Study F 28 weeks Regular insulin Study G 5 years Regular insulin Another Insulin Glargine Product NPH Another Insulin Glargine Product NPH Another Insulin Glargine Product NPH Number of subjects treated 289 281 259 259 513 504 HbA 1c Baseline mean 9.0 8.9 8.6 8.5 8.4 8.3 Adjusted mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8 Another insulin glargine product, 100 units/mL – NPH -0.1 +0.2 +0.2 95% CI for Treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) Fasting blood glucose (mg/dL) Baseline mean 179 180 164 166 190 180 Adjusted mean change from baseline -49 -46 -24 -22 -45 -44 Another Insulin Glargine Product, 100 units/mL, Timing of Daily Dosing ( see Table 12) The safety and efficacy of this other insulin glargine product administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in patients with type 1 diabetes (Study H; n=378).

Patients were also treated with insulin lispro at mealtime.

The average age was 40.9 years.

All patients were Caucasian (100%) and 53.7% were male.

The mean BMI was approximately 25.3 kg/m 2 .

The mean duration of diabetes was 17.3 years.

This other insulin glargine product administered at different times of the day resulted in similar reductions in HbA 1c compared to that with bedtime administration ( see Table 12 ).

In these patients, data are available from 8-point home glucose monitoring.

The maximum mean blood glucose was observed just prior to injection of this other insulin glargine product regardless of time of administration.

In this study, 5% of patients in this other insulin glargine product-breakfast arm discontinued treatment because of lack of efficacy.

No patients in the other two arms discontinued for this reason.

The safety and efficacy of this other insulin glargine product administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n=697) in patients with type 2 diabetes not adequately controlled on oral anti-diabetic therapy.

All patients in this study also received glimepiride 3 mg daily.

The average age was 60.8 years.

The majority of patients were Caucasian (96.6%) and 53.7% were male.

The mean BMI was approximately 28.7 kg/m 2 .

The mean duration of diabetes was 10.1 years.

This other insulin glargine product given before breakfast was at least as effective in lowering HbA 1c as this other insulin glargine product given at bedtime or NPH insulin given at bedtime ( see Table 12 ).

Table 12: Type 1 Diabetes Mellitus – Adults (Another Insulin Glargine Product, 100 units/mL, plus Insulin Lispro) and Type 2 Diabetes Mellitus – Adults (Another Insulin Glargine Product, 100 units/mL, plus Glimepiride versus NPH plus Glimepiride) a Intent to treat.

b Total number of patients evaluable for safety.

c Not applicable.

Treatment duration Treatment in combination with Study H 24 weeks Insulin lispro Study I 24 weeks Glimepiride Another Insulin Glargine Product Breakfast Another Insulin Glargine Product Dinner Another Insulin Glargine Product Bedtime Another Insulin Glargine Product Breakfast Another Insulin Glargine Product Bedtime NPH Bedtime Number of subjects treated a 112 124 128 234 226 227 HbA 1c Baseline mean 7.6 7.5 7.6 9.1 9.1 9.1 Mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8 Five-year Trial Evaluating the Progression of Retinopathy Retinopathy was evaluated in clinical studies with another insulin glargine product, 100 units/mL, by analysis of reported retinal adverse events and fundus photography.

The numbers of retinal adverse events reported for this other insulin glargine product and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.

Another insulin glargine product, 100 units/mL, was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS).

Patients had type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline.

Mean baseline HbA 1c was 8.4%.

The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint.

Patients with pre-specified post-baseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressions regardless of actual change in ETDRS score from baseline.

Retinopathy graders were blinded to treatment group assignment.

The results for the primary endpoint are shown in Table 13 for both the per-protocol and Intent-to-Treat populations, and indicate similarity of this other insulin glargine product to NPH in the progression of diabetic retinopathy as assessed by this outcome.

Table 13: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint a Difference = another insulin glargine product, 100 units/mL – NPH.

b Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA 1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function.

