Author: druginteractionchecker_lgaiz4

Terazosin 5 MG Oral Capsule

WARNINGS

Syncope and “First-dose” Effect Terazosin capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy.

A similar effect can be anticipated if therapy is interrupted for several days and then restarted.

Syncope has also been reported with other alpha-adrenergic blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug.

Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120 to 160 beats per minute.

Additionally, the possibility of the contribution of hemodilution to the symptoms of postural hypotension should be considered.

To decrease the likelihood of syncope or excessive hypotension, treatment should always be initiated with a 1 mg dose of terazosin capsules, given at bedtime.

The 2 mg, 5 mg and 10 mg capsules are not indicated as initial therapy.

Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution.

The patient should be cautioned to avoid situations, such as driving or hazardous tasks, where injury could result should syncope occur during initiation of therapy.

In early investigational studies, where increasing single doses up to 7.5 mg were given at 3 day intervals, tolerance to the first dose phenomenon did not necessarily develop and the “first-dose” effect could be observed at all doses.

Syncopal episodes occurred in 3 of the 14 subjects given terazosin at doses of 2.5, 5 and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) was seen in two others and dizziness, tachycardia, and lightheadedness occurred in most subjects.

These adverse effects all occurred within 90 minutes of dosing.

In three placebo-controlled BPH studies 1, 2, and 3 (see CLINICAL PHARMACOLOGY ), the incidence of postural hypotension in the terazosin treated patients was 5.1%, 5.2%, and 3.7% respectively.

In multiple dose clinical trials involving nearly 2000 hypertensive patients treated with terazosin capsules, syncope was reported in about 1% of patients.

Syncope was not necessarily associated only with the first dose.

If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.

There is evidence that the orthostatic effect of terazosin is greater, even in chronic use, shortly after dosing.

The risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals.

Priapism Rarely, (probably less than once in every several thousand patients), terazosin and other α 1-antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation).

Two or three dozen cases have been reported.

Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS: Information for Patients ).

DRUG INTERACTIONS

Drug Interactions In controlled trials, terazosin have been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed.

Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed.

Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes: analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin); antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole); anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride); antigout (e.g., allopurinol); antihistamines (e.g., chlorpheniramine); cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol); corticosteroids; gastrointestinal agents (e.g., antacids); hypoglycemics; sedatives and tranquilizers (e.g., diazepam).

OVERDOSAGE

Should overdosage of terazosin capsules lead to hypotension, support of the cardiovascular system is of first importance.

Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position.

If this measure is inadequate, shock should first be treated with volume expanders.

If necessary, vasopressors should then be used and renal function should be monitored and supported as needed.

Laboratory data indicate that terazosin is 90-94% protein bound; therefore, dialysis may not be of benefit.

DESCRIPTION

Terazosin hydrochloride, an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following chemical name,molecular formula and structural formula: (RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl]-, monohydrochloride.C 19H 26ClN 5O 4 Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has a molecular weight of 423.93.

Each capsule, for oral administration, contains 1 mg, 2 mg, 5 mg or 10 mg of terazosin as terazosin hydrochlolde.

In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and pregelatinized starch.

The gelatin capsule contains gelatin, silicon dioxide, sodium lauryl sulfate, and titanium dioxide.

The 1 mg shell also contains black iron oxide; the 2 mg capsule shell also contains D&C Yellow #10; the 5 mg capsule shell also contains D&C Yellow #10, FD&C Red #40 and D&C Red #28; the 10 mg capsule shell also contains FD&C Green #3 and D&C Yellow#10.

HOW SUPPLIED

Terazosin Capsules are available in four dosage strengths: 1 mg Terazosin Capsules, USP are available as gray opaque cap/body printed “TL 383” in black ink.

Bottles of 90: NDC 59746-383-90 Bottles of 100: NDC 59746-383-06 Bottles of 500: NDC 59746-383-09 Bottles of 1000: NDC 59746-383-10 2 mg Terazosin Capsules, USP are available as ivory opaque cap/body printed “TL 384” in black ink.

Bottles of 90: NDC 59746-384-90 Bottles of 100: NDC 59746-384-06 Bottles of 500: NDC 59746-384-09 Bottles of 1000: NDC 59746-384-10 5 mg Terazosin Capsules, USP are available as bright orange opaque cap/body printed “TL 385” in black ink.

Bottles of 90: NDC 59746-385-90 Bottles of 100: NDC 59746-385-06 Bottles of 500: NDC 59746-385-09 Bottles of 1000: NDC 59746-385-10 10 mg Terazosin Capsules, USP are available as light green opaque cap/body printed “TL 386” in black ink.

Bottles of 90: NDC 59746-386-90 Bottles of 100: NDC 59746-386-06 Bottles of 500: NDC 59746-386-09 Bottles of 1000: NDC 59746-386-10 Dispense in a tight, light-resistant container as defined in the USP.

Recommended storage: Store at 20° – 25°C (68° – 77°F) [see USP Controlled Room Temperature].

Protect from light and moisture.

Rx only Revised 08/12 Jubilant Cadista Pharmaceuticals Inc.

Salisbury, MD 21801, USA For additional copies of the printed patient information/medication guide, please visit www.cadista.com or call 1-800-313-4623.

INDICATIONS AND USAGE

Terazosin capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH).

There is a rapid response, with approximately 70% of patients experiencing an increase in urinary flow and improvement in symptoms of BPH when treated with terazosin capsules.

The long-term effects of terazosin capsules on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined.

Terazosin capsules are also indicated for the treatment of hypertension.

Terazosin capsules can be used alone or in combination with other antihypertensive agents such as diuretics or beta-adrenergic blocking agents.

PEDIATRIC USE

Pediatric Use : Safety and effectiveness in pediatric patients have not been determined.

PREGNANCY

Pregnancy Teratogenic Effects : Pregnancy Category C Terazosin capsules were not teratogenic in either rats or rabbits when administered at oral doses up to 280 and 60 times, respectively, the maximum recommended human dose.

Fetal resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum recommended human dose.

Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose.

These findings (in both species) were most likely secondary to maternal toxicity.

There are no adequate and well-controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established.

Terazosin capsules are not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus.

Nonteratogenic Effects : In a peri- and post-natal development study in rats, significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended human dose) than in the control group during the three-week postpartum period.

NUSRING MOTHERS

Nursing Mothers : It is not known whether terazosin is excreted in breast milk.

Because many drugs are excreted in breast milk, caution should be exercised when terazosin capsules are administered to a nursing woman.

INFORMATION FOR PATIENTS

Information for Patients (see Patient Package Insert) Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and to avoid driving or hazardous tasks for 12 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed.

They should be cautioned to avoid situations where injury could result should syncope occur during initiation of terazosin therapy.

They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position.

If dizziness, lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered.

Patients should also be told that drowsiness or somnolence can occur with terazosin, requiring caution in people who must drive or operate heavy machinery.

Patients should be advised about the possibility of priapism as a result of treatment with terazosin capsules and other similar medications.

Patients should know that this reaction to terazosin capsules is extremely rare, but that if it is not brought to immediate medical attention, it can lead to permanent erectile dysfunction (impotence).

DOSAGE AND ADMINISTRATION

If terazosin capsules administration is discontinued for several days, therapy should be reinstituted using the initial dosing regimen.

Benign Prostatic Hyperplasia Initial Dose : 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded as an initial dose.

Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response.

Subsequent Doses : The dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates.

Doses of 10 mg once daily are generally required for the clinical response.

Therefore, treatment with 10 mg for a minimum of 4 to 6 weeks may be required to assess whether a beneficial response has been achieved.

Some patients may not achieve a clinical response despite appropriate titration.

Although some additional patients responded at a 20 mg daily dose, there was an insufficient number of patients studied to draw definitive conclusions about this dose.

There are insufficient data to support the use of higher doses for those patients who show inadequate or no response to 20 mg daily.

If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen.

Use With Other Drugs : Caution should be observed when terazosin capsules are administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension.

When using terazosin capsules and other antihypertensive agents concomitantly, dosage reduction and retitration of either agent may be necessary (see PRECAUTIONS ).

Hypotension has been reported when terazosin capsules have been used with phosphodiesterase-5 (PDE-5) inhibitors.

Hypertension The dose of terazosin capsules and the dose interval (12 or 24 hours) should be adjusted according to the patient’s individual blood pressure response.

The following is a guide to its administration: Initial Dose 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded.

This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects.

Subsequent Doses The dose may be slowly increased to achieve the desired blood pressure response.

The usual recommended dose range is 1 mg to 5 mg administered once a day; however, some patients may benefit from doses as high as 20 mg per day.

Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied.

Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval.

It may also be helpful to measure blood pressure 2 to 3 hours after dosing to see if the maximum and minimum responses are similar, and to evaluate symptoms such as dizziness or palpitations which can result from excessive hypotensive response.

If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered.

If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen.

In clinical trials, except for the initial dose, the dose was given in the morning.

Use With Other Drugs (See above.)

guaifenesin 100 MG per 5 ML Oral Solution

Generic Name: GUAIFENESIN
Brand Name: Broncomar SF
  • Substance Name(s):
  • GUAIFENESIN

WARNINGS

Warnings Do not exceed recommended dosage

INDICATIONS AND USAGE

Uses Help loosen phlegm (mucus) and thin bronchial secretions to drain bronchial tubes and make cough more productive.

INACTIVE INGREDIENTS

Inactive ingredients Blue cohosh, citric acid, echinacea, eucalyptus oil, ginkgo biloba, glycerin, gold seal root, honey flavor, horehound herb, licorice root, menthol, mullein, myrrh, potassium sorbate, slippery elm bark, sodium benzoate, propylene glycol, water, sodium chloride, sucralose, wild cherry bark and zinc sulfate.

PURPOSE

Purpose Expectorant

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.

DOSAGE AND ADMINISTRATION

Directions Do not take more than 6 doses in any 24-hour period Shake well before use Age Dose Adults and children 12 years and over 10 mL (2 tsps) every 4 hours Children 6 to under 12 years of age.

5 mL (1 tsps) every 4 hours Children under 6 years of age Do not use

PREGNANCY AND BREAST FEEDING

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

DO NOT USE

Do not use if you have a chronic pulmonary disease or shortness of breath unless directed by a doctor Ask the doctor before use if you have cough that occurs with too much phlegm (mucus) cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis or emphysema

STOP USE

Stop use and ask the doctor if Nervoisness, dizziness or sleeplessness occurs.

Cough persists for more than 1 week, tends to recur, or accompanied by fever, rash or persistent headache.

A persistent cough may be sign of a serious condition

ACTIVE INGREDIENTS

Acvtive ingredients: (in each 5ml) Purpose Guaifenesin 100 mg ……………………………..

Expectorant

diphenhydrAMINE HCl 25 MG Oral Tablet

Generic Name: DIPHENHYDRAMINE HCL
Brand Name: Allergy Antihistamine
  • Substance Name(s):
  • DIPHENHYDRAMINE HYDROCHLORIDE

WARNINGS

Warnings Do not use with any other product containing diphenhydramine, even one used on skin Ask a doctor before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma difficulty in urination due to an enlargement of the prostate gland Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives.

When using this product excitability may occur especially in children drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness use caution when operating machinery or driving a motor vehicle If pregnant of breast-feeding, ask a health professional before use.

Keep out of reach of children.

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

INDICATIONS AND USAGE

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

INACTIVE INGREDIENTS

Inactive ingredients carnauba wax, colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Aluminum Lake, dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol (PEG) 400, polysorbate 80 and titanium dioxide May also contain: polyvinyl alcohol and talc.

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 a breathing problem such as emphysema or chronic bronchitis glaucoma difficulty in urination due to an enlargement of the prostate gland

OTHER SAFETY INFORMATION

Other information each tablet contains: calcium 25 mg/ tablet store at room temperature 15°-30°C (59°-86°F) protect from light and moisture

DOSAGE AND ADMINISTRATION

Directions take every 4 to 6 hours, not more than 6 doses in 24 hours adults and children 12 years of age and over take 1 or 2 tablets children 6 to under 12 years of age take 1 tablet children under 6 years of age consult a doctor children under 4 years of age do not use

PREGNANCY AND BREAST FEEDING

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

DO NOT USE

Do not use with any other product containing diphenhydramine, even one used on skin

ACTIVE INGREDIENTS

Active ingredient (in each tablet) Diphenhydramine HCl 25 mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives.

Xarelto 30-Day Starter Pack Kit

Generic Name: RIVAROXABAN
Brand Name: Xarelto
  • Substance Name(s):
  • RIVAROXABAN

DRUG INTERACTIONS

7 Combined P-gp and strong CYP3A4 inhibitors and inducers: Avoid concomitant use (7.2, 7.3) Anticoagulants: Avoid concomitant use (7.4) 7.1 General Inhibition and Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters.

