Drug Intercation

Maxalt 5 MG Disintegrating Oral Tablet

WARNINGS

MAXALT should only be used where a clear diagnosis of migraine has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: Because of the potential of this class of compounds (5-HT 1B/1D agonists) to cause coronary vasospasm, MAXALT should not be given to patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS ).

It is strongly recommended that rizatriptan not be given to patients in whom unrecognized coronary artery disease (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, or 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, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, rizatriptan 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 rizatriptan take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received rizatriptan.

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 MAXALT, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of MAXALT and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use MAXALT.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to rizatriptan.

Cardiac Events and Fatalities Associated with 5-HT 1 Agonists: Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following the administration of rizatriptan.

Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other 5-HT 1 agonists.

Considering the extent of use of 5-HT 1 agonists in patients with migraine, the incidence of these events is extremely low.

MAXALT can cause coronary vasospasm.

Because of the close proximity of the events to MAXALT use, a causal relationship cannot be excluded.

In the cases where there has been known underlying coronary artery disease, the relationship is uncertain.

Premarketing experience with rizatriptan: Among the 3700 patients with migraine who participated in premarketing clinical trials of MAXALT, one patient was reported to have chest pain with possible ischemic ECG changes following a single dose of 10 mg.

Postmarketing experience with rizatriptan: Serious cardiovascular events have been reported in association with the use of MAXALT.

The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by rizatriptan or to reliably assess causation in individual cases.

Cerebrovascular Events and Fatalities Associated with 5-HT 1 Agonists: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT 1 agonists; and some have resulted in fatalities.

In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Other Vasospasm-Related Events: 5-HT 1 agonists 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 with 5-HT 1 agonists.

Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving 5-HT 1 agonists with and without a history of hypertension.

In healthy young male and female subjects who received maximal doses of MAXALT (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed.

Rizatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS ).

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT 1 agonist in a study evaluating subjects undergoing cardiac catheterization.

Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with triptans, including MAXALT treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

If concomitant treatment with rizatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

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) (see PRECAUTIONS, Drug Interactions ).

DRUG INTERACTIONS

Drug Interactions (See also PRECAUTIONS, Drug Interactions .) Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, ‘A’ subtype (MAO-A).

Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline).

In a drug interaction study, when MAXALT 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and C max of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%.

The interaction would be expected to be greater with irreversible MAO inhibitors.

No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors.

(See CONTRAINDICATIONS ; PRECAUTIONS, Drug Interactions .) Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a fourfold increase was observed in one subject.

The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol.

(See PRECAUTIONS ; DOSAGE AND ADMINISTRATION .) Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12).

No pharmacokinetic interactions were observed.

Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of MAXALT 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine (see WARNINGS and PRECAUTIONS, Information for Patients ).

Oral contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of MAXALT (10-30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone.

OVERDOSAGE

No overdoses of MAXALT were reported during clinical trials.

Rizatriptan 40 mg (administered as either a single dose or as two doses with a 2-hour interdose interval) was generally well tolerated in over 300 patients; dizziness and somnolence were the most common drug-related adverse effects.

In a clinical pharmacology study in which 12 subjects received rizatriptan, at total cumulative doses of 80 mg (given within four hours), two subjects experienced syncope and/or bradycardia.

One subject, a female aged 29 years, developed vomiting, bradycardia, and dizziness beginning three hours after receiving a total of 80 mg rizatriptan (administered over two hours); a third degree AV block, responsive to atropine, was observed an hour after the onset of the other symptoms.

The second subject, a 25 year old male, experienced transient dizziness, syncope, incontinence, and a 5-second systolic pause (on ECG monitor) immediately after a painful venipuncture.

The venipuncture occurred two hours after the subject had received a total of 80 mg rizatriptan (administered over four hours).

In addition, based on the pharmacology of rizatriptan, hypertension or other more serious cardiovascular symptoms could occur after overdosage.

Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with MAXALT.

Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.

The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.

DESCRIPTION

Rizatriptan benzoate is described chemically as: N,N -dimethyl-5-(1 H -1,2,4-triazol-1-ylmethyl)-1 H -indole-3-ethanamine monobenzoate and its structural formula is: Its empirical formula is C 15 H 19 N 5 •C 7 H 6 O 2 , representing a molecular weight of the free base of 269.4.

Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively).

Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, ferric oxide (red), and magnesium stearate.

Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, and peppermint flavor.

image of structural formula

CLINICAL STUDIES

Clinical Studies The efficacy of MAXALT Tablets was established in four multicenter, randomized, placebo-controlled trials.

Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71).

Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4).

Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours postdose were evaluated.

A second dose of MAXALT Tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2.

Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.

In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either MAXALT 5 or 10 mg compared to those who received placebo.

In a separate study, doses of 2.5 mg were not different from placebo.

Doses greater than 10 mg were associated with an increased incidence of adverse effects.

The results from the 4 controlled studies using the marketed formulation are summarized in Table 1.

Table 1: Response Rates 2 Hours Following Treatment of Initial Headache Study Placebo MAXALT Tablets 5 mg MAXALT Tablets 10 mg 1 35% (n=304) 62% p value < 0.05 in comparison with placebo (n=458) 71% , (n=456) 2 37% (n=82) — 77% (n=320) 3 23% (n=80) 63% (n=352) — 4 40% (n=159) 60% (n=164) 67% (n=385) 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.

The estimated probability of achieving an initial headache response within 2 hours following treatment is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours †† For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of MAXALT compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response 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: Estimated Probability of Patients Taking a Second Dose of MAXALT Tablets or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment ††† Efficacy was unaffected by the presence of aura; by the gender, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives.

In two additional similar studies, efficacy was unaffected by relationship to menses.

There were insufficient data to assess the impact of race on efficacy.

In a single study in adolescents (n=291), there were no statistically significant differences between treatment groups.

The headache response rates at 2 hours were 66% and 56% for MAXALT 5 mg Tablets and placebo, respectively.

MAXALT-MLT Orally Disintegrating Tablets The efficacy of MAXALT-MLT was established in two multicenter, randomized, placebo-controlled trials that were similar in design to the trials of MAXALT Tablets.

Patients were instructed to treat a moderate to severe headache.

Patients treated in these studies were primarily female (88%) and Caucasian (95%), with a mean age of 42 years (range 18-72).

In both studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either MAXALT-MLT 5 or 10 mg compared to those who received placebo.

The results from the 2 controlled studies using the marketed formulation are summarized in Table 2.