Another Insulin Glargine Product, 100 units/mL (%) NPH (%) Difference a,b (SE) 95% CI for difference Per-protocol 53/374 (14.2%) 57/363 (15.5%) -2.0% (2.6%) -7.0% to +3.1% Intent-to-Treat 63/502 (12.5%) 71/487 (14.6%) -2.1% (2.1%) -6.3% to +2.1% The ORIGIN Study The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 2-by-2, factorial design study.

One intervention in ORIGIN compared the effect of another insulin glargine product, 100 units/mL, to standard care on major adverse cardiovascular outcomes in 12,537 participants ≥50 years of age with abnormal glucose levels [i.e., impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] or early type 2 diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline.

The objective of the trial was to demonstrate that use of this other insulin glargine product could significantly lower the risk of major cardiovascular outcomes compared to standard care.

Two co-primary composite cardiovascular endpoints were used in ORIGIN.

The first co-primary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke.

The second co-primary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.

Participants were randomized to either this other insulin glargine product (N=6264) titrated to a goal fasting plasma glucose of ≤95 mg/dL or to standard care (N=6273).

Anthropometric and disease characteristics were balanced at baseline.

The mean age was 64 years and 8% of participants were 75 years of age or older.

The majority of participants were male (65%).

Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black.

The median baseline BMI was 29 kg/m 2 .

Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes.

For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure.

The mean HbA 1c (SD) at baseline was 6.5% (1.0).

Fifty nine percent of participants had had a prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors.

Vital status was available for 99.9% and 99.8% of participants randomized to this other insulin glargine product and standard care respectively at end of trial.

The median duration of follow-up was 6.2 years [range: 8 days to 7.9 years].

The mean HbA 1c (SD) at the end of the trial was 6.5% (1.1) and 6.8% (1.2) in this other insulin glargine product and standard group respectively.

The median dose of this other insulin glargine product at end of trial was 0.45 U/kg.

Eighty-one percent of patients randomized to this other insulin glargine product were using this other insulin glargine product at end of the study.

The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in this other insulin glargine group than in the standard care group.

Overall, the incidence of major adverse cardiovascular outcomes was similar between groups ( see Table 14 ).

All-cause mortality was also similar between groups.

Table 14: Cardiovascular Outcomes in ORIGIN – Time to First Event Analyses Another Insulin Glargine Product, 100 units/mL N=6264 Standard Care N=6273 Another Insulin Glargine Product, 100 units/mL vs.

Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Co-primary endpoints CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 (2.9) 1013 (2.9) 1.02 (0.94, 1.11) CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 (5.5) 1727 (5.3) 1.04 (0.97, 1.11) Components of co-primary endpoints CV death 580 576 1.00 (0.89, 1.13) Myocardial Infarction (fatal or nonfatal) 336 326 1.03 (0.88, 1.19) Stroke (fatal or nonfatal) 331 319 1.03 (0.89, 1.21) Revascularizations 908 860 1.06 (0.96, 1.16) Hospitalization for heart failure 310 343 0.90 (0.77, 1.05) In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancer in the ORIGIN trial ( see Table 15 ) was similar between treatment groups.

Table 15: Cancer Outcomes in ORIGIN – Time to First Event Analyses Another Insulin Glargine Product, 100 units/mL N=6264 Standard Care N=6273 Another Insulin Glargine Product, 100 units/mL vs.

Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 (1.56) 561 (1.56) 0.99 (0.88, 1.11) New cancer events 524 (1.46) 535 (1.49) 0.96 (0.85, 1.09) Death due to Cancer 189 (0.51) 201 (0.54) 0.94 (0.77, 1.15)

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied BASAGLAR (insulin glargine) injection is a clear, colorless solution, 100 units/mL (U-100), available as: a Tempo Pen contains a component that allows for data connectivity when used with a compatible transmitter.

BASAGLAR Total Volume NDC Number Package Size BASAGLAR single-patient-use KwikPen 3 mL 0002-7715-59 5 pens BASAGLAR single-patient-use Tempo Pen a 3 mL 0002-8214-05 5 pens The BASAGLAR KwikPen and Tempo Pen dial in 1 unit increments.

Needles are not included.

This device is recommended for use with Becton, Dickinson & Company’s insulin pen needles which are sold separately.