Combined P-gp and strong CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding.

Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

7.2 Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A4 Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3)].

Interaction with Combined P-gp and Moderate CYP3A4 Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

7.3 Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St.

John’s wort) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

7.4 Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3)].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)].

OVERDOSAGE

10 Overdose of XARELTO may lead to hemorrhage.

Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered.

Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.

DESCRIPTION

11 Rivaroxaban, a FXa inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.

The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89.

The structural formula is: Rivaroxaban is a pure (S)-enantiomer.

It is an odorless, non-hygroscopic, white to yellowish powder.

Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban.

The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

Additionally, the proprietary film coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

Chemical Structure

CLINICAL STUDIES

14 14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation The evidence for the efficacy and safety of XARELTO was derived from ROCKET AF, a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF).

Patients had to have one or more of the following additional risk factors for stroke: a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non‑CNS systemic embolism, or 2 or more of the following risk factors: age ≥75 years, hypertension, heart failure or left ventricular ejection fraction ≤35%, or diabetes mellitus ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin’s effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.

A total of 14264 patients were randomized and followed on study treatment for a median of 590 days.

The mean age was 71 years and the mean CHADS2 score was 3.5.

The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black.

There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening.

Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%.

At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel.

Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%).

Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.

In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated.

There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled.

Table 8 displays the overall results for the primary composite endpoint and its components.

Table 8: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population) XARELTO Warfarin XARELTO vs.

Warfarin Event N=7081 n (%) Event Rate (per 100 Pt-yrs) N=7090 n (%) Event Rate (per 100 Pt-yrs) Hazard Ratio (95% CI) Primary Composite EndpointThe primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic embolism.

Data are shown for all randomized patients followed to site notification that the study would end.

269 (3.8) 2.1 306 (4.3) 2.4 0.88 (0.74, 1.03) Stroke 253 (3.6) 2.0 281 (4.0) 2.2 Hemorrhagic StrokeDefined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification 33 (0.5) 0.3 57 (0.8) 0.4 Ischemic Stroke 206 (2.9) 1.6 208 (2.9) 1.6 Unknown Stroke Type 19 (0.3) 0.2 18 (0.3) 0.1 Non-CNS Systemic Embolism 20 (0.3) 0.2 27 (0.4) 0.2 Figure 4 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.

Figure 4: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population) Figure 5 shows the risk of stroke or non-CNS systemic embolism across major subgroups.

Figure 5: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AFData are shown for all randomized patients followed to site notification that the study would end.

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score).

The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.

Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

(Intent-to-Treat Population) The efficacy of XARELTO was generally consistent across major subgroups.

The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin.

XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR.

During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs.

6 in the 4691 patients taking warfarin.

Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation.

The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.

Figure 4 Figure 5 14.2 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies XARELTO for the treatment of DVT and/or PE and for the reduction in the risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached.

Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies.

The intended treatment duration was 3, 6, or 12 months based on investigator’s assessment prior to randomization.

A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group.

The mean age was approximately 57 years.

The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black.

About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days.

Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days.

Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups.

Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.

In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline.

Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).

In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)].

In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.

Table 9 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.

Table 9: Primary Composite Endpoint ResultsFor the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (3, 6 or 12 months) irrespective of the actual treatment duration.

If the same patient had several events, the patient may have been counted for several components.

in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population Event XARELTO 20 mgTreatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0–3.0)] Enoxaparin/VKA XARELTO vs.

Enoxaparin/VKA Hazard Ratio (95% CI) EINSTEIN DVT Study N=1731 n (%) N=1718 n (%) Primary Composite Endpoint 36 (2.1) 51 (3.0) 0.68 (0.44, 1.04) Death (PE) 1 (<0.1) 0 Death (PE cannot be excluded) 3 (0.2) 6 (0.3) Symptomatic PE and DVT 1 (<0.1) 0 Symptomatic recurrent PE only 20 (1.2) 18 (1.0) Symptomatic recurrent DVT only 14 (0.8) 28 (1.6) EINSTEIN PE Study N=2419 n (%) N=2413 n (%) Primary Composite Endpoint 50 (2.1) 44 (1.8) 1.12 (0.75, 1.68) Death (PE) 3 (0.1) 1 (<0.1) Death (PE cannot be excluded) 8 (0.3) 6 (0.2) Symptomatic PE and DVT 0 2 (<0.1) Symptomatic recurrent PE only 23 (1.0) 20 (0.8) Symptomatic recurrent DVT only 18 (0.7) 17 (0.7) Figures 6 and 7 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.

Figure 6: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study Figure 6 Figure 7 EINSTEIN Extension Study XARELTO for reduction in the risk of recurrence of DVT and of PE was studied in the EINSTEIN Extension study, a multi-national, double-blind, superiority study comparing XARELTO (20 mg once daily with food) to placebo in patients who had completed 6 to 14 months of treatment for DVT and/or PE following the acute event.

The intended treatment duration was 6 or 12 months based on investigator’s assessment prior to randomization.

A total of 1196 patients were randomized and followed on study treatment for a mean of 190 days for both XARELTO and placebo treatment groups.

The mean age was approximately 58 years.

The population was 58% male, 78% Caucasian, 8% Asian and about 2% Black.

Aspirin was taken as on-treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups.

In the EINSTEIN Extension study about 60% of patients had a history of proximal index DVT without PE event and 29% of patients had a PE without symptomatic DVT event.

About 59% of patients had an idiopathic DVT/PE.

Other risk factors included previous episode of DVT/PE (16%), immobilization (14%), known thrombophilic conditions (8%), or active cancer (5%).

In the EINSTEIN Extension study XARELTO was demonstrated to be superior to placebo for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [HR (95% CI): 0.18 (0.09, 0.39)].

Table 10 displays the overall results for the primary composite endpoint and its components.

Table 10: Primary Composite Endpoint ResultsFor the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (6 or 12 months) irrespective of the actual treatment duration.

in EINSTEIN Extension Study – Intent-to-Treat Population Event XARELTO 20 mg N=602 n (%) Placebo N=594 n (%) XARELTO vs.

Placebo Hazard Ratio (95% CI) Primary Composite Endpoint 8 (1.3) 42 (7.1) 0.18 (0.09, 0.39) p-value = <0.0001 Death (PE) 0 1 (0.2) Death (PE cannot be excluded) 1 (0.2) 0 Symptomatic recurrent PE 2 (0.3) 13 (2.2) Symptomatic recurrent DVT 5 (0.8) 31 (5.2) Figure 8 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.

Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN Extension Study Figure 8 14.3 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.

The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively.

In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug.

The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female.

More than 82% of patients were White, 7% were Asian, and less than 2% were Black.

The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis).

In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively.

In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively.

After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration.

The efficacy data for RECORD 1 and 2 are provided in Table 11.

Table 11: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery – Modified Intent-to-Treat Population RECORD 1 RECORD 2 Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRRRelative Risk Reduction; CI = confidence interval, p-value XARELTO 10 mg once daily EnoxaparinIncludes the placebo-controlled period of RECORD 2 40 mg once daily RRR, p-value Number of Patients N=1513 N=1473 N=834 N=835 Total VTE 17 (1.1%) 57 (3.9%) 71% (95% CI: 50, 83), p<0.001 17 (2.0%) 70 (8.4%) 76% (95% CI: 59, 86), p<0.001 Components of Total VTE Proximal DVT 1 (0.1%) 31 (2.1%) 5 (0.6%) 40 (4.8%) Distal DVT 12 (0.8%) 26 (1.8%) 11 (1.3%) 43 (5.2%) Non-fatal PE 3 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%) Death (any cause) 4 (0.3%) 4 (0.3%) 2 (0.2%) 4 (0.5%) Number of Patients N=1600 N=1587 N=928 N=929 Major VTE Proximal DVT, nonfatal PE or VTE-related death 3 (0.2%) 33 (2.1%) 91% (95% CI: 71, 97), p<0.001 6 (0.7%) 45 (4.8%) 87% (95% CI: 69, 94), p<0.001 Number of Patients N=2103 N=2119 N=1178 N=1179 Symptomatic VTE 5 (0.2%) 11 (0.5%) 3 (0.3%) 15 (1.3%) One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin.

In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively.

The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years.

Sixty-eight percent (68%) of patients were female.

Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black.

The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis).

The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively.

The efficacy data are provided in Table 12.

Table 12: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery – Modified Intent-to-Treat Population RECORD 3 Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRRRelative Risk Reduction; CI = confidence interval, p-value Number of Patients N=813 N=871 Total VTE 79 (9.7%) 164 (18.8%) 48% (95% CI: 34, 60), p<0.001 Components of events contributing to Total VTE Proximal DVT 9 (1.1%) 19 (2.2%) Distal DVT 74 (9.1%) 154 (17.7%) Non-fatal PE 0 4 (0.5%) Death (any cause) 0 2 (0.2%) Number of Patients N=895 N=917 Major VTE Proximal DVT, nonfatal PE or VTE-related death 9 (1.0%) 23 (2.5%) 60% (95% CI: 14, 81), p = 0.024 Number of Patients N=1206 N=1226 Symptomatic VTE 8 (0.7%) 24 (2.0%)

HOW SUPPLIED

16 /STORAGE AND HANDLING XARELTO (rivaroxaban) Tablets are available in the strengths and packages listed below: 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a “10” on one side, and “Xa” on the other side.

The tablets are supplied in the packages listed: NDC 50458-580-30 Bottle containing 30 tablets NDC 50458-580-90 Bottle containing 90 tablets NDC 50458-580-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a “15” marked on one side and “Xa” on the other side.

The tablets are supplied in the packages listed: NDC 50458-578-30 Bottle containing 30 tablets NDC 50458-578-90 Bottle containing 90 tablets NDC 50458-578-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a “20” marked on one side and “Xa” on the other side.

The tablets are supplied in the packages listed: NDC 50458-579-30 Bottle containing 30 tablets NDC 50458-579-90 Bottle containing 90 tablets NDC 50458-579-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism: NDC 50458-584-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg Store at 25°C (77°F) or room temperature; excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

Keep out of the reach of children.

RECENT MAJOR CHANGES

Warnings and Precautions (5.2, 5.4) 05/2016 Warnings and Precautions (5.3) 08/2016

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients in the RECORD 1–3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years.

In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years.

In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years.

In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years.

Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

DOSAGE FORMS AND STRENGTHS

3 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a “10” marked on one side and “Xa” on the other side 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a “15” marked on one side and “Xa” on the other side 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a “20” marked on one side and “Xa” on the other side Tablets: 10 mg, 15 mg, and 20 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action XARELTO is a selective inhibitor of FXa.

It does not require a cofactor (such as Anti-thrombin III) for activity.

Rivaroxaban inhibits free FXa and prothrombinase activity.

Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.

By inhibiting FXa, rivaroxaban decreases thrombin generation.

INDICATIONS AND USAGE

1 XARELTO is a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (1.1) for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction in the risk of recurrence of DVT and of PE (1.2, 1.3, 1.4) for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (1.5) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1)].

1.2 Treatment of Deep Vein Thrombosis XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

1.3 Treatment of Pulmonary Embolism XARELTO is indicated for the treatment of pulmonary embolism (PE).

1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE.

1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

PEDIATRIC USE

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

PREGNANCY

8.1 Pregnancy Pregnancy Category C There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established.

Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible.

The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing.

Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits.

XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions (5.7)].

Rivaroxaban crosses the placenta in animals.

Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post‑implantation pregnancy loss in rabbits.

Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis.

This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day.

Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg.

This dose corresponds to about 14 times the human exposure of unbound drug.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known if rivaroxaban is excreted in human milk.

Rivaroxaban and/or its metabolites were excreted into the milk of rats.

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

BOXED WARNING

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning (A) Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events.

To reduce this risk, consider coverage with another anticoagulant if XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy (2.3, 2.7, 5.1, 14.1).

(B) Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture.

These hematomas may result in long-term or permanent paralysis (5.2, 5.3, 6.2).

Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently.

Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated (5.3).

A.

Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events.

If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.7), Warnings and Precautions (5.1), and Clinical Studies (14.1)].

B.

Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture.

These hematomas may result in long-term or permanent paralysis.

Consider these risks when scheduling patients for spinal procedures.

Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of XARELTO and neuraxial procedures is not known [see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Risk of bleeding: XARELTO can cause serious and fatal bleeding.

Promptly evaluate signs and symptoms of blood loss.

(5.2) Pregnancy-related hemorrhage: Use XARELTO with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery.

Promptly evaluate signs and symptoms of blood loss.

(5.7) Prosthetic heart valves: XARELTO use not recommended (5.8) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.

An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients.

If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.7) and Clinical Studies (14.1)].