Table 2: Response Rates 2 Hours Following Treatment of Initial Headache Study Placebo MAXALT-MLT 5 mg MAXALT-MLT 10 mg 1 47% (n=98) 66% p value < 0.01 in comparison with placebo (n=100) 66% (n=113) 2 28% (n=180) 59% (n=181) 74% , (n=186) The estimated probability of achieving an initial headache response by 2 hours following treatment with MAXALT-MLT is depicted in Figure 3.

Figure 3: Estimated Probability of Achieving an Initial Headache Response with MAXALT-MLT by 2 Hours ‡ For patients with migraine-associated photophobia and phonophobia at baseline, there was a decreased incidence of these symptoms following administration of MAXALT-MLT as compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response 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 4.

Figure 4: Estimated Probability of Patients Taking a Second Dose of MAXALT-MLT or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment ‡‡

HOW SUPPLIED

No.

3732 — MAXALT Tablets, 5 mg, are pale pink, capsule-shaped, compressed tablets coded MRK on one side and 266 on the other.

They are supplied as follows: NDC 0006-0266-18, carton of 18 tablets.

No.

3733 — MAXALT Tablets, 10 mg, are pale pink, capsule-shaped, compressed tablets coded MAXALT on one side and MRK 267 on the other.

They are supplied as follows: NDC 0006-0267-18, carton of 18 tablets.

No.

3800 — MAXALT-MLT Orally Disintegrating Tablets, 5 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified triangle on one side, and measuring 10.0-11.5 mm (side-to-side) with a peppermint flavor.

Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet).

They are supplied as follows: NDC 0006-3800-18, 6 x unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).

No.

3801 — MAXALT-MLT Orally Disintegrating Tablets, 10 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified square on one side, and measuring 12.0-13.8 mm (side-to-side) with a peppermint flavor.

Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet).

They are supplied as follows: NDC 0006-3801-18, 6 x unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).

Storage Store MAXALT Tablets at room temperature, 15-30°C (59-86°F).

Dispense in a tight container, if product is subdivided.

Store MAXALT-MLT Orally Disintegrating Tablets at room temperature, 15-30°C (59-86°F).

The patient should be instructed not to remove the blister from the outer aluminum pouch until the patient is ready to consume the orally disintegrating tablet inside.

MAXALT Tablets are manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA By: MSD, Ltd.

Cramlington, Northumberland, NE23 3JU, UK MAXALT-MLT Orally Disintegrating Tablets are manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA By: Catalent UK Swindon, Zydis Ltd.

Swindon, Wiltshire, SN5 8RU, UK US Patent No.: 5,298,520 Issued August 2010 9652508

GERIATRIC USE

Geriatric Use The pharmacokinetics of rizatriptan were similar in elderly (aged ≥ 65 years) and in younger adults.

Because migraine occurs infrequently in the elderly, clinical experience with MAXALT is limited in such patients.

In clinical trials, there were no apparent differences in efficacy or in overall adverse experience rates between patients under 65 years of age and those 65 and above (n=17).

MECHANISM OF ACTION

Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B and 5-HT 1D receptors.

Rizatriptan has weak affinity for other 5-HT 1 receptor subtypes (5-HT 1A , 5-HT 1E , 5-HT 1F ) and the 5-HT 7 receptor, but has no significant activity at 5-HT 2 , 5-HT 3 , alpha- and beta-adrenergic, dopaminergic, histaminergic, muscarinic or benzodiazepine receptors.

Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system.

The therapeutic activity of rizatriptan in migraine can most likely be attributed to agonist effects at 5-HT 1B/1D receptors on the extracerebral, intracranial blood vessels that become dilated during a migraine attack and on nerve terminals in the trigeminal system.

Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release and reduced transmission in trigeminal pain pathways.

INDICATIONS AND USAGE

MAXALT is indicated for the acute treatment of migraine attacks with or without aura in adults.

MAXALT is 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 MAXALT have not been established for cluster headache, which is present in an older, predominantly male population.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of rizatriptan in pediatric patients have not been established; therefore, MAXALT is not recommended for use in patients under 18 years of age.

The efficacy of MAXALT Tablets (5 mg) in patients aged 12 to 17 years was not established in a randomized placebo-controlled trial of 291 adolescent migraineurs (see Clinical Studies ).

Adverse events observed were similar in nature to those reported in clinical trials in adults.

Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.

The long-term safety of rizatriptan in pediatric patients has not been studied.

PREGNANCY

Pregnancy: Pregnancy Category C In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day.

Maternal drug exposures (AUC) at these doses were approximately 15 and 225 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 30 mg.

In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre- and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day.

The no-effect dose for all of these effects was 5 mg/kg/day, approximately 7.5 times the exposure in humans receiving the MRDD.

With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood.

All of these effects on the offspring in both reproductive toxicity studies occurred in the absence of any apparent maternal toxicity.

In embryofetal development studies, no teratogenic effects were observed when pregnant rats and rabbits were administered doses of 100 and 50 mg/kg/day, respectively, during organogenesis.

Fetal weights were decreased in conjunction with decreased maternal weight gain at the highest doses (maternal exposures approximately 225 and 115 times the human exposure at the MRDD in rats and rabbits, respectively).

The developmental no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (maternal exposures approximately 15 times human exposure at the MRDD).

Toxicokinetic studies demonstrated placental transfer of drug in both species.

There are no adequate and well-controlled studies in pregnant women; therefore, rizatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to MAXALT while pregnant.

Healthcare providers are encouraged to report any prenatal exposure to MAXALT by calling the Pregnancy Registry at (800) 986-8999.

NUSRING MOTHERS

Nursing Mothers It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when MAXALT is administered to women who are breast-feeding.

Rizatriptan is extensively excreted in rat milk, at a level of 5-fold or greater than maternal plasma levels.

INFORMATION FOR PATIENTS

Information for Patients Migraine or treatment with MAXALT may cause somnolence in some patients.

Dizziness has also been reported in some patients receiving MAXALT.

Patients should, therefore, evaluate their ability to perform complex tasks during migraine attacks and after administration of MAXALT.

Physicians should instruct their patients to read the patient package insert before taking MAXALT.

See the accompanying PATIENT INFORMATION leaflet.

Patients should be cautioned about the risk of serotonin syndrome with the use of rizatriptan or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (see WARNINGS ).

DOSAGE AND ADMINISTRATION

In controlled clinical trials, single doses of 5 and 10 mg of MAXALT Tablets or MAXALT-MLT were effective for the acute treatment of migraines in adults.

There is evidence that the 10-mg dose may provide a greater effect than the 5-mg dose (see CLINICAL PHARMACOLOGY, Clinical Studies ).

Individuals may vary in response to doses of MAXALT Tablets.

The choice of dose should therefore be made on an individual basis, weighing the possible benefit of the 10-mg dose with the potential risk for increased adverse events.