16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use.

Protect BASAGLAR from heat and light.

Do not freeze BASAGLAR.

In-use BASAGLAR prefilled pens must be used within 28 days or be discarded, even if they still contain BASAGLAR.

Storage conditions are summarized in the following table: Not In-Use (Unopened) Room Temperature (up to 86°F [30°C]) Not In-Use (Unopened) Refrigerated (36°F to 46°F [2°C to 8°C]) In-Use (Opened) Room Temperature, (up to 86°F [30°C]) 3 mL single-patient-use BASAGLAR KwikPen 28 days Until expiration date 28 days, Do not refrigerate.

3 mL single-patient-use BASAGAR Tempo Pen 28 days Until expiration date 28 days, Do not refrigerate.

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in clinical studies of patients with type 2 diabetes who were treated with BASAGLAR or another insulin glargine product, 100 units/mL, each in combination with oral agents in a controlled clinical trial environment, 28.3% were 65 and over, while 4.5% were 75 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.

Nevertheless, caution should be exercised when BASAGLAR is administered to geriatric patients.

In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions.

Hypoglycemia may be difficult to recognize in the elderly.

DOSAGE FORMS AND STRENGTHS

3 Injection: 100 units/mL (U-100) clear and colorless solution available as: 3 mL single-patient-use BASAGLAR KwikPen 3 mL single-patient-use BASAGLAR Tempo Pen Injection: 100 units/mL (U-100) is available as: ( 3 ) 3 mL single-patient-use BASAGLAR KwikPen ® 3 mL single-patient-use BASAGLAR Tempo Pen TM

MECHANISM OF ACTION

12.1 Mechanism of Action The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism.

Insulin and its analog lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production.

Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

INDICATIONS AND USAGE

1 BASAGLAR ® is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.

BASAGLAR ® is a long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.

( 1 ) Limitations of Use : Not recommended for treating diabetic ketoacidosis.

( 1 ) Limitations of Use BASAGLAR is not recommended for the treatment of diabetic ketoacidosis.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of BASAGLAR have been established in pediatric patients (age 6 to 15 years) with type 1 diabetes based on an adequate and well-controlled trial of another insulin glargine product, 100 units/mL, in pediatric patients (age 6 to 15 years) with type 1 diabetes and additional data in adults with type 1 diabetes [see Clinical Studies ( 14.2 )] .

The safety and effectiveness of BASAGLAR in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes has not been established.

In the pediatric clinical trial, pediatric patients (age 6 to 15 years) with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes [see Adverse Reactions ( 6.1 )] .

PREGNANCY

8.1 Pregnancy Risk Summary Published studies with use of insulin glargine products during pregnancy have not reported a clear association with insulin glargine products and adverse developmental outcomes (see Data).

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

In animal reproduction studies, another insulin glargine product was administered to rats before, during and throughout pregnancy at doses up to 7 times the clinical dose of 10 units/day and to rabbits during organogenesis at doses approximately 2 times the clinical dose of 10 units/day.

The effects of this other insulin glargine product did not generally differ from those observed with regular human insulin in rats or rabbits (see Data).

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

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

In the US 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 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 do not report a clear association with insulin glargine products and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine products are used during pregnancy.

However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some with no comparative group.

Animal Data Subcutaneous reproduction and teratology studies have been performed with another insulin glargine product and with regular human insulin in rats and Himalayan rabbits.

This other insulin glargine product was given to female rats before mating, during mating, and throughout pregnancy at dose up to 0.36 mg/kg/day, which is approximately 7 times the recommended human subcutaneous starting dose of 10 units/day (0.008 mg/kg/day) based on mg/m 2 .

In rabbits, doses of 0.072 mg/kg/day, which is approximately 2 times the recommended human subcutaneous starting dose of 10 units/day (0.008 mg/kg/day), based on mg/m 2 , were administered during organogenesis.

The effects of this other insulin glargine product did not generally differ from those observed with regular human insulin in rats and rabbits.

However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles.

Fertility and early embryonic development appeared normal.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Never share a BASAGLAR prefilled pen between patients, even if the needle is changed.