5.2 Risk of Bleeding XARELTO increases the risk of bleeding and can cause serious or fatal bleeding.

In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement.

Discontinue XARELTO in patients with active pathological hemorrhage.

The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding.

These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.4)], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A4 inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.2)].

Reversal of Anticoagulant Effect A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3)].

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers.

The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.

5.3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3)].

Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology (12.3)].

The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter.

If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction.

Instruct patients to immediately report if they experience any of the above signs or symptoms.

If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

5.4 Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.4)].

Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations (8.7)].

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations (8.7)].

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min.

Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations (8.7)].

5.5 Use in Patients with Hepatic Impairment No clinical data are available for patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations (8.8)].

5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.2)].

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A4 inducers [see Drug Interactions (7.3)].

5.7 Risk of Pregnancy-Related Hemorrhage In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus.

XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed.

Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

5.8 Patients with Prosthetic Heart Valves The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves.

Therefore, use of XARELTO is not recommended in these patients.

5.9 Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

Instructions for Patient Use Advise patients to take XARELTO only as directed.

Remind patients to not discontinue XARELTO without first talking to their healthcare professional.

Advise patients with atrial fibrillation to take XARELTO once daily with the evening meal.

Advise patients with DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day [see Dosage and Administration (2.5)].

Advise patients who cannot swallow the tablet whole to crush XARELTO and combine with a small amount of applesauce followed by food [see Dosage and Administration (2.9)].

For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the XARELTO tablet and mix it with a small amount of water before administering via the tube [see Dosage and Administration (2.9)].

If a dose is missed, advise the patient to take XARELTO as soon as possible on the same day and continue on the following day with their recommended daily dose regimen.

Bleeding Risks Advise patients to report any unusual bleeding or bruising to their physician.

Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with XARELTO [see Warnings and Precautions (5.2)].

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence.

If any of these symptoms occur, advise the patient to contact his or her physician immediately [see Boxed Warning].

Invasive or Surgical Procedures Instruct patients to inform their healthcare professional that they are taking XARELTO before any invasive procedure (including dental procedures) is scheduled.

Concomitant Medication and Herbals Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions [see Drug Interactions (7)].

Pregnancy and Pregnancy-Related Hemorrhage Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with XARELTO [see Use in Specific Populations (8.1)].

Advise pregnant women receiving XARELTO to immediately report to their physician any bleeding or symptoms of blood loss [see Warnings and Precautions (5.7)].

Nursing Advise patients to discuss with their physician if they are nursing or intend to nurse during anticoagulant treatment [see Use in Specific Populations (8.3)].

Females of Reproductive Potential Advise patients who can become pregnant to discuss pregnancy planning with their physician [see Use in Specific Populations (8.6)].

DOSAGE AND ADMINISTRATION

2 Take 15 mg and 20 mg tablets with food; take 10 mg tablets with or without food (2.2) Nonvalvular Atrial Fibrillation: For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal (2.4) For patients with CrCl 15 – 50 mL/min: 15 mg orally, once daily with the evening meal (2.4) Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE: 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE.

After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and of PE.

(2.5) Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally, once daily with or without food (2.6) 2.1 Recommended Dosage Indication Dosage Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation (2.4) CrCl >50 mL/min: 20 mg once daily with the evening meal CrCl 15 to 50 mL/min: 15 mg once daily with the evening meal Treatment of DVT (2.5) Treatment of PE (2.5) 15 mg twice daily with food, for first 21 days ▼after 21 days, transition to ▼ 20 mg once daily with food, for remaining treatment Reduction in the Risk of Recurrence of DVT and of PE (2.5) 20 mg once daily with food Prophylaxis of DVT Following Hip or Knee Replacement Surgery (2.6) Hip replacement: 10 mg once daily for 35 days Knee replacement: 10 mg once daily for 12 days 2.2 Important Food Effect Information The 15 mg and 20 mg XARELTO tablets should be taken with food, while the 10 mg tablet can be taken with or without food [see Clinical Pharmacology (12.3)].

In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with the evening meal.

2.3 Switching to and from XARELTO Switching from Warfarin to XARELTO – When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.

Switching from XARELTO to Warfarin – No clinical trial data are available to guide converting patients from XARELTO to warfarin.

XARELTO affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin.

One approach is to discontinue XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.

Switching from XARELTO to Anticoagulants other than Warfarin – For patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken [see Drug Interactions (7.4)].

Switching from Anticoagulants other than Warfarin to XARELTO – For patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant.

For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO at the same time.

2.4 Nonvalvular Atrial Fibrillation For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO is 20 mg taken orally once daily with the evening meal.

For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal [see Use in Specific Populations (8.7)].

2.5 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE The recommended dose of XARELTO for the initial treatment of acute DVT and/or PE is 15 mg taken orally twice daily with food for the first 21 days.

After this initial treatment period, the recommended dose of XARELTO is 20 mg taken orally once daily with food, at approximately the same time each day.

The recommended dose of XARELTO for reduction in the risk of recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same time each day [see Clinical Studies (14.2)].

2.6 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose of XARELTO is 10 mg taken orally once daily with or without food.

The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established [see Dosage and Administration (2.7)].

For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.

For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

2.7 Discontinuation for Surgery and other Interventions If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions (5.2)].

In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention.

XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions (5.1)].

If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

2.8 Missed Dose If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day as follows: For patients receiving 15 mg twice daily: The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day.

In this particular instance, two 15 mg tablets may be taken at once.

The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed XARELTO dose immediately.

2.9 Administration Options For patients who are unable to swallow whole tablets, 10 mg, 15 mg or 20 mg XARELTO tablets may be crushed and mixed with applesauce immediately prior to use and administered orally.

After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should be immediately followed by food [see Dosage and Administration (2.2, 2.4, 2.5) and Clinical Pharmacology (12.3)].

Administration via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, 10 mg, 15 mg or 20 mg XARELTO tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube.

Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of XARELTO distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure.

After the administration of a crushed XARELTO 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding [see Clinical Pharmacology (12.3)].

Crushed 10 mg, 15 mg or 20 mg XARELTO tablets are stable in water and in applesauce for up to 4 hours.

An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed XARELTO tablet to PVC or silicone nasogastric (NG) tubing.

Voltaren 1 % Topical Gel

Generic Name: DICLOFENAC SODIUM
Brand Name: Voltaren
  • Substance Name(s):
  • DICLOFENAC SODIUM

DRUG INTERACTIONS

7 7.1 Aspirin When diclofenac is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered.

The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.

7.2 Anticoagulants The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

7.3 ACE-Inhibitors NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors.

This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

7.4 Diuretics Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients.

The response has been attributed to inhibition of renal prostaglandin synthesis.

During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure [see Warnings and Precautions (5.6)], as well as to assure diuretic efficacy.

7.5 Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.

The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID.

Thus, when NSAIDs, including diclofenac, and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.

7.6 Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.

This may indicate that they could enhance the toxicity of methotrexate.

Caution should be used when NSAIDs, including diclofenac, are administered concomitantly with methotrexate.

7.7 Cyclosporine Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs.

Therefore concomitant therapy with diclofenac may increase cyclosporine’s nephrotoxicity.

Caution should be used when diclofenac is administered concomitantly with cyclosporine.

7.8 Oral Nonsteroidal Anti-inflammatory Drugs Specific interaction studies of Voltaren® Gel and oral NSAIDs were not performed.

Also, the clinical trials of Voltaren® Gel prohibited concomitant use of oral NSAIDS.

There is systemic exposure to diclofenac following normal use of Voltaren® Gel, up to 6% of the systemic levels of a single oral dose of diclofenac sodium.

[see Clinical Pharmacology (12.3)] Therefore, concomitant administration of Voltaren® Gel with oral NSAIDs or aspirin may result in increased adverse NSAID effects.

7.9 Topical Treatments Concomitant use of Voltaren® Gel with other topical products, including topical medications, sunscreens, lotions, moisturizers, and cosmetics, on the same skin site has not been tested and should be avoided because of the potential to alter local tolerability and absorption.

OVERDOSAGE

10 There has been no experience of overdose with Voltaren® Gel.

No events of accidental ingestion have been reported with Voltaren® Gel.

Effects similar to those observed after an overdose of diclofenac tablets can be expected if substantial amounts of Voltaren® Gel are ingested.

Symptoms following acute oral NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care.

Gastrointestinal bleeding can occur.

Hypertension, acute renal failure, respiratory depression, and coma may occur.

Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur after an overdose.

In the event of oral ingestion resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage.

Forced diuresis may theoretically be beneficial because the drug is excreted in the urine.

The effect of dialysis or hemoperfusion in the elimination of diclofenac (99% protein-bound) remains unproven.

In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac.

Supportive and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation, and respiratory depression.

For additional information about overdose treatment, call a poison control center (1-800-222-1222).

DESCRIPTION

11 Voltaren® Gel (diclofenac sodium topical gel) is a nonsteroidal anti-inflammatory drug (NSAID) for topical use only.

It contains the active ingredient, diclofenac sodium, in an opaque, white gel base.

Diclofenac sodium is a white to slightly yellow crystalline powder.

Diclofenac sodium is a benzene–acetic acid derivative.

The chemical name is 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, monosodium salt.

The molecular weight is 318.14.

Its molecular formula is C14H10C12NNaO2.

It has the following structural formula: Voltaren® Gel also contains carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution.

Image 1

CLINICAL STUDIES

14 14.1 Pivotal Studies in Osteoarthritis of the Superficial Joints of the Extremities Study 1 evaluated the efficacy of Voltaren® Gel for the treatment of osteoarthritis of the knee in a 12-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial.

Voltaren® Gel was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g per day).

Pain as assessed by the patients at Week 12 using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) Pain Subindex was lower in the Voltaren® Gel group than the placebo group.

Study 2 evaluated the efficacy of Voltaren® Gel for the treatment of osteoarthritis in subjects with osteoarthritis of the hand in an 8-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group study.

Voltaren® Gel was administered at a dose of 2 g per hand, 4 times daily, on both hands (16 g per day).

Pain in the target hand as assessed by the patients at Weeks 4 and 6 on a visual analog scale from 0 to 100 was lower in the Voltaren® Gel group than the placebo group.

Table 3.

Efficacy outcomes of Voltaren® Gel in Studies 1 and 2 Voltaren ® Gel Placebo (Vehicle) Adjusted Difference (Placebo – Voltaren ® Gel ) Study 1 (Knee) WOMAC Pain * # at Week 12 Sample Size 127 119 Mean outcome 28 37 ∆ = 7 † 95% confidence interval (1, 12) Study 2 (Hand) Pain Intensity # at Week 4 Sample size 198 187 Mean outcome 43 50 ∆ = 7 †† 95% confidence interval (2, 12) Study 2 (Hand) Pain Intensity # at Week 6 Sample size 198 187 Mean outcome 40 47 ∆ = 7 †† 95% confidence interval (1, 13) * WOMAC = Western Ontario McMaster Osteoarthritis Index.

# Scale from 0 (best) to 100 (worst), † Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment and center and baseline covariate.

†† Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment, center, indicator for pain in the CMC-1 joint, and baseline as a covariate, and the treatment-by-CMC-1 indicator interaction.

Difference is weighted by size of CMC-1 strata

HOW SUPPLIED

16 /STORAGE AND HANDLING Voltaren® Gel is available in tubes containing 100 g of the topical gel in each tube.

Physician samples are packaged in 20 g tubes.

Each tube contains diclofenac sodium in a gel base (10 mg of diclofenac sodium per gram of gel or 1%).

100 gram tube NDC 21695-791-00 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature] Keep from freezing.

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects treated with Voltaren® Gel in clinical studies, 498 were 65 years of age and over.

No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity to the effect of NSAIDs in some older individuals cannot be ruled out.

Diclofenac, as with any NSAID, is known to be substantially excreted by the kidney, and the risk of toxic reactions to Voltaren® Gel may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken when using Voltaren® Gel in the elderly, and it may be useful to monitor renal function.

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of diclofenac is similar to that of other nonsteroidal anti-inflammatory drugs.

Diclofenac inhibits the enzyme, cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin.

It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.

INDICATIONS AND USAGE

1 Voltaren® Gel is indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands.

Voltaren® Gel has not been evaluated for use on the spine, hip, or shoulder.

PEDIATRIC USE

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

PREGNANCY

5.9 Pregnancy As with other NSAIDs, Voltaren® Gel should be avoided in late pregnancy, because it may cause premature closure of the ductus arteriosus.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether diclofenac is excreted in human milk; however, studies in animals detected diclofenac in the milk after oral administration.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Voltaren® Gel 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.

BOXED WARNING

WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISK Cardiovascular Risk Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal.

This risk may increase with duration of use.

Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)] .

Voltaren® Gel is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)] .