Redosing: Doses should be separated by at least 2 hours; no more than 30 mg should be taken in any 24-hour period.

The safety of treating, on average, more than four headaches in a 30-day period has not been established.

Patients receiving propranolol: In patients receiving propranolol, the 5-mg dose of MAXALT should be used, up to a maximum of 3 doses in any 24-hour period.

(See CLINICAL PHARMACOLOGY, Drug Interactions .) For MAXALT-MLT Orally Disintegrating Tablets, administration with liquid is not necessary.

The orally disintegrating tablet is packaged in a blister within an outer aluminum pouch.

Patients should be instructed not to remove the blister from the outer pouch until just prior to dosing.

The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.

diurex 50 MG Oral Capsule

Generic Name: PAMABROM

Brand Name: Diurex

Substance Name(s):
PAMABROM

WARNINGS

Warnings

INDICATIONS AND USAGE

Uses For the relief of temporary water retention bloating swelling full feeling associated with the premenstrual and menstrual periods.

INFORMATION FOR PATIENTS

Other information **Contents sealed: Each Diurex Aquagel, clear translucent blue colored, oval shaped soft gel capsule bears the identifying mark “ALVA” and is sealed in a clear plastic blister with a foil backing.

Do not use if seal appears broken or if product contents do not match product description.

You may report serious side effects to the phone number provided under Questions? below.

INACTIVE INGREDIENTS

Inactive ingredients FD&C Blue #1, gelatin, glycerin, hypromellose, polyethylene glycol, povidone, propylene glycol, purified water, sorbitol and titanium dioxide.

PURPOSE

Purpose Diuretic

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 Read all package directions and warnings before use.

Use only as directed.

Adults: One (1) soft gel capsule after breakfast with a full glass of water.

Dose may be repeated after 6 hours, not to exceed four (4) soft gel capsules in 24 hours.

Start taking 5 or 6 days before onset of period and continue until desired relief is obtained or end of period.

Drink 6 to 8 glasses of water daily.

For use by normally healthy adults only.

Persons under 18 years of age should use only as directed by a doctor.

PREGNANCY AND BREAST FEEDING

If pregnant or breastfeeding, ask a health professional before use.

STOP USE

Stop use and ask a doctor if symptoms last for more than ten consecutive days.

ACTIVE INGREDIENTS

Active ingredient (in each soft gel capsule) Solubilized pamabrom, 50 mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking any other medication.

Methylphenidate Hydrochloride 10 MG Oral Tablet

WARNINGS

Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.

Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD.

Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems.

Adults with such abnormalities should also generally not be treated with stimulant drugs.

Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases.

While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure.

Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram).

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Psychiatric Adverse Events Preexisting Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients.

Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses.

If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate.

In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.

Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD.

Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.

Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well.

Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures.

In the presence of seizures, the drug should be discontinued.

Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients.

Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose.

Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation).

Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including methylphenidate hydrochloride tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon.

Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown.

Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment.

Signs and symptoms generally improve after reduction in dose or discontinuation of drug.

Careful observation for digital changes is necessary during treatment with ADHD stimulants.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Use in Children Under Six Years of Age Methylphenidate should not be used in children under 6 years, since safety and efficacy in this age group have not been established.

Drug Dependence Methylphenidate should be given cautiously to patients with a history of drug dependence or alcoholism.

Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior.

Frank psychotic episodes can occur, especially with parenteral abuse.

Careful supervision is required during drug withdrawal from abusive use, since severe depression may occur.

Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

DRUG INTERACTIONS

Drug Interactions Methylphenidate hydrochloride tablets should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors ).

Because of possible effects on blood pressure, Methylphenidate hydrochloride tablets should be used cautiously with pressor agents.

Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.

Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways.

Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g.

phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g.

imipramine, clomipramine, desipramine).

Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate.

It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing methylphenidate.

OVERDOSAGE

Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.

Rhabdomyolysis has also been reported in overdose.

Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.

Treatment consists of appropriate supportive measures.

The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present.

Gastric contents may be evacuated by gastric lavage.

In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage.

Other measures to detoxify the gut include administration of activated charcoal and a cathartic.

Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.

Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established.

DESCRIPTION

Methylphenidate hydrochloride is a mild central nervous system (CNS) stimulant.

Methylphenidate hydrochloride is available as 5, 10, and 20 mg tablets for oral administration.

Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is: Methylphenidate hydrochloride is a white, odorless, fine crystalline powder.

Its solutions are acid to litmus.

It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone.

Its chemical formula is C 14 H 19 NO 2 •HCl, and its molecular weight is 269.77.

Inactive Ingredients: Lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate; 5 mg contains D&C Yellow #10; 10 mg contains FD&C Green #3, and 20 mg contains FD&C Yellow #6.

Chemical Structure

HOW SUPPLIED

Methylphenidate Hydrochloride Tablets, USP are available as follows: 5 mg: Round, yellow, uncoated, unscored, debossed “531 MD”.

NDC 65580-531-01 Bottle of 100’s 10 mg: Round, pale blue/green, uncoated, scored, debossed “530 MD”.

NDC 65580-530-01 Bottle of 100’s 20 mg: Round, orange, uncoated, scored, debossed “532 MD”.

NDC 65580-532-01 Bottle of 100’s Store at 20° – 25°C (68°-77°F); excursions permitted to 15° – 30°C (59° – 86°F) [See USP Controlled Room Temperature].

Protect from light.

Pharmacist Dispense in a tight container as defined in the USP with a child-resistant closure.

For Medical Information Contact: UCBCares™ Phone: (844) 599-2273 Fax: (770) 970-8859 Manufactured for Upstate Pharma, LLC Smyrna, GA 30080 Rev.

INDICATIONS AND USAGE

Attention Deficit Disorders, Narcolepsy Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children).

Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.

Methylphenidate hydrochloride is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.

The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin.

Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.

Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test.

Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources.

Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG.

Learning may or may not be impaired.

The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of 1 or more of these characteristics.

Drug treatment is not indicated for all children with this syndrome.

Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis.

Appropriate educational placement is essential and psychosocial intervention is generally necessary.

When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms.

PEDIATRIC USE

Pediatric Use Methylphenidate Hydrochloride Tablets should not be used in children under 6 years of age (see WARNINGS ).

In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10).

When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m 2 basis).

The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m 2 basis).

The clinical significance of the long-term behavioral effects observed in rats is unknown.

PREGNANCY

Pregnancy Pregnancy Category C In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis.

Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m 2 basis.

The no effect level for embryofetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m 2 basis).

There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m 2 basis), which was also maternally toxic.