( 5.1 ) Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring.

( 5.2 ) Hypoglycemia: May be life-threatening.

Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness.

( 5.3 , 6.1 ) Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur.

Instruct patients to check insulin labels before injection.

( 5.4 ) Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur.

Discontinue BASAGLAR, monitor and treat if indicated.

( 5.5 , 6.1 ) Hypokalemia: May be life-threatening.

Monitor potassium levels in patients at risk of hypokalemia and treat if indicated.

( 5.6 ) Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs.

( 5.7 ) 5.1 Never Share a BASAGLAR Prefilled Pen Between Patients BASAGLAR prefilled pens must never be shared between patients, even if the needle is changed.

Sharing poses a risk for transmission of blood-borne pathogens.

5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia.

Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6 )] .

Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring.

Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia.

For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulins, including BASAGLAR [see Adverse Reactions ( 6.1 )] .

Severe hypoglycemia can cause seizures, may be life-threatening or cause death.

Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

BASAGLAR, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications ( 4 )] .

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.

Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or in patients who experience recurrent hypoglycemia.

Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal.

As with all insulins, the glucose lowering effect time course of BASAGLAR may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology ( 12.2 )] .

The risk of hypoglycemia generally increases with intensity of glycemic control.

Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions ( 7 )] .

Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] .

Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia.

Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia.

In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

The long-acting effect of BASAGLAR may delay recovery from hypoglycemia.

5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported.

To avoid medication errors between BASAGLAR and other insulins, instruct patients to always check the insulin label before each injection.

5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including BASAGLAR.

If hypersensitivity reactions occur, discontinue BASAGLAR; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions ( 6.1 )] .

BASAGLAR is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients [see Contraindications ( 4 )] .

5.6 Hypokalemia All insulins, including BASAGLAR, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia.

Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.

Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin.

Fluid retention may lead to or exacerbate heart failure.

Patients treated with insulin, including BASAGLAR, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure.

If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use).

Never Share a BASAGLAR Prefilled Pen Between Patients Advise patients that they must never share a BASAGLAR prefilled pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )] .

Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin.

Inform patients of the symptoms of hypoglycemia.

Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia.

This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )] .

Medication errors Inform patients to always check the insulin label before each injection [see Warnings and Precautions ( 5.4 )].

Literature revised July 2021 Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 Copyright © 2015, 2021, Eli Lilly and Company.

All rights reserved.

BAS-0007-USPI-20210727

DOSAGE AND ADMINISTRATION

2 Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, prior insulin use.

( 2.2 , 2.3 , 2.4 ) Administer subcutaneously once daily at any time of day, but at the same time every day.

( 2.2 ) Rotate injection sites into the abdominal area, thigh, or deltoid to reduce the risk of lipodystrophy and localized cutaneous amyloidosis.

( 2.1 ) Closely monitor glucose when converting to BASAGLAR and during initial weeks thereafter.

( 2.2 ) Do not dilute or mix with any other insulin or solution.

( 2.1 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] .

Visually inspect BASAGLAR prefilled pens for particulate matter and discoloration prior to administration.

Only use if the solution is clear and colorless with no visible particles.

Administer BASAGLAR subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis.

Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6 )] .

During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] .

Use BASAGLAR with caution in patients with visual impairment that may rely on audible clicks to dial their dose.

Do not dilute or mix BASAGLAR with any other insulin or solution.

Do not administer intravenously or via an insulin pump.

2.2 General Dosing Instructions In patients with type 1 diabetes, BASAGLAR must be used concomitantly with short-acting insulin.

Inject BASAGLAR subcutaneously once daily at any time of day but at the same time every day.

Individualize and adjust the dosage of BASAGLAR based on the individual’s metabolic needs, blood glucose monitoring results and glycemic control goal.

Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function.

Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions ( 5.2 )] .

The BASAGLAR prefilled pens each dials in 1 unit increments and delivers a maximum dose of 80 units per injection.

2.3 Initiation of BASAGLAR Therapy The recommended starting dose of BASAGLAR in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements.