Gastrointestinal Risk NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.

These events can occur at any time during use and without warning symptoms.

Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions(5.2)].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Elevations of one or more liver tests may occur during therapy with diclofenac sodium.

These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy.

Borderline elevations (i.e.

less than 3 times the ULN [ULN = the upper limit of normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients.

Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment.

In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.

Meaningful elevations of ALT and/orAST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients.

In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs.

Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic.

Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac.

Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure.

Some of these reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms.

The optimum times for making the first and subsequent transaminase measurements are not known.

Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.

However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium should be discontinued immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium, the lowest effective dose should be used for the shortest duration possible.

Caution should be exercised in prescribing diclofenac sodium with concomitant drugs that are know to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

(5.3) Almost all meaningful elevations in transaminases were detected before patients became symptomatic.

Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac.

Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure.

Some of these reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms.

The optimum times for making the first and subsequent transaminase measurements are not known.

Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.

However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium should be discontinued immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium, the lowest effective dose should be used for the shortest duration possible.

Caution should be exercised in prescribing diclofenac sodium with concomitant drugs that are know to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

(5.3) Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

In these patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly.

Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

(5.6) As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to Voltaren® Gel.

Voltaren® Gel should not be given to patients with the aspirin triad.

This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4), Warnings and Precautions (5.7)].

Emergency help should be sought in cases where an anaphylactoid reaction occurs.

(5.7) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.

All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.

Patients with known CV disease or risk factors for CV disease may be at greater risk.

To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms.

Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAIDs use.

The concurrent use of aspirin and NSAIDs such as diclofenac, does increase the risk of serious GI events [see Warnings and Precautions (5.2) ].

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4)].

5.2 Gastrointestinal Effects – Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.

Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year.

These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy.

However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding.

Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors.

Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIDs therapy, smoking, use of alcohol, older age, and poor general health status.

Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration.

Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during diclofenac therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.

For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

5.3 Hepatic Effects Elevations of one or more liver tests may occur during therapy with diclofenac sodium.

These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy.

Borderline elevations (i.e.

less than 3 times the ULN [ULN = the upper limit of normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients.

Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment.

In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.

Meaningful elevations of ALT and/orAST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients.

In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs.

Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic.

Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac.

Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure.

Some of these reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms.

The optimum times for making the first and subsequent transaminase measurements are not known.

Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.

However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium should be discontinued immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium, the lowest effective dose should be used for the shortest duration possible.

Caution should be exercised in prescribing diclofenac sodium with concomitant drugs that are know to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

5.4 Hypertension NSAIDs, including Voltaren® Gel, can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events.

Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.

NSAIDs, including Voltaren® Gel should be used with caution in patients with hypertension.

Blood pressure should be monitored closely during the initiation of therapy with Voltaren® Gel and throughout the course of therapy.

5.5 Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients treated with NSAIDs, including Voltaren® Gel.

Voltaren® Gel should be used with caution in patients with fluid retention or heart failure.

5.6 Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly.

Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of Voltaren® Gel in patients with advanced renal disease.

Therefore, treatment with Voltaren® Gel is not recommended in patients with advanced renal disease.

If Voltaren® Gel therapy is initiated, close monitoring of the patient’s renal function is advisable.

5.7 Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to Voltaren® Gel.

Voltaren® Gel should not be given to patients with the aspirin triad.

This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4), Warnings and Precautions (5.7)].

Emergency help should be sought in cases where an anaphylactoid reaction occurs.

5.8 Skin Reactions NSAIDs, including Voltaren® Gel, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

These serious events may occur without warning.

Patients should be informed about the signs and symptoms of serious skin manifestations, and the use of the drug should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity.

Voltaren® Gel should not be applied to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.

Voltaren® Gel should not be allowed to come into contact with the eyes or with mucous membranes.

The effect of Voltaren® Gel under occlusive dressings has not been evaluated, and should be avoided.

5.9 Pregnancy As with other NSAIDs, Voltaren® Gel should be avoided in late pregnancy, because it may cause premature closure of the ductus arteriosus.

5.10 Corticosteroid treatment Voltaren® Gel cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.

Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness.

Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

5.11 Inflammation The pharmacological activity of diclofenac in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.

5.12 Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs.

This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoeisis.

Patients on long-term treatment with NSAIDs, including Voltaren® Gel, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.

Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.

Patients treated with Voltaren® Gel who may be adversely affected by alteration in platelet function, such as those with coagulation disorders or patients receiving anticoagulants should be carefully monitored.

5.13 Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma.

The use of aspirin in patients with aspirin sensitive asthma has been associated with severe bronchospasm, which can be fatal.

Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Voltaren® Gel should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

5.14 Sun Exposure Patients should minimize or avoid exposure to natural or artificial sunlight on treated areas because studies in animals indicated topical diclofenac treatment resulted in an earlier onset of ultraviolet light induced skin tumors.

The potential effects of Voltaren® Gel on skin response to ultraviolet damage in humans are not known.

5.15 Eye Exposure Contact of Voltaren® Gel with eyes and mucosa, although not studied, should be avoided.

Patients should be advised that if eye contact occurs, they should immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

5.16 Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.

Patients on long-term treatment with NSAIDs, should have a CBC and a chemistry profile checked periodically.

If abnormal liver tests or renal tests persist or worsen, Voltaren® Gel should be discontinued.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Also See Section 18 Medical Guide Below.

17.1 Medication Guide Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.

Patients should be informed of the availability of a Medication Guide for Non-Steroidal Anti-inflammatory Drugs (NSAIDs), and they should be instructed to read the Medication Guide prior to using Voltaren® Gel.

17.2 Cardiovascular effects Voltaren® Gel, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death.

Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms.

Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1)].

17.3 Gastrointestinal effects Voltaren® Gel, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death.

Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.

Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.2)].

17.4 Hepatotoxicity Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).

If these occur, patients should be instructed to stop therapy with Voltaren® Gel and seek immediate medical therapy [see Warnings and Precautions (5.3)].

17.5 Adverse Skin Reactions Voltaren® Gel, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death.

Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms [see Warnings and Precautions (5.8)].

Patients should be advised to stop Voltaren® Gel immediately if they develop any type of rash and contact their physicians as soon as possible.

Patients should be instructed not to apply Voltaren® Gel to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.

Patients should be instructed to avoid concomitant use of Voltaren® Gel with other topical products, including sunscreens, cosmetics lotions, moisturizers, insect repellants, on the treated skin site.

Concomitant use may result in skin reactions or change the absorption of Voltaren® Gel.

Patients should be instructed to minimize or avoid exposure of treated areas to natural or artificial sunlight.

17.6 Weight gain and edema Patients should promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with Voltaren® Gel [see Warnings and Precautions (5.5)].

17.7 Anaphylactoid reactions Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat).

If these occur, patients should be instructed to seek immediate emergency help [see Warnings and Precautions (5.7)].

17.8 Effects during pregnancy In late pregnancy, as with other NSAIDs, Voltaren® Gel should be avoided because it will cause premature closure of the ductus arteriosus [see Warnings and Precautions (5.9)].

17.9 Eye Exposure Patients should be instructed to avoid contact of Voltaren® Gel with the eyes and mucosa, although not studied, should be avoided.

Patients should be advised that if eye contact occurs, they should immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

Comments or Questions? Call toll-free 1-800-452-0051 Marketed by: Endo Pharmaceuticals Inc.

Chadds Ford, PA 19317 Manufactured for: Novartis Consumer Health, Inc.

Parsippany, NJ 07054 Manufactured by: Novartis Pharma Produktions GmbH Wehr, Germany Repackaged by: Rebel Distributors Corp Thousand Oaks, CA 91320

DOSAGE AND ADMINISTRATION

2 Total dose should not exceed 32 g per day, over all affected joints.

(2.3) Voltaren Gel should be measured onto the enclosed dosing card to the appropriate 2 g or 4 g designation.

(2) 2.1 Dosing Card [See the Medication Guide – Patient Instructions for Use] The proper amount of Voltaren® Gel should be measured using the dosing card supplied in the drug product carton.

The dosing card is made of polypropylene, like the tube cap containing Voltaren® Gel, but without the white colorant.

The dosing card should be used for each application of drug product.

The gel should be applied within the oblong area of the dosing card up to the 2 gram or 4 gram line (2 g for each elbow, wrist, or hand, and 4 g for each knee, ankle, or foot).

The dosing card containing Voltaren® Gel can be used to apply the gel.

The hands should then be used to gently rub the gel into the skin.

After using the dosing card, hold with fingertips, rinse, and dry.

It treatment site is the hands, patients should wait at least one (1) hour to wash their hands 2.2 Lower extremities, including the knees, ankles, and feet Apply the gel (4 g) to the affected foot or knee or ankle, 4 times daily.

Voltaren® Gel should be gently massaged into the skin ensuring application to the entire affected foot or knee or ankle.

The entire foot includes the sole, top of the foot and the toes.

Do not apply more than 16 g daily to any single joint of the lower extremities.

2.3 Upper extremities including the elbows, wrists and hands Apply the gel (2 g) to the affected hand or elbow or wrist, 4 times daily.

Voltaren® Gel should be gently massaged into the skin ensuring application to the entire affected hand or elbow or wrist.

The entire hand includes the palm, back of the hands, and the fingers.

Do not apply more than 8 g daily to any single joint of the upper extremities.

Total dose should not exceed 32 g per day, over all affected joints.

2.4 Special Precautions Showering/bathing should be avoided for at least 1 hour after the application.

Patient should wash his/her hands after use, unless the hands are the treated joint.

If Voltaren® Gel is applied to the hand(s) for treatment; patient should not wash the treated hand(s) for at least 1 hour after the application.

Voltaren® Gel should not be applied to open wounds.

Contact of Voltaren® Gel with eyes and mucous membranes should be avoided.

External heat and/or occlusive dressings should not be applied to treated joints.

Exposure of the treated joint(s) to sunlight should be avoided.

Voltaren® Gel should not be used concomitantly with sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medications on the same skin sites has not been evaluated.

Concomitant use of Voltaren® Gel with oral non-steroidal anti-inflammatory drugs (NSAIDs) has not been evaluated, and may increase adverse NSAIDs effects.

Wearing of clothing or gloves should be avoided for at least 10 minutes after applying Voltaren® Gel.

Zosyn (piperacillin / tazobactam) 3.375 GM Injection

Generic Name: PIPERACILLIN SODIUM AND TAZOBACTAM SODIUM
Brand Name: Zosyn
  • Substance Name(s):
  • PIPERACILLIN SODIUM
  • TAZOBACTAM SODIUM

DRUG INTERACTIONS

7 ZOSYN administration can significantly reduce tobramycin concentrations in hemodialysis patients.

Monitor tobramycin concentrations in these patients.

(7.1) Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with ZOSYN unless the benefit outweighs the risk.

(7.2) Co-administration of ZOSYN with vancomycin may increase the incidence of acute kidney injury.

Monitor kidney function in patients receiving ZOSYN and vancomycin.

(7.3) Monitor coagulation parameters in patients receiving ZOSYN and heparin or oral anticoagulants.

(7.4) ZOSYN may prolong the neuromuscular blockade of vecuronium and other non-depolarizing muscle relaxants.

Monitor for adverse reactions related to neuromuscular blockade.

(7.5) 7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.

In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored.

Sequential administration of ZOSYN and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary.

In vitro inactivation: Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration.

ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated.

ZOSYN, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations.

ZOSYN is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.7) ].

7.2 Probenecid Probenecid administered concomitantly with ZOSYN prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam.

Probenecid should not be co-administered with ZOSYN unless the benefit outweighs the risk.

7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone [see Warnings and Precautions (5.5) ].

Monitor kidney function in patients concomitantly administered with piperacillin/tazobactam and vancomycin.

No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.

7.4 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [see Warnings and Precautions (5.3) ].

7.5 Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium.

ZOSYN could produce the same phenomenon if given along with vecuronium.

Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of piperacillin.

Monitor for adverse reactions related to neuromuscular blockade (See package insert for vecuronium bromide).

7.6 Methotrexate Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion.

The impact of tazobactam on the elimination of methotrexate has not been evaluated.

If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.

7.7 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection.

Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.

Therefore, positive test results in patients receiving piperacillin/tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.

As with other penicillins, the administration of ZOSYN may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST®).

It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

OVERDOSAGE

10 There have been postmarketing reports of overdose with piperacillin/tazobactam.

The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages.

Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure) [see Warnings and Precautions (5.4) ].

Treatment should be supportive and symptomatic according the patient’s clinical presentation.

Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis.

Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively [see Clinical Pharmacology (12) ].

DESCRIPTION

11 ZOSYN (piperacillin and tazobactam) for Injection and ZOSYN (piperacillin and tazobactam) Injection are injectable antibacterial combination products consisting of the semisynthetic antibacterial piperacillin sodium and the β-lactamase inhibitor tazobactam sodium for intravenous administration.

Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin.

The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate.

The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5.

The chemical structure of piperacillin sodium is: Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.

Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide.

The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3.

The chemical structure of tazobactam sodium is: ZOSYN (piperacillin and tazobactam) for Injection, is a white to off-white sterile, cryodesiccated powder consisting of piperacillin and tazobactam as their sodium salts packaged in glass vials.

The formulation also contains edetate disodium dihydrate (EDTA) and sodium citrate.

Each ZOSYN 2.25 g single dose vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam.

The product also contains 0.5 mg of EDTA per vial.

Each ZOSYN 3.375 g single dose vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam.

The product also contains 0.75 mg of EDTA per vial.

Each ZOSYN 4.5 g single dose vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam.

The product also contains 1 mg of EDTA per vial.

Each Zosyn 40.5 g pharmacy bulk vial contains piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 g of tazobactam sufficient for delivery of multiple doses.

ZOSYN Injection in the GALAXY Container is a frozen iso-osmotic sterile non-pyrogenic premixed solution.

The components and dosage formulations are given in the table below: Table 5: ZOSYN In GALAXY Containers Premixed Frozen Solution ComponentPiperacillin and tazobactam are present in the formulation as sodium salts.

Dextrose hydrous, sodium citrate dihydrate, and edetate disodium dihydrate amounts are approximate.

Function Dosage Formulations 2.25 g/50 mL 3.375 g/50 mL 4.5 g/100 mL Piperacillin active ingredient 2 g 3 g 4 g Tazobactam β-lactamase inhibitor 250 mg 375 mg 500 mg Dextrose Hydrous osmolality adjusting agent 1 g 350 mg 2 g Sodium Citrate Dihydrate buffering agent 100 mg 150 mg 200 mg Edetate Disodium Dihydrate metal chelator 0.5 mg 0.75 mg 1 mg Water for Injection solvent q.s.

50 mL q.s.

50 mL q.s.

100 mL ZOSYN contains a total of 2.84 mEq (65 mg) of sodium (Na+) per gram of piperacillin in the combination product.

Chemical Structure Chemical Structure

HOW SUPPLIED

16 /STORAGE AND HANDLING ZOSYN® (piperacillin and tazobactam) for Injection are supplied as single-dose vials and pharmacy bulk vials in the following sizes: Each ZOSYN 2.25 g vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam.

Each vial contains 5.68 mEq (130 mg) of sodium.

Supplied 10 per box—NDC 0206-2404-02 Each ZOSYN 3.375 g vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam.

Each vial contains 8.52 mEq (195 mg) of sodium.

Supplied 10 per box—NDC 0206-2405-02 Each ZOSYN 4.5 g vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam.

Each vial contains 11.36 mEq (260 mg) of sodium.

Supplied 10 per box—NDC 0206-2408-02 Each ZOSYN 40.5 g pharmacy bulk vial provides piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 grams of tazobactam.

Each pharmacy bulk vial contains 100.4 mEq (2,304 mg) of sodium.

NDC 0206-2416-01 ZOSYN® for Injection vials should be stored at controlled room temperature (20°C to 25°C [68°F to 77°F]) prior to reconstitution.

ZOSYN® (piperacillin and tazobactam) Injection in GALAXY Containers are supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in single dose plastic containers as follows: 2.25 g (piperacillin sodium equivalent to 2 g piperacillin/tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL.

Each container has 5.58 mEq (128 mg) of sodium.

Supplied 24/box—NDC 0206-2409-02 3.375 g (piperacillin sodium equivalent to 3 g piperacillin/tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL.

Each container has 8.38 mEq (192 mg) of sodium.

Supplied 24/box—NDC 0206-2411-02 4.5 g (piperacillin sodium equivalent to 4 g piperacillin/tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL.

Each container has 11.17 mEq (256 mg) of sodium.

Supplied 12/box—NDC 0206-2413-02 ZOSYN® Injection in GALAXY Containers should be stored at or below -20°C (-4°F).

RECENT MAJOR CHANGES

Warnings and Precautions, Nephrotoxicity in Critically Ill Patients (5.5) 6/2017

GERIATRIC USE

8.5 Geriatric Use Patients over 65 years are not at an increased risk of developing adverse effects solely because of age.

However, dosage should be adjusted in the presence of renal impairment [see Dosage and Administration (2) ].

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ZOSYN contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product.

At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium.

The geriatric population may respond with a blunted natriuresis to salt loading.

This may be clinically important with regard to such diseases as congestive heart failure.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

DOSAGE FORMS AND STRENGTHS

3 ZOSYN® (piperacillin and tazobactam) for Injection is supplied as a white to off-white powder in vials of the following sizes: Each ZOSYN 2.25 g vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam.

Each ZOSYN 3.375 g vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam.

Each ZOSYN 4.5 g vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam.

Each ZOSYN 40.5 g pharmacy bulk vial contains piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 grams tazobactam.

ZOSYN® (piperacillin and tazobactam) Injection is supplied in GALAXY Containers as a frozen, iso-osmotic, sterile, non-pyrogenic solution in single-dose plastic containers: 2.25 g (piperacillin sodium equivalent to 2 g piperacillin/tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL.

3.375 g (piperacillin sodium equivalent to 3 g piperacillin/tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL.

4.5 g (piperacillin sodium equivalent to 4 g piperacillin/tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL.

ZOSYN® for Injection: 2.25 g, 3.375 g, and 4.5 g lyophilized powder for reconstitution in single-dose vials.

and 40.5 g lyophilized powder for reconstitution in pharmacy bulk vials.

(3) ZOSYN® Injection: 2.25 g in 50 mL, 3.375 g in 50 mL, and 4.5 g in 100 mL frozen solution in single-dose GALAXY containers.

(3, 16)

MECHANISM OF ACTION

12.1 Mechanism of Action ZOSYN is an antibacterial drug [see Microbiology (12.4) ].

INDICATIONS AND USAGE

1 ZOSYN is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed below.

ZOSYN is a combination penicillin-class antibacterial and β-lactamase inhibitor indicated for treatment of: Intra-abdominal infections (1.1) Skin and skin structure infections (1.2) Female pelvic infections (1.3) Community-acquired pneumonia (1.4) Nosocomial pneumonia (1.5) Usage (1.6) To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

(1.6) 1.1 Intra-abdominal Infections Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B.

fragilis, B.

ovatus, B.

thetaiotaomicron, or B.

vulgatus.

The individual members of this group were studied in fewer than 10 cases.

1.2 Skin and Skin Structure Infections Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by β-lactamase producing isolates of Staphylococcus aureus.

1.3 Female Pelvic Infections Postpartum endometritis or pelvic inflammatory disease caused by β-lactamase producing isolates of Escherichia coli.

1.4 Community-acquired Pneumonia Community-acquired pneumonia (moderate severity only) caused by β-lactamase producing isolates of Haemophilus influenzae.

1.5 Nosocomial Pneumonia Nosocomial pneumonia (moderate to severe) caused by β-lactamase producing isolates of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P.

aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2) ].

1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PEDIATRIC USE

8.4 Pediatric Use Use of ZOSYN in pediatric patients 2 months of age or older with appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients.

This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2–12 years of age with complicated intra-abdominal infections, in which 273 pediatric patients received piperacillin/tazobactam.

Safety and efficacy in pediatric patients less than 2 months of age have not been established [see Clinical Pharmacology (12) and Dosage and Administration (2) ].

It has not been determined how to adjust ZOSYN dosage in pediatric patients with renal impairment.

PREGNANCY

8.1 Pregnancy Risk Summary Piperacillin and tazobactam cross the placenta in humans.

However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

No fetal structural abnormalities were observed in rats or mice when piperacillin/tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2).

However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m2) [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 In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin/tazobactam up to 3000/750 mg/kg/day during the period of organogenesis.

There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m2).

Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m2).

A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin/tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area).

Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin/tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving ZOSYN.

Discontinue ZOSYN if a reaction occurs.

(5.1) ZOSYN may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis (5.2).

Discontinue ZOSYN for progressive rashes.

Hematological effects (including bleeding, leukopenia and neutropenia) have occurred.

Monitor hematologic tests during prolonged therapy.

(5.3) Nephrotoxicity in critically ill patients has been observed; the use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients.

Based on this study, alternative treatment options should be considered in the critically ill population.

If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN.

(5.5) Clostridium difficile associated diarrhea: evaluate patients if diarrhea occurs.

(5.7) 5.1 Hypersensitivity Adverse Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with ZOSYN.

These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens.

Before initiating therapy with ZOSYN, careful inquiry should be made concerning previous hypersensitivity reactions.

If an allergic reaction occurs, ZOSYN should be discontinued and appropriate therapy instituted.

5.2 Severe Cutaneous Adverse Reactions ZOSYN may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis.

If patients develop a skin rash they should be monitored closely and ZOSYN discontinued if lesions progress.

5.3 Hematologic Adverse Reactions Bleeding manifestations have occurred in some patients receiving β-lactam drugs, including piperacillin.

These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure.

If bleeding manifestations occur, ZOSYN should be discontinued and appropriate therapy instituted.

The leukopenia/neutropenia associated with ZOSYN administration appears to be reversible and most frequently associated with prolonged administration.

Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥ 21 days [see Adverse Reactions (6.1) ].

5.4 Central Nervous System Adverse Reactions As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

5.5 Nephrotoxicity in Critically Ill Patients The use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients [see Adverse Reactions (6.1) ].

Based on this study, alternative treatment options should be considered in the critically ill population.

If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN [see Dosage and Administration (2.3) ].

Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3) ].

5.6 Electrolyte Effects ZOSYN contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product.

This should be considered when treating patients requiring restricted salt intake.

Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

5.7 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ZOSYN, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile.

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C.

difficile, and surgical evaluation should be instituted as clinically indicated.

5.8 Development of Drug-Resistant Bacteria Prescribing ZOSYN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Serious Hypersensitivity Reactions Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur that require immediate treatment.

Ask them about any previous hypersensitivity reactions to ZOSYN, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2) ].

Diarrhea Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs which usually ends when the drug is discontinued.

Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug.

If this occurs, patients should contact their physician as soon as possible.

Antibacterial Resistance Counsel patients that antibacterial drugs including ZOSYN should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When ZOSYN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

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

Counsel patients that ZOSYN can cross the placenta in humans and is excreted in human milk.

DOSAGE AND ADMINISTRATION

2 ZOSYN should be administered by intravenous infusion over 30 minutes.

The usual daily dose of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).

(2.1) Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).

(2.2) Dosage in patients with renal impairment (≤40 mL/min of CRCL) and dialysis patients should be reduced, based on the degree of actual renal function impairment.

(2.3) For children with appendicitis and/or peritonitis the recommended ZOSYN dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours in pediatric patients 9 months of age and older.

For pediatric patients 2 to 9 months of age, the recommended dosage is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours.

(2.4) ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately.

Co-administration via Y-site can be done under certain conditions.

(2.7) 2.1 Adult Patients The usual total daily dose of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).

The usual duration of ZOSYN treatment is from 7 to 10 days.

ZOSYN should be administered by intravenous infusion over 30 minutes.

2.2 Nosocomial Pneumonia Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).

The recommended duration of ZOSYN treatment for nosocomial pneumonia is 7 to 14 days.

Treatment with the aminoglycoside should be continued in patients from whom P.

aeruginosa is isolated.

2.3 Renal Impairment In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced to the degree of actual renal function impairment.

The recommended daily doses of ZOSYN for patients with renal impairment are as follows: Table 1: Recommended Dosing of ZOSYN in Patients with Normal Renal Function and Renal-Impairment (As total grams piperacillin/tazobactam) Renal Function (creatinine clearance, mL/min) All Indications (except nosocomial pneumonia) Nosocomial Pneumonia >40 mL/min 3.375 q 6 h 4.5 q 6 h 20–40 mL/minCreatinine clearance for patients not receiving hemodialysis 2.25 q 6 h 3.375 q 6 h <20 mL/min 2.25 q 8 h 2.25 q 6 h Hemodialysis0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days 2.25 q 12 h 2.25 q 8 h CAPD 2.25 q 12 h 2.25 q 8 h For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.

Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g ZOSYN (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days.

No additional dosage of ZOSYN is necessary for CAPD patients.

2.4 Pediatric Patients For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended ZOSYN dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.

For pediatric patients between 2 months and 9 months of age, the recommended ZOSYN dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ].

Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.

It has not been determined how to adjust ZOSYN dosage in pediatric patients with renal impairment.

2.5 Reconstitution and Dilution of Powder Formulations Pharmacy bulk vials Reconstituted stock solution must be transferred and further diluted for intravenous infusion.