The no effect level for embryofetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m 2 basis).

When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m 2 basis), but no other effects on postnatal development were observed.

The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m 2 basis).

Adequate and well-controlled studies in pregnant women have not been conducted.

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

NUSRING MOTHERS

Nursing Mothers It is not known whether methylphenidate is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised if Methylphenidate Hydrochloride Tablets are administered to a nursing woman.

BOXED WARNING

Drug Dependence Methylphenidate should be given cautiously to patients with a history of drug dependence or alcoholism.

Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior.

Frank psychotic episodes can occur, especially with parenteral abuse.

Careful supervision is required during drug withdrawal from abusive use, since severe depression may occur.

Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

INFORMATION FOR PATIENTS

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use.

A patient Medication Guide is available for methylphenidate hydrochloride tablets.

The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

The complete text of the Medication Guide is reprinted at the end of this document.

The Medication Guide may also be obtained by calling 1-844-599-2273.

Priapism Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism).

Instruct the patient to seek immediate medical attention in the event of priapism .

Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] Instruct patients beginning treatment with methylphenidate hydrochloride tablets about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.

Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.

Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

DOSAGE AND ADMINISTRATION

Dosage should be individualized according to the needs and responses of the patient.

Adults Tablets Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals.

Average dosage is 20 to 30 mg daily.

Some patients may require 40 to 60 mg daily.

In others, 10 to 15 mg daily will be adequate.

Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.

Extended-Release Tablets Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours.

Therefore, the extended-release tablets may be used in place of the immediate-release tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of the immediate-release tablets.

Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

Children (6 Years and over) Methylphenidate hydrochloride tablets should be initiated in small doses, with gradual weekly increments.

Daily dosage above 60 mg is not recommended.

If improvement is not observed after appropriate dosage adjustment over a 1-month period, the drug should be discontinued.

Tablets Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly.

Extended-Release Tablets Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours.

Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug.

Methylphenidate should be periodically discontinued to assess the child’s condition.

Improvement may be sustained when the drug is either temporarily or permanently discontinued.

Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.

Desmopressin Acetate 0.2 MG Oral Tablet

Generic Name: DESMOPRESSIN ACETATE

Brand Name: Desmopressin Acetate

Substance Name(s):
DESMOPRESSIN ACETATE

WARNINGS

: Very rare cases of hyponatremia have been reported from world-wide postmarketing experience in patients treated with desmopressin acetate.

Desmopressin acetate is a potent antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia.

Unless properly diagnosed and treated hyponatremia can be fatal.

Therefore, fluid restriction is recommended and should be discussed with the patient and/or guardian.

Careful medical supervision is required.

When desmopressin acetate tablets are administered, in particular in pediatric and geriatric patients, fluid intake should be adjusted downward to decrease the potential occurrence of water intoxication and hyponatremia.

(See PRECAUTIONS, Pediatric Use and Geriatric Use .) All patients receiving desmopressin acetate therapy should be observed for the following signs of symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness and confusion.

Severe symptoms may include one or a combination of the following: seizure, coma and/or respiratory arrest.

Particular attention should be paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that may result in seizures which could lead to coma.

Desmopressin acetate should be used with caution in patients with habitual or psychogenic polydipsia who may be more likely to drink excessive amounts of water, putting them at greater risk of hyponatremia.

DRUG INTERACTIONS

Drug Interactions: Although the pressor activity of desmopressin acetate is very low compared to its antidiuretic activity, large doses of desmopressin acetate tablets should be used with other pressor agents only with careful patient monitoring.

The concomitant administration of drugs that may increase the risk of water intoxication with hyponatremia, (e.g.

tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and carbamazepine) should be performed with caution.

OVERDOSAGE

: Signs of overdose may include confusion, drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid retention.

(See WARNINGS .) In case of overdose, the dose should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition.

There is no known specific antidote for desmopressin acetate.

The patient should be observed and treated with appropriate symptomatic therapy.

An oral LD 50 has not been established.

Oral doses up to 0.2 mg/kg/day have been administered to dogs and rats for 6 months without any significant drug-related toxicities reported.

An intravenous dose of 2 mg/kg in mice demonstrated no effect.

DESCRIPTION

: Desmopressin acetate is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), is an antidiuretic hormone affecting renal water conservation.

It is chemically defined as 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.

The structural formula is as follows: Desmopressin Acetate Tablets contain desmopressin acetate equivalent to either 0.1 mg or 0.2 mg of desmopressin acetate.

In addition, each tablet contains the following inactive ingredients: butylated hydroxyanisole, butylated hydroxytoluene, crospovidone, lactose monohydrate, magnesium stearate, povidone and potato starch.

chemical structure

HOW SUPPLIED

: Desmopressin Acetate Tablets are available as: 0.1 mg: White, oval, flat-faced, beveled-edge scored tablet.

Debossed with WPI on one side and 22/25 on the scored side.

Available in unit dose packages of 30 (3 x 10) NDC 68084-606-21 0.2 mg: White, oval, flat-faced, beveled-edge scored tablet.

Debossed with WPI on one side and 22/26 on the scored side.

Available in unit dose packages of 30 (3 x 10) NDC 68084-604-21 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Avoid exposure to excessive heat or light.

Keep out of the reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

INDICATIONS AND USAGE

: Central Diabetes Insipidus: Desmopressin acetate tablets are indicated as antidiuretic replacement therapy in the management of central diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region.

Desmopressin acetate tablets are ineffective for the treatment of nephrogenic diabetes insipidus.

Patients were selected for therapy based on the diagnosis by means of the water deprivation test, the hypertonic saline infusion test, and/or response to antidiuretic hormone.

Continued response to desmopressin acetate can be monitored by measuring urine volume and osmolality.

Primary Nocturnal Enuresis: Desmopressin acetate tablets are indicated for the management of primary nocturnal enuresis.

Desmopressin acetate tablets may be used alone or as an adjunct to behavioral conditioning or other non-pharmacologic intervention.

PEDIATRIC USE

Pediatric Use: Central Diabetes Insipidus: Desmopressin acetate tablets have been used safely in pediatric patients, age 4 years and older, with diabetes insipidus for periods up to 44 months.

In younger pediatric patients the dose must be individually adjusted in order to prevent an excessive decrease in plasma osmolality leading to hyponatremia and possible convulsions; dosing should start at 0.05 mg (1/2 of the 0.1 mg tablet).

Use of desmopressin acetate in pediatric patients requires careful fluid intake restrictions to prevent possible hyponatremia and water intoxication.

Fluid restriction should be discussed with the patient and/or guardian.