Short- or rapid-acting, pre-meal insulin should be used to satisfy the remainder of the daily insulin requirements.

The recommended starting dose of BASAGLAR in patients with type 2 diabetes is 0.2 units/kg or up to 10 units once daily.

2.4 Changing to BASAGLAR from Other Insulin Therapies If changing patients from another insulin glargine product, 100 units/mL, to BASAGLAR, the dose of BASAGLAR should be the same as the other insulin glargine product, 100 units/mL.

If changing patients from a once-daily insulin glargine product, 300 units/mL, to once-daily BASAGLAR, the recommended initial BASAGLAR dosage is 80% of the insulin glargine product, 300 units/mL [see Warnings and Precautions ( 5.2 )] .

If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with BASAGLAR, a change in the dose of the basal insulin may be required.

If changing patients from twice-daily NPH insulin to once-daily BASAGLAR, the recommended initial BASAGLAR dosage is 80% of the total daily NPH dosage [see Warnings and Precautions ( 5.2 )] .

Lysol Touch of Foam 0.1 G per 100 ML Medicated Liquid Soap

WARNINGS

Warnings For external use only When using this product Avoid contact with eyes.

In case of eye contact, flush with water.

Stop use and ask a doctor if irritation or redness develops.

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Uses for handwashing to decrease bacteria on the skin

INACTIVE INGREDIENTS

Inactive Ingredients Water, Glycerin, Lauramine Oxide, PEG-150 Distearate, Cetrimonium Chloride, Propylene Glycol, Fragrance, Citric Acid, Tetrasodium EDTA, Cocamide MEA, Methylchloroisothiazolinone, Methylisothiazolinone, D&C Green No.

5, D&C Red No.

33.

PURPOSE

Purpose Antibacterial

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

DOSAGE AND ADMINISTRATION

Directions Apply product to hands.

Wash hands.

Rinse hands with water.

STOP USE

Stop use and ask a doctor if irritation or redness develops.

ACTIVE INGREDIENTS

Active Ingredient Benzalkonium Chloride 0.10%

tiZANidine HCl 6 MG Oral Capsule

DRUG INTERACTIONS

7 7.1 Fluvoxamine Concomitant use of fluvoxamine and tizanidine is contraindicated.

Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ].

7.2 Ciprofloxacin Concomitant use of ciprofloxacin and tizanidine is contraindicated.

Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ] .

7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided.

If their use is clinically necessary, therapy should be initiated with 2 mg (base) dose and increased in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy.

If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ] .

7.4 Oral Contraceptives Concomitant use of tizanidine with oral contraceptives is not recommended.

However, if concomitant use is clinically necessary, initiate tizanidine with a single 2 mg (base) dose and increase in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy.

If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy [see Clinical Pharmacology (12.3) ] .

7.5 Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine.

This was associated with an increase in adverse reactions of tizanidine.

The CNS depressant effects of tizanidine and alcohol are additive [see Clinical Pharmacology (12.3) ] .

7.6 Other CNS Depressants The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive.

Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3) ] .

7.7 α 2 -adrenergic Agonists Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with other α 2 -adrenergic agonists [see Warnings and Precautions (5.1) ] .

OVERDOSAGE

10 A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose.

Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants.

The clinical manifestations of tizanidine overdose were consistent with its known pharmacology.

In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma.

Depressed cardiac function is also observed including most often bradycardia and hypotension.

Respiratory depression is another common feature of tizanidine overdose.

Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken.

Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol.

Therefore, dialysis is not likely to be an efficient method of removing drug from the body.

In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy.

Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose.

For the most recent information concerning the management of overdose, contact a poison control center.

DESCRIPTION

11 Tizanidine hydrochloride capsules are a central alpha 2 -adrenergic agonist.

Tizanidine hydrochloride, USP is an almost white to slightly yellow crystalline powder, which is odorless or with a faint characteristic odor.

Tizanidine is slightly soluble in water and methanol; solubility in water decreases as the pH increases.

Its chemical name is 5-Chloro- N -(4,5-dihydro-1 H -imidazol-2yl)-2,1,3-benzothiadiazol-4-amine hydrochloride.