The pharmacy bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow hood.

After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique.

Use entire contents of pharmacy bulk vial promptly.

Discard unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Reconstitute the pharmacy bulk vial with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.

Shake well until dissolved.

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

Single dose vials Reconstitute ZOSYN vials with a compatible reconstitution diluent from the list provided below.

2.25 g, 3.375 g, and 4.5 g ZOSYN should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively.

Swirl until dissolved.

Compatible Reconstitution Diluents for Pharmacy and Single Dose Vials 0.9% sodium chloride for injection Sterile water for injection Dextrose 5% Bacteriostatic saline/parabens Bacteriostatic water/parabens Bacteriostatic saline/benzyl alcohol Bacteriostatic water/benzyl alcohol Reconstituted ZOSYN solutions for both bulk and single dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below.

Administer by infusion over a period of at least 30 minutes.

During the infusion it is desirable to discontinue the primary infusion solution.

Compatible Intravenous Solutions for Pharmacy and Single Dose Vials 0.9% sodium chloride for injection sterile water for injectionMaximum recommended volume per dose of sterile water for injection is 50 mL.

Dextran 6% in saline Dextrose 5% Lactated Ringer’s Solution (compatible only with reformulated ZOSYN containing EDTA and is compatible for co-administration via a Y-site) ZOSYN should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

ZOSYN is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

ZOSYN should not be added to blood products or albumin hydrolysates.

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

Stability of ZOSYN Powder Formulations Following Reconstitution ZOSYN reconstituted from bulk and single vials is stable in glass and plastic containers (plastic syringes, I.V.

bags and tubing) when used with compatible diluents.

The pharmacy bulk vial should NOT be frozen after reconstitution.

Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Single dose or pharmacy vials should be used immediately after reconstitution.

Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Vials should not be frozen after reconstitution.

Stability studies in the I.V.

bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature.

ZOSYN contains no preservatives.

Appropriate consideration of aseptic technique should be used.

ZOSYN reconstituted from bulk and single vials can be used in ambulatory intravenous infusion pumps.

Stability of ZOSYN in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature.

Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL.

One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V.

bags or cartridge).

The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer’s instructions.

Stability of ZOSYN is not affected when administered using an ambulatory intravenous infusion pump.

2.6 Directions for Use of ZOSYN in GALAXY Containers ZOSYN Injection is to be administered using sterile equipment, after thawing to room temperature.

ZOSYN containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer’s injection, USP.

Do not add supplementary medication.

Unused portions of ZOSYN should be discarded.

CAUTION: Do not use plastic containers in series connections.

Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Thawing of Plastic Container Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]).

Do not force thaw by immersion in water baths or by microwave irradiation.

Check for minute leaks by squeezing container firmly.

If leaks are detected, discard solution as sterility may be impaired.

The container should be visually inspected.

Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation.

Potency is not affected.

Agitate after solution has reached room temperature.

If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.

Administer by infusion over a period of at least 30 minutes.

During the infusion it is desirable to discontinue the primary infusion solution.

Storage Store in a freezer capable of maintaining a temperature of -20°C (-4°F).

For GALAXY containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F].

Do not refreeze thawed ZOSYN.

2.7 Compatibility with Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration.

ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1) ].

In circumstances where co-administration via Y-site is necessary, ZOSYN formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 2: Compatibility with Aminoglycosides Aminoglycoside ZOSYN Dose (grams) ZOSYN Diluent Volume Diluent volumes apply only to single vials and bulk pharmacy containers (mL) Aminoglycoside Concentration Range The concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10–15 mg/kg/day in two daily doses for amikacin and 3–5 mg/kg/day in three daily doses for gentamicin).

Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with ZOSYN containing EDTA has not been evaluated.

See package insert for each aminoglycoside for complete Dosage and Administration instructions.

(mg/mL) Acceptable Diluents Amikacin 2.25 50 1.75 – 7.5 0.9% sodium chloride or 5% dextrose 3.375 100 4.5 150 Gentamicin 2.25 50 0.7 – 3.32 0.9% sodium chloride or 5% dextrose 3.375ZOSYN 3.375 g per 50 mL GALAXY containers are NOT compatible with gentamicin for co-administration via a Y-site due to the higher concentrations of piperacillin and tazobactam.

100 4.5 150 Only the concentration and diluents for amikacin or gentamicin with the dosages of ZOSYN listed above have been established as compatible for co-administration via Y-site infusion.

Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by ZOSYN.

ZOSYN is not compatible with tobramycin for simultaneous co-administration via Y-site infusion.

Compatibility of ZOSYN with other aminoglycosides has not been established.

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

heparin sodium, porcine 25,000 UNT in 500 ML Injection

Generic Name: HEPARIN SODIUM
Brand Name: Heparin Sodium
  • Substance Name(s):
  • HEPARIN SODIUM

DRUG INTERACTIONS

7 •Drugs that interfere with platelet aggregation: May induce bleeding.

(7.2) 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time.

Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.

7.2 Platelet Inhibitors Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.

7.3 Other Interactions Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous (IV) nitroglycerin may partially counteract the anticoagulant action of heparin sodium.

7.4 Drug/Laboratory Test Interactions Prothrombin time – Heparin sodium may prolong the one-stage prothrombin time.

Therefore, when heparin sodium is given with warfarin, allow a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain a valid prothrombin time.

OVERDOSAGE

10 Bleeding is the chief sign of heparin overdosage.

Neutralization of heparin effect.

When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium.

No more than 50 mg should be administered, very slowly in any 10 minute period.

Each mg of protamine sulfate neutralizes approximately 100 USP Heparin Units.

The amount of protamine required decreases over time as heparin is metabolized.

Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about ½ hour after intravenous injection.

Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information, consult the prescribing information for Protamine Sulfate Injection, USP.

DESCRIPTION

11 Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans possessing anticoagulant properties.

It is composed of polymers of alternating derivations of α-D-glucosamido (N-Sulfated O-Sulfated or N-acetylated) and O-sulfated uronic acid (α-L-iduronic acid or β-D-glucoronic acid).

Structure of Heparin Sodium (representative subunits): HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION is a sterile preparation of heparin sodium (derived from porcine intestinal mucosa) for intravenous administration.

It contains no bacteriostatic or antimicrobial agent or added buffer.

The solution may contain sodium hydroxide and/or hydrochloric acid for pH adjustment.

The pH range is 6.1 (5.0 – 7.5) and the osmolarity mOsmol/L (calc.) is 155.

The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Each mL of the 50 USP units per mL preparations contains: 50 USP units of heparin sodium, 4.5 mg sodium chloride and 0.1 mg edetate disodium, anhydrous added as a stabilizer.

Each mL of the 100 USP units per mL preparations contains: 100 USP units of heparin sodium, 4.5 mg sodium chloride and 0.1 mg edetate disodium, anhydrous added as a stabilizer structural formula for heparin

HOW SUPPLIED

16 /STORAGE AND HANDLING Intravenous solutions with heparin sodium are supplied in single-dose flexible plastic containers in varied sizes and concentrations as shown in the accompanying Table.

Unit of Sale Concentration Each NDC 0409-7650-62 Case containing 24 25,000 USP units/250 mL (100 USP units/mL) 0409-7650-52 250 mL flexible plastic container NDC 0409-7651-62 Case containing 24 12,500 USP units/250 mL (50 USP units/mL) 0409-7651-52 250 mL flexible plastic container NDC 0409-7651-03 Case containing 24 25,000 USP units/500 mL (50 USP units/mL) 0409-7651-13 500 mL flexible plastic container Store at 20 to 25°C (68 to 77°F).

[See USP Controlled Room Temperature.] Protect from freezing.

GERIATRIC USE

8.5 Geriatric Use There are limited adequate and well-controlled studies in patients 65 years and older.

However, a higher incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings and Precautions (5.2) ].

Lower doses of heparin may be indicated in these patients [see Clinical Pharmacology (12.3) ].

DOSAGE FORMS AND STRENGTHS

3 HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION is available as: •Injection: 100 USP Units/mL in 0.45% Sodium Chloride clear solution (25,000 USP Units/250 mL) in single-dose plastic container •Injection: 50 USP Units/mL in 0.45% Sodium Chloride clear solution (12,500 USP Units/250 mL) in single-dose plastic container •Injection: 50 USP Units/mL in 0.45% Sodium Chloride clear solution (25,000 USP Units/500 mL) in single-dose plastic container •Heparin sodium is available as: (3) •Injection: 100 USP Units/mL in 0.45% Sodium Chloride clear solution (25,000 USP Units/250 mL) in single-dose plastic container •Injection: 50 USP Units/mL in 0.45% Sodium Chloride clear solution (12,500 USP Units/250 mL) in single-dose plastic container •Injection: 50 USP Units/mL in 0.45% Sodium Chloride clear solution (25,000 USP Units/500 mL) in single-dose plastic container

MECHANISM OF ACTION

12.1 Mechanism of Action Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo.

Heparin acts at multiple sites in the normal coagulation system.

Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.

Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin.

Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

INDICATIONS AND USAGE

1 Heparin sodium is indicated for: •Prophylaxis and treatment of venous thrombosis and pulmonary embolism; •Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation; •Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation); •Prevention of clotting in arterial and cardiac surgery; •Prophylaxis and treatment of peripheral arterial embolism; •Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures.

Heparin sodium is indicated for: (1) •Prophylaxis and treatment of venous thromboembolism •Prophylaxis and treatment of the thromboembolic complications associated with atrial fibrillation •Treatment of acute and chronic consumption coagulopathies •Prevention of clotting in arterial and cardiac surgery •Prophylaxis and treatment of peripheral arterial embolism •Anticoagulant use in extracorporeal circulation and dialysis procedure

PEDIATRIC USE

2.4 Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients.

Pediatric dosing recommendations are based on clinical experience.

In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain a PTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70.

PREGNANCY

8.1 Pregnancy Risk Summary In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans.

No teratogenicity was observed in animal reproduction studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses up to 10,000 units/kg/day, approximately 10 times the maximum recommended human dose (MRHD) of 40,000 units/24 hours infusion [see Data].

In pregnant animals, doses up to10 times higher than the maximum human daily dose based on body weight resulted in increased resorptions.

Consider the benefits and risks of HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION to a pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM IN 0.45% SODIUM CHLORIDE INJECTION.

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 Human Data The maternal and fetal outcomes associated with uses of heparin via various dosing methods and administration routes during pregnancy have been investigated in numerous studies.

These studies generally reported normal deliveries with no maternal or fetal bleeding and no other complications.

Animal Data In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight.

The number of early resorptions increased in both species.

There was no evidence of teratogenic effects.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Fatal Medication Errors: Confirm choice of correct strength prior to administration.

(5.1) •Hemorrhage: Fatal cases have occurred.

Use caution in conditions with increased risk of hemorrhage.

(5.2) •HIT (With or Without Thrombosis): Monitor for signs and symptoms and discontinue if indicative of HIT (With or Without Thrombosis).

(5.3) •Monitoring: Blood coagulation tests guide therapy for full-dose heparin.

Monitor platelet count and hematocrit in all patients receiving heparin.

(5.5) 5.1 Fatal Medication Errors Do not use this product as a “catheter lock flush” product.

Heparin is supplied in various strengths.

Fatal hemorrhages have occurred due to medication errors.

Carefully examine all heparin products to confirm the correct container choice prior to administration of the drug.

5.2 Hemorrhage Hemorrhage, including fatal events, has occurred in patients receiving HEPARIN SODIUM.

Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks.

Hemorrhage can occur at virtually any site in patients receiving heparin.

Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1) ].

A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3) ].

An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a hemorrhagic event.

Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including: • Cardiovascular — Subacute bacterial endocarditis.

Severe hypertension.

• Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye.

• Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.

• Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency.

To reduce the risk of bleeding, reduce the heparin dose during concomitant treatment with antithrombin III (human).

• Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine.

• Other — Menstruation, liver disease with impaired hemostasis.

5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) HIT is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets.

HIT may progress to the development of venous and arterial thromboses, a condition known as HIT with thrombosis.

Thrombotic events may also be the initial presentation for HIT.

These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death.

Monitor thrombocytopenia of any degree closely.

If the platelet count falls below 100,000/mm 3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant.

HIT can occur up to several weeks after the discontinuation of heparin therapy.

Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT.

5.4 Thrombocytopenia Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%.

It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy.

Obtain platelet counts before and periodically during heparin therapy.

Monitor thrombocytopenia of any degree closely.

If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3) ].

5.5 Coagulation Testing and Monitoring When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests.

If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly [see Overdosage (10) ].

Periodic platelet counts, hematocrits are recommended during the entire course of heparin therapy [see Dosage and Administration (2.2) ].

5.6 Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and patients with antithrombin III deficiency.

Close monitoring of coagulation tests is recommended in these cases.

Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.

5.7 Hypersensitivity Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [see Adverse Reactions (6) ].

Because heparin sodium is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Hemorrhage Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they are treated with heparin, and that they should report any unusual bleeding or bruising to their physician.

Hemorrhage can occur at virtually any site in patients receiving heparin.

Fatal hemorrhages have occurred [see Warnings and Precautions (5.2) ].

Prior to Surgery Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [see Warnings and Precautions (5.2) ].

Heparin-Induced Thrombocytopenia Inform patients of the risk of heparin-induced thrombocytopenia (HIT).

HIT may progress to the development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia and thrombosis.

HIT (With or Without Thrombosis) can occur up to several weeks after the discontinuation of heparin therapy [see Warnings and Precautions (5.3 and 5.4)].

Hypersensitivity Inform patients that generalized hypersensitivity reactions have been reported.

Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.7), Adverse Reactions (6) ].

Other Medications Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all medications they are taking, including non-prescription medications, and before starting any new medication [see Drug Interactions (7.2) ].

EN-4244 Hospira, Inc., Lake Forest, IL 60045 USA Hospira logo

DOSAGE AND ADMINISTRATION

2 Recommended Adult Dosages: •Therapeutic Anticoagulant Effect with Full-Dose Heparin* (2.3) Intermittent IV injection Initial Dose 10,000 units Every 4 to 6 hours 5,000 to 10,000 units Continuous IV infusion Initial Dose 5,000 units Continuous 20,000 to 40,000 units/24 hours *Based on 150 lb.

(68 kg) patient.

•Surgery of the Heart and Blood Vessels (2.5) Intravascular via Total Body Perfusion Initial Dose ≥ 150 units/kg; adjust for longer procedures •Extracorporeal Dialysis (2.8) Intravascular via Extracorporeal Dialysis Follow equipment manufacturer’s operating directions carefully.

2.1 Preparation for Administration Confirm the selection of the correct formulation and strength prior to administration of the drug.

Do not use Heparin Sodium in 0.45% Sodium Chloride Injection as a “catheter lock flush” product.

Administer this product by intravenous infusion.

Do not admix with other drugs.

Do not use flexible container in series connections.

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

2.2 Laboratory Monitoring for Efficacy and Safety Adjust the dosage of heparin sodium according to the patient’s coagulation test results.

When heparin is given by continuous intravenous infusion, determine the coagulation time approximately every 4 hours in the early stages of treatment.

When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the early stages of treatment and at appropriate intervals thereafter.

Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times the normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value.

Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy.

2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin The dosing recommendations in Table 1 are based on clinical experience.

Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect Method of Administration Frequency Recommended Dose Based on 150 lb.

(68 kg) patient.

Intermittent Intravenous Injection Initial Dose 10,000 Units Every 4 to 6 hours 5,000 – 10,000 Units Continuous Intravenous Infusion Initial Dose 5,000 Units by IV injection Continuous 20,000 – 40,000 Units/24 hours 2.4 Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients.

Pediatric dosing recommendations are based on clinical experience.

In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain a PTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70.

2.5 Cardiovascular Surgery Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight.

Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes or 400 units per kilogram for those estimated to last longer than 60 minutes.

2.6 Converting to Warfarin To ensure continuous anticoagulation when converting from HEPARIN SODIUM to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range.

Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.4) ].

2.7 Converting to Oral Anticoagulants other than Warfarin For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered.

2.8 Extracorporeal Dialysis Follow equipment manufacturer’s operating directions carefully.

A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers’ recommendations are not available.

Sumatriptan 100 MG Oral Tablet [Imitrex]

Generic Name: SUMATRIPTAN SUCCINATE
Brand Name: IMITREX
  • Substance Name(s):
  • SUMATRIPTAN SUCCINATE

WARNINGS

IMITREX Tablets should only be used where a clear diagnosis of migraine headache has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS).

It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease.

The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best.

If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan .

Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following IMITREX Tablets in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan .

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan .

Drug-Associated Cardiac Events and Fatalities Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of IMITREX® (sumatriptan succinate) Injection or IMITREX Tablets.

Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low.

The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug.

In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Premarketing Experience With Sumatriptan : Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm.

Neither of these adverse events was associated with a serious clinical outcome.

Among the more than 1,900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm.

Six of these 8 patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs.

Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.

Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.

Postmarketing Experience With Sumatriptan : Serious cardiovascular events, some resulting in death, have been reported in association with the use of IMITREX Injection or IMITREX Tablets.

The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan or to reliably assess causation in individual cases.

On clinical grounds, the longer the latency between the administration of IMITREX and the onset of the clinical event, the less likely the association is to be causative.

Accordingly, interest has focused on events beginning within 1 hour of the administration of IMITREX.

Cardiac events that have been observed to have onset within 1 hour of sumatriptan administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.

Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm.

However, among domestic reports of serious cardiac events within 1 hour of sumatriptan administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see CONTRAINDICATIONS).

Drug-Associated Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities.

The relationship of sumatriptan to these events is uncertain.

In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack).

Other Vasospasm-Related Events Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm.

Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported.

Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan.

Visual disorders may also be part of a migraine attack.

Serotonin Syndrome Serotonin syndrome may occur with triptans, including IMITREX, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication.

Treatment with IMITREX should be discontinued if serotonin syndrome is suspected.

Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension.

Sumatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS).

Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

Concomitant Drug Use In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions.

Accordingly, the coadministration of IMITREX Tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Hypersensitivity Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan.

Such reactions can be life threatening or fatal.

In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).

DRUG INTERACTIONS

Drug Interactions Monoamine Oxidase Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS).

Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan.

In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan.

Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration × time curve (AUC), corresponding to a 40% increase in elimination half-life.

This interaction was not evident with an MAO-B inhibitor.

A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.

Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

OVERDOSAGE

Patients (N = 670) have received single oral doses of 140 to 300 mg without significant adverse effects.

Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events.

Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation.

The elimination half-life of sumatriptan is approximately 2.5 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with IMITREX Tablets should continue for at least 12 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

DESCRIPTION

IMITREX Tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 receptor subtype agonist.

Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5.

Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline.

Each IMITREX Tablet for oral administration contains 35, 70, or 140 mg of sumatriptan succinate equivalent to 25, 50, or 100 mg of sumatriptan, respectively.

Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate.

Each 100-mg tablet also contains hypromellose, iron oxide, titanium dioxide, and triacetin.

Imitrex Tablets Chemical Structure

CLINICAL STUDIES

The efficacy of IMITREX Tablets in the acute treatment of migraine headaches was demonstrated in 3, randomized, double-blind, placebo-controlled studies.

Patients enrolled in these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range, 18 to 65 years).

Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing.

Associated symptoms such as nausea, photophobia, and phonophobia were also assessed.

Maintenance of response was assessed for up to 24 hours postdose.

A second dose of IMITREX Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache.

Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or worsened.

Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 studies.

The frequency and time to use of these additional treatments were also determined.

In all studies, doses of 25, 50, and 100 mg were compared to placebo in the treatment of migraine attacks.

In 1 study, doses of 25, 50, and 100 mg were also compared to each other.

In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving IMITREX Tablets at all doses compared to those who received placebo.

In 1 of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50- or 100-mg group when compared to the 25-mg dose groups.

There were no statistically significant differences between the 50- and 100-mg dose groups in any study.

The results from the 3 controlled clinical trials are summarized in Table 1.

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable.

Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

Table 1.

Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment Placebo 2 hr 4 hr IMITREX Tablets 25 mg 2 hr 4 hr IMITREX Tablets 50 mg 2 hr 4 hr IMITREX Tablets 100 mg 2 hr 4 hr Study 1 27% 38% 52%a 67%a 61%ab 78%ab 62%ab 79%ab (N = 94) (N = 298) (N = 296) (N = 296) Study 2 26% 38% 52%a 70%a 50%a 68%a 56%a 71%a (N = 65) (N = 66) (N = 62) (N = 66) Study 3 17% 19% 52%a 65%a 54%a 72%a 57%a 78%a (N = 47) (N = 48) (N = 46) (N = 46) a P<0.05 in comparison with placebo.

b P<0.05 in comparison with 25 mg.

The estimated probability of achieving an initial headache response over the 4 hours following treatment is depicted in Figure 1.

Figure 1.

Estimated Probability of Achieving Initial Headache Response Within 240 Minutesa aThe figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with sumatriptan.

The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy.

Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes.

For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, and 3) following administration of IMITREX Tablets compared to placebo.

As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication.

The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2.

The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatmenta aKaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours.

Plot also includes patients who had no response to the initial dose.

No remedication was allowed within 2 hours postdose.

There is evidence that doses above 50 mg do not provide a greater effect than 50 mg.

There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches.

The efficacy of IMITREX Tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants).

There were insufficient data to assess the impact of race on efficacy.

Figure 1.

Estimated Probability of Achieving Initial Headache Response Within 240 Minutes* Figure 2.

The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment*

HOW SUPPLIED

IMITREX Tablets, 100 mg of sumatriptan (base) as the succinate.

IMITREX Tablets, 100 mg, are pink, triangular-shaped, film-coated tablets debossed with “IMITREX 100” on one side and a chevron shape (^) on the other in blister packs of 9 tablets (NDC 54868-5118-0).

Store between 36° and 86°F (2° and 30°C).

GERIATRIC USE

Geriatric Use The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).

MECHANISM OF ACTION

Mechanism of Action Sumatriptan is an agonist for a vascular 5‑hydroxytryptamine1 receptor subtype (probably a member of the 5‑HT1D family) having only a weak affinity for 5‑HT1A, 5‑HT5A, and 5‑HT7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5‑HT2, 5‑HT3, or 5‑HT4 receptor subtypes or at alpha1‑, alpha2‑, or beta‑adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors.

The vascular 5‑HT1 receptor subtype that sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction.

This action in humans correlates with the relief of migraine headache.

In addition to causing vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5‑HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels.

Such an action may also contribute to the antimigrainous effect of sumatriptan in humans.

In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance.

In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

INDICATIONS AND USAGE

IMITREX Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults.

IMITREX Tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS).

Safety and effectiveness of IMITREX Tablets have not been established for cluster headache, which is present in an older, predominantly male population.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of IMITREX Tablets in pediatric patients under 18 years of age have not been established; therefore, IMITREX Tablets are not recommended for use in patients under 18 years of age.

Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack.

The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents.

Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single attack studies, 3 multiple attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs.

These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents.

Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents.

Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan.

These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death.

A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration.

Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in patients aged younger than 18 years is not recommended.

PREGNANCY

Pregnancy Pregnancy Category C.

In reproductive toxicity studies in rats and rabbits, oral treatment with sumatriptan was associated with embryolethality, fetal abnormalities, and pup mortality.

When administered by the intravenous route to rabbits, sumatriptan has been shown to be embryolethal.

There are no adequate and well-controlled studies in pregnant women.

Therefore, IMITREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In assessing this information, the following findings should be considered.

Embryolethality : When given orally or intravenously to pregnant rabbits daily throughout the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity.

In the oral studies this dose was 100 mg/kg/day, and in the intravenous studies this dose was 2.0 mg/kg/day.

The mechanism of the embryolethality is not known.

The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, which is approximately 9 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or approximately one tenth of the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality.

This dose is equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Additionally, in a study in rats given subcutaneous sumatriptan daily prior to and throughout pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased embryo/fetal lethality.

This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Teratogenicity : Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic and umbilical) at doses of approximately 250 mg/kg/day or higher.

The highest no-effect dose was approximately 60 mg/kg/day, which is approximately 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Oral treatment of pregnant rabbits with sumatriptan during the period of organogenesis resulted in an increased incidence of cervicothoracic vascular and skeletal abnormalities.

The highest no-effect dose for these effects was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

A study in which rats were dosed daily with oral sumatriptan prior to and throughout gestation demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased incidence of rib variations) and an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) at 500 mg/kg/day.

The highest no-effect dose was 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no evidence of teratogenicity.

This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Pup Deaths: Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses of approximately 250 mg/kg/day or higher.

The highest no-effect dose for this effect was approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Oral treatment of pregnant rats with sumatriptan from gestational day 17 through postnatal day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the dose of 1,000 mg/kg/day.

The highest no-effect dose for this finding was 100 mg/kg/day, approximately 10 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

In a similar study in rats by the subcutaneous route there was no increase in pup death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

NUSRING MOTHERS

Nursing Mothers Sumatriptan is excreted in human breast milk following subcutaneous administration.

Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Tablets.

INFORMATION FOR PATIENTS

Information for Patients See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.

DOSAGE AND ADMINISTRATION

In controlled clinical trials, single doses of 25, 50, or 100 mg of IMITREX Tablets were effective for the acute treatment of migraine in adults.

There is evidence that doses of 50 and 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS).