(See WARNINGS .) Primary Nocturnal Enuresis: Desmopressin acetate tablets have been safely used in pediatric patients age 6 years and older with primary nocturnal enuresis for up to 6 months.

Some patients respond to a dose of 0.2 mg; however, increasing responses are seen at doses of 0.4 mg and 0.6 mg.

No increase in the frequency or severity of adverse reactions or decrease in efficacy was seen with an increased dose or duration.

The dose should be individually adjusted to achieve the best results.

Treatment with desmopressin for primary nocturnal enuresis should be interrupted during acute intercurrent illness characterized by fluid and/or electrolyte imbalance (e.g., systemic infections, fever, recurrent vomiting or diarrhea) or under conditions of extremely hot weather, vigorous exercise or other conditions associated with increased water intake.

PREGNANCY

Pregnancy: Category B: Fertility studies have not been done.

Teratology studies in rats and rabbits at doses from 0.05 to 10 µg/kg/day (approximately 0.1 times the maximum systemic human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area, mg/m 2 ) revealed no harm to the fetus due to desmopressin acetate.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Several publications where desmopressin acetate was used in the management of diabetes insipidus during pregnancy are available; these include a few anecdotal reports of congenital anomalies and low birth weight babies.

However, no causal connection between these events and desmopressin acetate has been established.

A fifteen year Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population; however, the statistical power of this study is low.

As opposed to preparations containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to weigh the possible therapeutic advantages against the possible risks in each case.

NUSRING MOTHERS

Nursing Mothers: There have been no controlled studies in nursing mothers.

A single study in postpartum women demonstrated a marked change in plasma, but little if any change in assayable desmopressin acetate in breast milk following an intranasal dose of 0.01 mg.

It is not known whether the drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when desmopressin acetate is administered to nursing mothers.

DOSAGE AND ADMINISTRATION

: Central Diabetes Insipidus: The dosage of desmopressin acetate tablets must be determined for each individual patient and adjusted according to the diurnal pattern of response.

Response should be estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover.

Patients previously on intranasal desmopressin acetate therapy should begin tablet therapy twelve hours after the last intranasal dose.

During the initial dose titration period, patients should be observed closely and appropriate safety parameters measured to assure adequate response.

Patients should be monitored at regular intervals during the course of desmopressin acetate tablets therapy to assure adequate antidiuretic response.

Modifications in dosage regimen should be implemented as necessary to assure adequate water turnover.

Fluid restriction should be observed.

(See WARNINGS , PRECAUTIONS, Pediatric Use and Geriatric Use .) Adults and Children: It is recommended that patients be started on doses of 0.05 mg (1/2 of the 0.1 mg tablet) two times a day and individually adjusted to their optimum therapeutic dose.

Most patients in clinical trials found that the optimal dosage range is 0.1 mg to 0.8 mg daily, administered in divided doses.

Each dose should be separately adjusted for an adequate diurnal rhythm of water turnover.

Total daily dosage should be increased or decreased in the range of 0.1 mg to 1.2 mg divided into two or three daily doses as needed to obtain adequate antidiuresis.

See Pediatric Use subsection for special considerations when administering desmopressin acetate to pediatric diabetes insipidus patients.

Geriatric Use: 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.

(See CLINICAL PHARMACOLOGY, Human Pharmacokinetics , CONTRAINDICATIONS , and PRECAUTIONS, Geriatric Use .) Primary Nocturnal Enuresis: The dosage of desmopressin acetate tablets must be determined for each individual patient and adjusted according to response.

Patients previously on intranasal desmopressin acetate therapy can begin tablet therapy the night following (24 hours after) the last intranasal dose.

The recommended initial dose for patients age 6 years and older is 0.2 mg at bedtime.

The dose may be titrated up to 0.6 mg to achieve the desired response.

Fluid restriction should be observed, and fluid intake should be limited to a minimum from 1 hour before desmopressin administration, until the next morning, or at least 8 hours after administration.

(See WARNINGS , PRECAUTIONS, Pediatric Use and Geriatric Use .

)

fluticasone propionate 0.1 MG/ACTUAT Dry Powder Inhaler, 60 ACTUAT

Generic Name: FLUTICASONE PROPIONATE

Brand Name: FLOVENT DISKUS

Substance Name(s):
FLUTICASONE PROPIONATE

DRUG INTERACTIONS

7 Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended.

May increase risk of systemic corticosteroid effects ( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4.

The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur.

Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)] .

During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

OVERDOSAGE

10 Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)] .

Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated.

Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated.

Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated.

Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

DESCRIPTION

11 FLOVENT DISKUS inhalation powder is a dry powder inhaler for oral inhalation.

The active component of FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S.

It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT DISKUS is an orange plastic inhaler containing a foil blister strip.

Each blister on the strip contains a white powder mix of micronized fluticasone propionate (50, 100, or 250 mcg) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins).

After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, FLOVENT DISKUS delivers 46, 94, and 229 mcg of fluticasone propionate from FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

In children with asthma aged 4 and 8 years, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range: 48 to 123 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Chemical structure

CLINICAL STUDIES

14 14.1 Adult and Adolescent Subjects Aged 12 Years and Older Four randomized, double-blind, parallel-group, placebo-controlled, U.S.

clinical trials were conducted in 1,036 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT DISKUS in the treatment of asthma.

Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity.

Subjects in these trials included those inadequately controlled with bronchodilators alone and those already maintained on daily ICS.

All doses were delivered by inhalation of the contents of 1 or 2 blisters from FLOVENT DISKUS twice daily.

Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV 1 prior to AM dose) for 3 recommended dosages of FLOVENT DISKUS (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults.

These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group.

Therefore, pulmonary function results at Endpoint (the last evaluable FEV 1 result, including most patients’ lung function data) are also displayed.

Pulmonary function, as determined by percent change from baseline in FEV 1 at recommended dosages of FLOVENT DISKUS improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone In all 4 efficacy trials, measures of pulmonary function (FEV 1 ) were statistically significantly improved as compared with placebo at all twice-daily doses.

Subjects on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 subjects with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated.

Both doses enabled a statistically significantly larger percentage of subjects to wean from oral prednisone as compared with placebo (75% of the subjects on 500 mcg twice daily and 89% of the subjects on 1,000 mcg twice daily as compared with 9% of subjects on placebo).

Accompanying the reduction in oral corticosteroid use, subjects treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric subjects (177 received FLOVENT DISKUS), approximately half of whom were receiving ICS at baseline.

In this trial, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV 1 (15% and 18% change from baseline at Endpoint, respectively) compared with placebo (7% change).

AM PEF was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared with placebo (14% change).

In this trial, subjects on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).

Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric subjects with asthma, approximately half of whom were receiving ICS at baseline.

In these trials, FLOVENT DISKUS was efficacious at doses of 50 and 100 mcg twice daily when compared with placebo on major endpoints including lung function and symptom scores.

Pulmonary function improved significantly compared with placebo by the first week of treatment, and subjects treated with FLOVENT DISKUS were also less likely to discontinue trial participation due to asthma deterioration.

One hundred ninety-two (192) subjects received FLOVENT DISKUS for up to 1 year during an open-label extension.

Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.

HOW SUPPLIED

16 /STORAGE AND HANDLING FLOVENT DISKUS 50 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0600-02).

FLOVENT DISKUS 100 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02).

FLOVENT DISKUS 100 mcg is also supplied in an institutional pack containing 28 blisters (NDC 0173-0602-00).

FLOVENT DISKUS 250 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02).

FLOVENT DISKUS 250 mcg is also supplied in an institutional pack containing 28 blisters (NDC 0173-0601-00).

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

Store in a dry place away from direct heat or sunlight.

Keep out of reach of children.

FLOVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use.

Discard FLOVENT DISKUS 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first.

The inhaler is not reusable.

Do not attempt to take the inhaler apart.

GERIATRIC USE

8.5 Geriatric Use Safety data have been collected on 280 subjects (FLOVENT DISKUS n = 83, FLOVENT Rotadisk n = 197) aged 65 years and older and 33 subjects (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) aged 75 years and older who have been treated with fluticasone propionate inhalation powder in U.S.

and non-U.S.

clinical trials.

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

DOSAGE FORMS AND STRENGTHS

3 Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation.

The strip contains fluticasone propionate 50, 100, or 250 mcg per blister.

Inhalation powder: Inhaler containing fluticasone propionate (50, 100, or 250 mcg) as a powder formulation for oral inhalation.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity.

Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide.

Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma.

Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate.

This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

INDICATIONS AND USAGE

1 Flovent DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

Important Limitation of Use FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

FLOVENT DISKUS is an inhaled corticosteroid (ICS) indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

( 1 ) Important limitation: • Not indicated for relief of acute bronchospasm.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of FLOVENT DISKUS in children aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] .

The safety and effectiveness of FLOVENT DISKUS in children younger than 4 years have not been established.

Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.

A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS.

The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients.

In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure.

This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.

The long‑term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.

The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown.

The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry).

The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies.

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S.

in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years.

The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100‑mcg group (n = 89).

An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data.

A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100‑mcg group (n = 79).

In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3 rd percentile = 3.8 cm/year, 50 th percentile = 5.4 cm/year, and 97 th percentile = 7.0 cm/year; girls – 3 rd percentile = 4.2 cm/year, 50 th percentile = 5.7 cm/year, and 97 th percentile = 7.3 cm/year.

The clinical relevance of these growth data is not certain.

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient data on the use of FLOVENT DISKUS in pregnant women.

There are clinical considerations with the use of FLOVENT DISKUS in pregnant women.

(See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis.

(See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis.

(See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

The estimated risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

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

Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species.

Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day).

The rat no observed adverse effect level (NOAEL) was observed at approximately 0.15 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).

Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day).

The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.13 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.

The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).

Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day).

The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Candida albicans infection of the mouth and pharynx may occur.

Monitor patients periodically.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk.

( 5.1 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

( 5.3 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue FLOVENT DISKUS slowly.

( 5.5 ) • Assess for decrease in bone mineral density initially and periodically thereafter.

( 5.7 ) • Monitor growth of pediatric patients.

( 5.8 ) • Glaucoma and cataracts may occur with long-term use of ICS.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

( 5.9 ) 5.1 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT DISKUS.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT DISKUS continues, but at times therapy with FLOVENT DISKUS may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.2 Acute Asthma Episodes FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS.

During such episodes, patients may require therapy with oral corticosteroids.

5.3 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.4 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although FLOVENT DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT DISKUS.

Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.5 Hypercorticism and Adrenal Suppression Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol.

Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use FLOVENT DISKUS [see Contraindications (4)] .

5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

5.8 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients .

Monitor the growth of pediatric patients receiving FLOVENT DISKUS routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2), Use in Specific Populations (8.4)] .

5.9 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of ICS, including fluticasone propionate.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

5.10 Paradoxical Bronchospasm As with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing.

If bronchospasm occurs following dosing with FLOVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; FLOVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted.

5.11 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] .

5.12 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.

These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate.

Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

A causal relationship between fluticasone propionate and these underlying conditions has not been established.

INFORMATION FOR PATIENTS

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

Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.

If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be temporarily interrupted under close medical supervision.

Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Status Asthmaticus and Acute Asthma Symptoms Inform patients that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations.

Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol.

Instruct patients to contact their physicians immediately if there is deterioration of their asthma.

Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay.

Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression Advise patients that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

Patients should discontinue FLOVENT DISKUS if such reactions occur.

Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including FLOVENT DISKUS, may cause a reduction in growth velocity when administered to pediatric patients.

Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Use Daily for Best Effect Patients should use Flovent DISKUS at regular intervals as directed.

Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer.

Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens.

Instruct patients not to stop use of FLOVENT DISKUS abruptly.

Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS.

Trademarks are owned by or licensed to the GSK group of companies.

FLD:13PI

DOSAGE AND ADMINISTRATION

2 For oral inhalation only.

( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity.

( 2.2 ) • Treatment of asthma in patients aged 12 years and older: 100 mcg twice daily up to a maximum recommended dosage of 1,000 mcg twice daily.

( 2.2 ) • Treatment of asthma in patients aged 4 to 11 years: 50 mcg twice daily up to a maximum recommended dosage of 100 mcg twice daily.

( 2.2 ) 2.1 Administration Information FLOVENT DISKUS should be administered by the orally inhaled route in patients aged 4 years and older.

After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS) is 100 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control.

The maximum recommended dosage for patients aged 12 years and older is 1,000 mcg twice daily.

Pediatric Patients Aged 4 to 11 Years The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

For patients aged 4 to 11 years not on an ICS, the recommended starting dosage is 50 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, increasing the dosage to 100 mcg twice daily may provide additional asthma control.

The maximum recommended dosage for patients aged 4 to 11 years is 100 mcg twice daily.

General Dosing Recommendations If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be used for immediate relief.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

If a dosage regimen fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength with a higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids, should be considered.

After asthma stability has been achieved, titrate to the lowest effective dosage to reduce the possibility of side effects.

fentanyl 25 MCG/HR 3 Day Transdermal Patch

WARNINGS

Fentanyl transdermal system is intended for transdermal use (on intact skin) only.

Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.

The safety of fentanyl transdermal system has not been established in children under 2 years of age.

Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, Pediatric Use).

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency.

Use in non-opioid tolerant patients may lead to fatal respiratory depression .

Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose.

The mean elimination half-life of fentanyl transdermal system is 17 hours.

Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.

Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists.

All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system.

Patients should be advised against taking hot baths or sunbathing.

There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death.

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40ºC (104ºF) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability.

Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary .

Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl transdermal system.

Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was applying or removing the patch.

Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.

Misuse, Abuse and Diversion of Opioids Fentanyl is an opioid agonist of the morphine-type.

Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Fentanyl can be abused in a manner similar to other opioids, legal or illicit.

This should be considered when prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Fentanyl transdermal system has been reported as being abused by other methods and routes of administration.

These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see and DRUG ABUSE AND ADDICTION ).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Hypoventilation (Respiratory Depression) Serious or life-threatening hypoventilation may occur at any time during the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and following increases in dose.

Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of fentanyl transdermal system.

Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized.

The use of concomitant CNS active drugs requires special patient care and observation.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl transdermal system.

Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses).

Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.

In such patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea.

In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Chronic Pulmonary Disease Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl transdermal system should be administered with caution to patients with preexisting medical conditions predisposing them to hypoventilation.

In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure Fentanyl transdermal system should not be used in patients who may be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma.

Opioids may obscure the clinical course of patients with head injury.

Fentanyl transdermal system should be used with caution in patients with brain tumors.

Interactions with other CNS Depressants The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma.

When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

Interactions with Alcohol and Drugs of Abuse Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Interactions with CYP3A4 Inhibitors The concomitant use of fentanyl transdermal with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

Patients receiving fentanyl transdermal system and any CYP3A4 inhibitors should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING ; CLINICAL PHARMACOLOGY , Drug Interactions ; PRECAUTIONS ; and DOSAGE AND ADMINISTRATION for further information) .

DRUG INTERACTIONS

Drug Interactions

OVERDOSAGE

Clinical Presentation The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious significant effect being hypoventilation.

Treatment For the management of hypoventilation, immediate countermeasures include removing the fentanyl transdermal system and physically or verbally stimulating the patient.

These actions can be followed by administration of a specific narcotic antagonist such as naloxone.

The duration of hypoventilation following an overdose may be longer than the effects of the narcotic antagonist’s action (the half-life of naloxone ranges from 30 to 81 minutes).

The interval between IV antagonist doses should be carefully chosen because of the possibility of re-narcotization after system removal; repeated administration of naloxone may be necessary.

Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines.

Always ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary.

Adequate body temperature and fluid intake should be maintained.

If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy.

DESCRIPTION

Fentanyl transdermal system is a transdermal system providing continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours.

The chemical name is N -phenyl- N -[1-(2-phenylethyl)-4-piperidyl] propanamide.

The structural formula is: C 22 H 28 N 2 O M.W.

336.5 The n-octanol:water partition coefficient is 860:1.

The pKa is 8.4.

System Components and Structure The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/hr per 10.7 cm 2 ).

The composition per unit area of all system sizes is identical.

Dose Nominal delivery rate per hour (mcg/hr) Size (cm 2 ) Fentanyl Content (mg) 25 10.7 2.76 50 21.4 5.52 75 32.1 8.28 100 42.8 11.04 Fentanyl transdermal system is a rectangular unit comprising a protective liner and two functional layers.

Proceeding from the outer surface toward the surface adhering to skin, these layers are: A BACKING LAYER OF POLYESTER FILM; FENTANYL IN A POLYISOBUTENE ADHESIVE MATRIX THAT CONTROLS THE RATE OF FENTANYL DELIVERY TO THE SKIN SURFACE; AND A PROTECTIVE POLYESTER RELEASE LINER.

Before use, a protective liner covering the adhesive layer is removed and discarded.

The active component of the system is fentanyl.

The remaining components are pharmacologically inactive.

Structural formula for fentanyl Graphic 1

HOW SUPPLIED

Fentanyl transdermal system is supplied in cartons containing 5 individually packaged systems.

See chart for information regarding individual systems: Label Strength (mcg/hr) Patch Size (cm 2 ) Fentanyl Content (mg) 25 10.7 2.76 50 21.4 5.52 75 32.1 8.28 100 42.8 11.04 They are supplied by Dispensing Solutions Inc.

as follows: NDC Strength Quantity/Form Source NDC 68258-3023-1 25 ug/1 h 5 BLISTER PACK 0093-6900-45 68258-3024-1 75 ug/1 h 5 BLISTER PACK 0093-6902-45 68258-3025-1 100 ug/1 h 5 BLISTER PACK 0093-6903-45 Safety and Handling Fentanyl transdermal systems are supplied in sealed blister packages which pose little risk of exposure to health care workers.

If the drug matrix accidentally contacts the skin, the area should be washed with copious amounts of water.

Do not use soap, alcohol, or other solvents because they may enhance the drug’s ability to penetrate the skin.

Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.

KEEP FENTANYL TRANSDERMAL SYSTEM OUT OF THE REACH OF CHILDREN AND PETS.

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

Apply immediately after removal from individually sealed blister package.

Do not use if the seal is broken.

For transdermal use only.

A SCHEDULE CII NARCOTIC.

DEA ORDER FORM REQUIRED.

Bioclusive™ is a trademark of Ethicon, Inc.

Dilaudid ® is a registered trademark of Abbott Laboratories.

Dolophine ® is a registered trademark of Roxane Laboratories, Inc.

Levo-Dromoran ® is a registered trademark of Valeant Pharmaceuticals International.

Numorphan ® is a registered trademark of Endo Pharmaceuticals.

Demerol ® is a registered trademark of Sanofi-Aventis U.S.

Manufactured By: Aveva Drug Delivery Systems A Nitto Denko Company Miramar, FL 33025 Distributed By: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 And Relabeled By: Dispensing Solutions Inc.

3000 West Warner Ave Santa Ana, CA 92704 United States

GERIATRIC USE

Geriatric Use Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N = 4) indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60.

The relevance of these findings to transdermal fentanyl system is unknown at this time.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND ADMINISTRATION ).

INDICATIONS AND USAGE

Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that: requires continuous, around-the-clock opioid administration for an extended period of time, and cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr (see DOSAGE AND ADMINISTRATION ).

Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS ).

An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid.

Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.

Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction.

Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

PEDIATRIC USE

Pediatric Use The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2 years of age through 18 years of age.

Starting doses of 25 mcg/hr and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid.

Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials.

Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication) was provided by fentanyl transdermal system.