Tizanidine’s molecular formula is C 9 H 8 ClN 5 S•HCl, its molecular weight is 290.2 and its structural formula is: Tizanidine hydrochloride capsules are supplied as 2 mg, 4 mg, and 6 mg capsules for oral administration.

Tizanidine hydrochloride capsules contain the active ingredient, tizanidine hydrochloride, USP (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, hypromellose, microcrystalline cellulose and talc.

In addition, each of the empty hard gelatin capsules contain the following: gelatin, red iron oxide, titanium dioxide and yellow iron oxide.

The imprinting ink contains the following: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

Tizanidine Hydrochloride Structural Formula

CLINICAL STUDIES

14 Tizanidine’s capacity to reduce increased muscle tone associated with spasticity was demonstrated in two adequate and well controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2).

Single-dose Study in Patients with Multiple Sclerosis with Spasticity: In Study 1, patients with multiple sclerosis were randomized to receive single oral doses of drug or placebo.

Patients and assessors were blind to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects).

In all, 140 patients received placebo, 8 mg (base) or 16 mg (base) of tizanidine.

Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone.

A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance.

A score of 3 was used to describe considerable increase in tone, making passive movement difficult.

A muscle immobilized by spasticity was given a score of 4.

Spasm counts were also collected.

Assessments were made at 1, 2, 3 and 6 hours after treatment.

A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment.

Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.

The greatest reduction in muscle tone was 1 to 2 hours after treatment.

By 6 hours after treatment, muscle tone in the 8 mg (base) and 16 mg (base) tizanidine groups was indistinguishable from muscle tone in placebo treated patients.

Within a given patient, improvement in muscle tone was correlated with plasma concentration.

Plasma concentrations were variable from patient to patient at a given dose.

Although 16 mg (base) produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg (base) group.

There were no differences in the number of spasms occurring in each group.

Figure 2: Single Dose Study – Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Seven-Week Study in Patients with Spinal Cord Injury with Spasticity: In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine.

Steps similar to those taken in the first study were employed to ensure the integrity of blinding.

Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg (base) daily given in three unequal doses (e.g., 10 mg (base) given in the morning and afternoon and 16 mg (base) given at night).

Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase).

Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose.

The number of daytime spasms was recorded daily by patients.

At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo.

The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living.

Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.

Figure 3: Seven Week Study – Mean Change in Muscle Tone 0.5 to 2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Figure 2: Single Dose Study – Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Figure 3: Seven Week Study – Mean Change in Muscle Tone 0.5 to 2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline)

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 Tizanidine Hydrochloride Capsules Tizanidine Hydrochloride Capsules are available containing tizanidine hydrochloride, USP equivalent to 2 mg, 4 mg, or 6 mg of tizanidine base.

The 2 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and an orange opaque body filled with light yellow to yellow granular powder.

The capsule is axially printed with MYLAN over TE 2 in black ink on both the cap and the body.

They are available as follows: NDC 0378-1665-19 bottles of 150 capsules The 4 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a white opaque body filled with light yellow to yellow granular powder.

The capsule is axially printed with MYLAN over TE 4 in black ink on both the cap and the body.

They are available as follows: NDC 0378-1666-19 bottles of 150 capsules The 6 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a peach opaque body filled with light yellow to yellow granular powder.

The capsule is axially printed with MYLAN over TE 6 in black ink on both the cap and the body.

They are available as follows: NDC 0378-1667-19 bottles of 150 capsules Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

GERIATRIC USE

8.5 Geriatric Use Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Clinical studies of tizanidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects.

Cross-study comparison of pharmacokinetic data following single dose administration of 6 mg (base) tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects.

In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect.

During titration, the individual doses should be reduced.

If higher doses are required, individual doses rather than dosing frequency should be increased.

Monitor elderly patients because they may have an increased risk for adverse reactions associated with tizanidine.

DOSAGE FORMS AND STRENGTHS

3 Tizanidine Hydrochloride Capsules are available containing tizanidine hydrochloride, USP equivalent to 2 mg, 4 mg, or 6 mg of tizanidine base.