There is also evidence that doses of 100 mg do not provide a greater effect than 50 mg.

Individuals may vary in response to doses of IMITREX Tablets.

The choice of dose should therefore be made on an individual basis, weighing the possible benefit of a higher dose with the potential for a greater risk of adverse events.

If the headache returns or the patient has a partial response to the initial dose, the dose may be repeated after 2 hours, not to exceed a total daily dose of 200 mg.

If a headache returns following an initial treatment with IMITREX Injection, additional single IMITREX Tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses.

The safety of treating an average of more than 4 headaches in a 30-day period has not been established.

Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the bioavailability of oral sumatriptan, their combined use is contraindicated (see CONTRAINDICATIONS).

Hepatic disease/functional impairment may also cause unpredictable elevations in the bioavailability of orally administered sumatriptan.

Consequently, if treatment is deemed advisable in the presence of liver disease, the maximum single dose should in general not exceed 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation).

Sumatriptan 25 MG Oral Tablet [Imitrex]

Generic Name: SUMATRIPTAN SUCCINATE
Brand Name: IMITREX
  • Substance Name(s):
  • SUMATRIPTAN SUCCINATE

WARNINGS

IMITREX Tablets should only be used where a clear diagnosis of migraine headache has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS).

It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease.

The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best.

If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan .

Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following IMITREX Tablets in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan .

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan .

Drug-Associated Cardiac Events and Fatalities Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of IMITREX® (sumatriptan succinate) Injection or IMITREX Tablets.

Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low.

The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug.

In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Premarketing Experience With Sumatriptan : Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm.

Neither of these adverse events was associated with a serious clinical outcome.

Among the more than 1,900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm.

Six of these 8 patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs.

Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.

Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.

Postmarketing Experience With Sumatriptan : Serious cardiovascular events, some resulting in death, have been reported in association with the use of IMITREX Injection or IMITREX Tablets.

The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan or to reliably assess causation in individual cases.

On clinical grounds, the longer the latency between the administration of IMITREX and the onset of the clinical event, the less likely the association is to be causative.

Accordingly, interest has focused on events beginning within 1 hour of the administration of IMITREX.

Cardiac events that have been observed to have onset within 1 hour of sumatriptan administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.

Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm.

However, among domestic reports of serious cardiac events within 1 hour of sumatriptan administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see CONTRAINDICATIONS).

Drug-Associated Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities.

The relationship of sumatriptan to these events is uncertain.

In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack).

Other Vasospasm-Related Events Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm.

Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported.

Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan.

Visual disorders may also be part of a migraine attack.

Serotonin Syndrome Serotonin syndrome may occur with triptans, including IMITREX, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication.

Treatment with IMITREX should be discontinued if serotonin syndrome is suspected.

Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension.

Sumatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS).

Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

Concomitant Drug Use In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions.

Accordingly, the coadministration of IMITREX Tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Hypersensitivity Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan.

Such reactions can be life threatening or fatal.

In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).

DRUG INTERACTIONS

Drug Interactions Monoamine Oxidase Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS).

Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan.

In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan.

Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration × time curve (AUC), corresponding to a 40% increase in elimination half-life.

This interaction was not evident with an MAO-B inhibitor.

A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.

Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

OVERDOSAGE

Patients (N = 670) have received single oral doses of 140 to 300 mg without significant adverse effects.

Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events.

Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation.

The elimination half-life of sumatriptan is approximately 2.5 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with IMITREX Tablets should continue for at least 12 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

DESCRIPTION

IMITREX Tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 receptor subtype agonist.

Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5.

Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline.

Each IMITREX Tablet for oral administration contains 35, 70, or 140 mg of sumatriptan succinate equivalent to 25, 50, or 100 mg of sumatriptan, respectively.

Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate.

Each 100-mg tablet also contains hypromellose, iron oxide, titanium dioxide, and triacetin.

Imitrex Tablets Chemical Structure

CLINICAL STUDIES

The efficacy of IMITREX Tablets in the acute treatment of migraine headaches was demonstrated in 3, randomized, double-blind, placebo-controlled studies.

Patients enrolled in these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range, 18 to 65 years).

Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing.

Associated symptoms such as nausea, photophobia, and phonophobia were also assessed.

Maintenance of response was assessed for up to 24 hours postdose.

A second dose of IMITREX Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache.

Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or worsened.

Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 studies.

The frequency and time to use of these additional treatments were also determined.

In all studies, doses of 25, 50, and 100 mg were compared to placebo in the treatment of migraine attacks.

In 1 study, doses of 25, 50, and 100 mg were also compared to each other.

In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving IMITREX Tablets at all doses compared to those who received placebo.

In 1 of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50- or 100-mg group when compared to the 25-mg dose groups.

There were no statistically significant differences between the 50- and 100-mg dose groups in any study.

The results from the 3 controlled clinical trials are summarized in Table 1.

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable.

Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

Table 1.

Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment Placebo 2 hr 4 hr IMITREX Tablets 25 mg 2 hr 4 hr IMITREX Tablets 50 mg 2 hr 4 hr IMITREX Tablets 100 mg 2 hr 4 hr Study 1 27% 38% 52%a 67%a 61%ab 78%ab 62%ab 79%ab (N = 94) (N = 298) (N = 296) (N = 296) Study 2 26% 38% 52%a 70%a 50%a 68%a 56%a 71%a (N = 65) (N = 66) (N = 62) (N = 66) Study 3 17% 19% 52%a 65%a 54%a 72%a 57%a 78%a (N = 47) (N = 48) (N = 46) (N = 46) a P<0.05 in comparison with placebo.

b P<0.05 in comparison with 25 mg.

The estimated probability of achieving an initial headache response over the 4 hours following treatment is depicted in Figure 1.

Figure 1.

Estimated Probability of Achieving Initial Headache Response Within 240 Minutesa aThe figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with sumatriptan.

The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy.

Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes.

For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, and 3) following administration of IMITREX Tablets compared to placebo.

As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication.

The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2.

The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatmenta aKaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours.

Plot also includes patients who had no response to the initial dose.

No remedication was allowed within 2 hours postdose.

There is evidence that doses above 50 mg do not provide a greater effect than 50 mg.

There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches.

The efficacy of IMITREX Tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants).

There were insufficient data to assess the impact of race on efficacy.

Figure 1.

Estimated Probability of Achieving Initial Headache Response Within 240 Minutes* Figure 2.

The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment*

HOW SUPPLIED

IMITREX Tablets, 100 mg of sumatriptan (base) as the succinate.

IMITREX Tablets, 100 mg, are pink, triangular-shaped, film-coated tablets debossed with “IMITREX 100” on one side and a chevron shape (^) on the other in blister packs of 9 tablets (NDC 54868-5118-0).

Store between 36° and 86°F (2° and 30°C).

GERIATRIC USE

Geriatric Use The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).

MECHANISM OF ACTION

Mechanism of Action Sumatriptan is an agonist for a vascular 5‑hydroxytryptamine1 receptor subtype (probably a member of the 5‑HT1D family) having only a weak affinity for 5‑HT1A, 5‑HT5A, and 5‑HT7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5‑HT2, 5‑HT3, or 5‑HT4 receptor subtypes or at alpha1‑, alpha2‑, or beta‑adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors.

The vascular 5‑HT1 receptor subtype that sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction.

This action in humans correlates with the relief of migraine headache.

In addition to causing vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5‑HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels.

Such an action may also contribute to the antimigrainous effect of sumatriptan in humans.

In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance.

In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

INDICATIONS AND USAGE

IMITREX Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults.

IMITREX Tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS).

Safety and effectiveness of IMITREX Tablets have not been established for cluster headache, which is present in an older, predominantly male population.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of IMITREX Tablets in pediatric patients under 18 years of age have not been established; therefore, IMITREX Tablets are not recommended for use in patients under 18 years of age.

Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack.

The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents.

Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single attack studies, 3 multiple attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs.

These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents.

Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents.

Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan.

These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death.

A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration.

Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in patients aged younger than 18 years is not recommended.

PREGNANCY

Pregnancy Pregnancy Category C.

In reproductive toxicity studies in rats and rabbits, oral treatment with sumatriptan was associated with embryolethality, fetal abnormalities, and pup mortality.

When administered by the intravenous route to rabbits, sumatriptan has been shown to be embryolethal.

There are no adequate and well-controlled studies in pregnant women.

Therefore, IMITREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In assessing this information, the following findings should be considered.

Embryolethality : When given orally or intravenously to pregnant rabbits daily throughout the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity.

In the oral studies this dose was 100 mg/kg/day, and in the intravenous studies this dose was 2.0 mg/kg/day.

The mechanism of the embryolethality is not known.

The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, which is approximately 9 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or approximately one tenth of the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality.

This dose is equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Additionally, in a study in rats given subcutaneous sumatriptan daily prior to and throughout pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased embryo/fetal lethality.

This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Teratogenicity : Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic and umbilical) at doses of approximately 250 mg/kg/day or higher.

The highest no-effect dose was approximately 60 mg/kg/day, which is approximately 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Oral treatment of pregnant rabbits with sumatriptan during the period of organogenesis resulted in an increased incidence of cervicothoracic vascular and skeletal abnormalities.

The highest no-effect dose for these effects was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

A study in which rats were dosed daily with oral sumatriptan prior to and throughout gestation demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased incidence of rib variations) and an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) at 500 mg/kg/day.

The highest no-effect dose was 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no evidence of teratogenicity.

This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis.

Pup Deaths: Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses of approximately 250 mg/kg/day or higher.

The highest no-effect dose for this effect was approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

Oral treatment of pregnant rats with sumatriptan from gestational day 17 through postnatal day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the dose of 1,000 mg/kg/day.

The highest no-effect dose for this finding was 100 mg/kg/day, approximately 10 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

In a similar study in rats by the subcutaneous route there was no increase in pup death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

NUSRING MOTHERS

Nursing Mothers Sumatriptan is excreted in human breast milk following subcutaneous administration.

Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Tablets.

INFORMATION FOR PATIENTS

Information for Patients See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.

DOSAGE AND ADMINISTRATION

In controlled clinical trials, single doses of 25, 50, or 100 mg of IMITREX Tablets were effective for the acute treatment of migraine in adults.

There is evidence that doses of 50 and 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS).

There is also evidence that doses of 100 mg do not provide a greater effect than 50 mg.

Individuals may vary in response to doses of IMITREX Tablets.

The choice of dose should therefore be made on an individual basis, weighing the possible benefit of a higher dose with the potential for a greater risk of adverse events.

If the headache returns or the patient has a partial response to the initial dose, the dose may be repeated after 2 hours, not to exceed a total daily dose of 200 mg.

If a headache returns following an initial treatment with IMITREX Injection, additional single IMITREX Tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses.

The safety of treating an average of more than 4 headaches in a 30-day period has not been established.

Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the bioavailability of oral sumatriptan, their combined use is contraindicated (see CONTRAINDICATIONS).

Hepatic disease/functional impairment may also cause unpredictable elevations in the bioavailability of orally administered sumatriptan.

Consequently, if treatment is deemed advisable in the presence of liver disease, the maximum single dose should in general not exceed 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation).

Phenylephrine Hydrochloride 5 MG/ML Nasal Spray [Neo-Synephrine]

WARNINGS

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

Ask a doctor before use if you have heart disease high blood pressure thyroid disease diabetes difficulty in urination due to enlargement of the prostate gland When using this product do not exceed recommended dosage do not use more than 3 days.

Use only as directed.

Frequent or prolonged use may cause nasal congestion to recur or worsen.

temporary discomfort may occur such as burning, stinging, sneezing, or an increase in nasal discharge use of this container by more than one person may spread infection Stop use and ask a doctor if symptoms persist for more than 3 days If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Uses temporarily relieves nasal congestion: due to common cold due to hay fever or other upper respiratory allergies (allergic rhinitis) temporarily relieves stuffy nose helps clear nasal passages; shrinks swollen membranes temporarily restores freer breathing through the nose helps decongest sinus openings and passages; temporarily relieves sinus congestion and pressure

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, benzalkonium chloride, purified water, sodium chloride, sodium citrate

PURPOSE

Purpose Nasal decongestant

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.

ASK DOCTOR

Ask a doctor before use if you have heart disease high blood pressure thyroid disease diabetes difficulty in urination due to enlargement of the prostate gland

DOSAGE AND ADMINISTRATION

Directions use only as directed to spray, squeeze bottle quickly and firmly adults and children 12 years and older 2 or 3 sprays in each nostril not more often than every 4 hours children under 12 years ask a doctor

PREGNANCY AND BREAST FEEDING

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

DO NOT USE

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

STOP USE

Stop use and ask a doctor if symptoms persist for more than 3 days

ACTIVE INGREDIENTS

Active ingredient Phenylephrine hydrochloride 0.5%