Capsules: • 2 mg: A hard-shell gelatin capsule with an orange opaque cap and an orange opaque body filled with light yellow to yellow granular powder.

The capsule is axially printed with MYLAN over TE 2 in black ink on both the cap and the body.

• 4 mg: A hard-shell gelatin capsule with an orange opaque cap and a white opaque body filled with light yellow to yellow granular powder.

The capsule is axially printed with MYLAN over TE 4 in black ink on both the cap and the body.

• 6 mg: A hard-shell gelatin capsule with an orange opaque cap and a peach opaque body filled with light yellow to yellow granular powder.

The capsule is axially printed with MYLAN over TE 6 in black ink on both the cap and the body.

• Capsules: 2 mg, 4 mg or 6 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons.

The effects of tizanidine are greatest on polysynaptic pathways.

The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.

INDICATIONS AND USAGE

1 Tizanidine hydrochloride capsules are a central alpha-2-adrenergic agonist indicated for the management of spasticity.

Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important [see Dosage and Administration (2.1) ] .

Tizanidine hydrochloride capsules are a central alpha-2-adrenergic agonist indicated for the management of spasticity.

Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important.

( 1 )

PEDIATRIC USE

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

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy Category C Tizanidine has not been studied in pregnant women.

Tizanidine should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus.

Reproduction studies performed in rats at a dose of 3 mg (base)/kg, equal to the maximum recommended human dose on a mg/m 2 basis, and in rabbits at 30 mg (base)/kg, 16 times the maximum recommended human dose on a mg/m 2 basis, did not show evidence of teratogenicity.

Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m 2 basis increased gestation duration in rats.

Prenatal and postnatal pup loss was increased and developmental retardation occurred.

Post-implantation loss was increased in rabbits at doses of 1 mg (base)/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m 2 basis.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when tizanidine is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; tizanidine should not be used with other α 2 -adrenergic agonists ( 5.1 , 7.7 ) • Risk of liver injury: monitor ALTs; discontinue tizanidine if liver injury occurs ( 5.2 ) • Sedation: Tizanidine may interfere with everyday activities; sedative effects of tizanidine, alcohol, and other CNS depressants are additive ( 5.3 , 7.5 , 7.6 ) • Hallucinations: consider discontinuation of tizanidine ( 5.4 ) • Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics, cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ( 5.5 , 7.3 , 12.3 ) • Renal impairment (creatinine clearance < 25 mL/min): use tizanidine with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose ( 5.7 ) 5.1 Hypotension Tizanidine is an α 2 -adrenergic agonist that can produce hypotension.

Syncope has been reported in the post-marketing setting.

The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement.

In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects.

Monitor for hypotension when tizanidine is used in patients receiving concurrent antihypertensive therapy.

It is not recommended that tizanidine be used with other α 2 -adrenergic agonists.

Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg (base) of tizanidine.

Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [see Contraindications (4) and Drug Interactions (7.1 , 7.2) ] .

5.2 Risk of Liver Injury Tizanidine may cause hepatocellular liver injury.

Tizanidine should be used with caution in patients with any hepatic impairment.

Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.3) and Use in Specific Populations (8.7) ] .

5.3 Sedation Tizanidine can cause sedation, which may interfere with everyday activity.

In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study.

The CNS depressant effects of tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive.

Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation [see Drug Interactions (7.5 , 7.6) ] .

5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine use has been associated with hallucinations.

Formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies.

Most of the patients were aware that the events were unreal.

One patient developed psychosis in association with the hallucinations.

One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine.

Consider discontinuing tizanidine in patients who develop hallucinations.

5.5 Interaction with CYP1A2 Inhibitors Because of potential drug interactions, tizanidine is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin.

Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when tizanidine is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine).

Concomitant use should be avoided unless the necessity for tizanidine therapy is clinically evident.

In such a case, use with caution [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] .

5.6 Hypersensitivity Reactions Tizanidine can cause anaphylaxis.

Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported.

Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue tizanidine and seek immediate medical care should these signs and symptoms occur [see Contraindications (4) ] .

5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment Tizanidine should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%.

In these patients, during titration, the individual doses should be reduced.

If higher doses are required, individual doses rather than dosing frequency should be increased.

These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ] .

5.8 Withdrawal Adverse Reactions Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia.

To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 mg (base) to 28 mg (base) daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg (base) to 4 mg (base) per day) [see Dosage and Administration (2.2) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Serious Drug Interactions: Advise patients they should not take tizanidine hydrochloride capsules if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation.

Instruct patients to inform their physicians or pharmacists when they start or stop taking any medication because of the risks associated with interaction between tizanidine hydrochloride capsules and other medicines.

Tizanidine Hydrochloride Capsules Dosing: Tell patients to take tizanidine hydrochloride capsules exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules.

Inform patients that they should not take more tizanidine hydrochloride capsules than prescribed because of the risk of adverse events at single doses greater than 8 mg (base) or total daily doses greater than 36 mg (base).

Tell patients that they should not suddenly discontinue tizanidine hydrochloride capsules, because rebound hypertension and tachycardia may occur.

Effects of Tizanidine Hydrochloride Capsules: Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position.

Tell patients that tizanidine hydrochloride capsules may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery.

Tell patients that the sedation may be additive when tizanidine hydrochloride capsules are taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants.

Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that tizanidine hydrochloride capsules decrease spasticity and caution should be used.

Manufactured for: Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Manufactured by: Mylan Laboratories Limited Hyderabad — 500 034, India Code No.: MH/DRUGS/25/NKD/89 75059379 Revised: 8/2016 MX:TZNDC:R4

DOSAGE AND ADMINISTRATION

2 • Recommended starting dose: 2 mg (base); dose can be repeated at 6 to 8 hour intervals, up to a maximum of 3 doses in 24 hours ( 2.1 ) • Dosage can be increased by 2 mg (base) to 4 mg (base) per dose, with 1 to 4 days between increases; total daily dose should not exceed 36 mg (base) ( 2.1 ) • Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food.

These differences could result in a change in tolerability and control of symptoms ( 2.1 , 12.3 ) • To discontinue tizanidine hydrochloride capsules, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia ( 2.2 ) 2.1 Dosing Information Tizanidine hydrochloride capsules may be prescribed with or without food.

Once the formulation has been selected and the decision to take with or without food has been made, this regimen should not be altered.

Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations.

Tizanidine hydrochloride capsules and tizanidine tablets are bioequivalent to each other under fasting conditions (more than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal).

These pharmacokinetic differences may result in clinically significant differences when switching administration of tablet and capsules and when switching administration between the fed or fasted state.

These changes may result in increased adverse events, or delayed or more rapid onset of activity, depending upon the nature of the switch.

For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions [see Clinical Pharmacology (12.3) ].

The recommended starting dose is 2 mg (base).

Because the effect of tizanidine hydrochloride capsules peaks at approximately 1 to 2 hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours.

Dosage can be gradually increased by 2 mg (base) to 4 mg (base) at each dose, with 1 to 4 days between dosage increases, until a satisfactory reduction of muscle tone is achieved.

The total daily dose should not exceed 36 mg (base).

Single doses greater than 16 mg (base) have not been studied.

2.2 Dosing in Patients with Renal Impairment Tizanidine hydrochloride capsules should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%.

In these patients, during titration, the individual doses should be reduced.

If higher doses are required, individual doses rather than dosing frequency should be increased [see Warnings and Precautions (5.7) ] .

2.3 Dosing in Patients with Hepatic Impairment Tizanidine hydrochloride capsules should be used with caution in patients with any hepatic impairment.

In these patients, during titration, the individual doses should be reduced.

If higher doses are required, individual doses rather than dosing frequency should be increased.

Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Use in Specific Populations (8.7) ] .

2.4 Drug Discontinuation If therapy needs to be discontinued, particularly in patients who have been receiving high doses (20 mg (base) to 36 mg (base) daily) for long periods (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg (base) to 4 mg (base) per day) to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia [see Drug Abuse and Dependence (9.3) ].

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

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

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