Fentanyl transdermal system was not studied in children under 2 years of age.

Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see DOSAGE AND ADMINISTRATION and BOX WARNING ).

To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl transdermal system (see DOSAGE AND ADMINISTRATION ) and monitor adhesion of the system closely.

PREGNANCY

Pregnancy

NUSRING MOTHERS

Nursing Mothers Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for use in nursing women because of the possibility of effects in their infants.

BOXED WARNING

Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl.

Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression.

Fentanyl can be abused and is subject to criminal diversion.

The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion.

Fentanyl transdermal system is indicated for management of persistent , moderate to severe chronic pain that: requires continuous, around-the-clock opioid administration for an extended period of time, and cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr.

Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated : in patients who are not opioid-tolerant in the management of acute pain or in patients who require opioid analgesia for a short period of time in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain (e.g., use on an as needed basis [prn]) (See CONTRAINDICATIONS for further information.) Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that serious or life threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period.

The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY, Drug Interactions; WARNINGS; PRECAUTIONS; and DOSAGE AND ADMINISTRATION for further information).

The safety of fentanyl transdermal system has not been established in children under 2 years of age.

Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, Pediatric Use).

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency.

Use in non-opioid tolerant patients may lead to fatal respiratory depression .

Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose.

Due to the mean elimination half-life of 17 hours of fentanyl transdermal system, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.

Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit.

This risk should be considered when administering, prescribing, or dispensing fentanyl transdermal system in situations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.

All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction.

Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only .

Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.

Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, while wearing the system.

Avoid taking hot baths or sunbathing.

There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death.

INFORMATION FOR PATIENTS

Information for Patients Patients and their caregivers should be provided with a Medication Guide each time fentanyl transdermal system is dispensed because new information may be available.

Patients receiving fentanyl transdermal systems should be given the following instructions by the physician: Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.

Patients should be advised that each fentanyl transdermal system may be worn continuously for 72 hours, and that each patch should be applied to a different skin site after removal of the previous transdermal patch.

Patients should be advised that fentanyl transdermal systems should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm.

Additionally, patients should be advised of the following: In young children or persons with cognitive impairment, the patch should be put on the upper back to lower the chances that the patch will be removed and placed in the mouth.

Hair at the application site should be clipped (not shaved) prior to patch application.

If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water.

Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics.

Allow the skin to dry completely prior to patch application.

Patients should be advised that fentanyl transdermal system should be applied immediately upon removal from the sealed blister package and after removal of the protective liner.

Additionally the patient should be advised of the following: The fentanyl transdermal system should not be used if the seal is broken, or if the patch is cut, damaged, or changed in any way.

The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.

The patch should not be folded so that only part of the patch is exposed.

Patients should be advised that the dose of fentanyl transdermal system or the number of patches applied to the skin should NEVER be adjusted without the prescribing healthcare professional’s instruction.

Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as: heating pads, electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and heated water beds, etc.

Patients should also be advised of a potential for temperature dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body temperature due to strenuous exertion while wearing the patch should contact their physician.

Patients should be advised that if they experience problems with adhesion of the fentanyl transdermal system, they may tape the edges of the patch with first aid tape.

If problems with adhesion persist, patients may overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive™).

Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a different skin site.

10.

Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down the toilet used fentanyl transdermal systems after removal from the skin.

11.

Patients should be instructed that, if the drug matrix accidentally contacts the skin, the area should be washed clean with clear water and not soap, alcohol, or other chemicals, because these products may increase the ability of fentanyl to go through the skin.

12.

Patients should be advised that fentanyl transdermal system may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).

13.

Patients should be advised to refrain from any potentially dangerous activity when starting on fentanyl transdermal system or when their dose is being adjusted, until it is established that they have not been adversely affected.

14.

Patients should be advised that fentanyl transdermal system should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death.

15.

Patients should be advised to consult their physician or pharmacist if other medications are being or will be used with fentanyl transdermal system.

16.

Patients should be advised of the potential for severe constipation.

17.

Patients should be advised that if they have been receiving treatment with fentanyl transdermal system and cessation of therapy is indicated, it may be appropriate to taper fentanyl transdermal system dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.

18.

Patients should be advised that fentanyl transdermal system contains fentanyl, a drug with high potential for abuse.

19.

Patients, family members and caregivers should be advised to protect fentanyl transdermal system from theft or misuse in the work or home environment.

20.

Patients should be instructed to keep fentanyl transdermal system in a secure place out of the reach of children due to the high risk of fatal respiratory depression.

21.

Patients should be advised that fentanyl transdermal system should never be given to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended.

22.

Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person, they should immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual.

23.

When fentanyl transdermal system is no longer needed, the unused patches should be removed from their blisters, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.

24.

Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult a physician prior to initiating or continuing therapy with fentanyl transdermal system.

25.

Patients should be informed that accidental exposure or misuse may lead to death or other serious medical problems.

26.

MRI : Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI).

Because this fentanyl transdermal system contains aluminum, it is recommended to remove the patch before undergoing any MRI procedures.

DOSAGE AND ADMINISTRATION

Special Precautions Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl.

Fentanyl can be abused and is subject to criminal diversion.

The high content of fentanyl in fentanyl transdermal system may be a particular target for abuse and diversion.

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only .

The fentanyl transdermal system should not be used if the seal is broken, or the patch is cut, damaged, or changed in any way.

Each fentanyl transdermal system may be worn continuously for 72 hours.

The next patch should be applied to a different skin site after removal of the previous transdermal system.

If problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape.

If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing (e.g., Bioclusive™).

If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet.

A new patch may be applied to a different skin site.

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency.

Use in non-opioid tolerant patients may lead to fatal respiratory depression .

Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose.

The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fasamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING; WARNINGS; CLINICAL PHARMACOLOGY, Drug Interactions; WARNINGS; and PRECAUTIONS for further information ).

Pediatric patients converting to fentanyl transdermal system with a 25 mcg/hr patch should be opiod-tolerant and receiving at least 60 mg of oral morphine or the equivalent per day.

The dose conversion schedule described in Table C, and method of titration described below are recommended in opioid-tolerant pediatric patients over 2 years of age with chronic pain (see PRCAUTIONS , Pediatric Use ).

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration .

Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see CLINICAL PHARMACOLOGY , Special Populations , Geriatric Use ).

General Principles Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that: requires continuous, around-the-clock opioid administration for an extended period of time cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids.

Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr.

Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphone daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, or an equianalgesic dose of another opioid.

in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain (e.g., use on an as needed basis [prn]) (See CONTRAINDICATIONS for further information.) Safety of fentanyl transdermal system has not been established in children under 2 years of age.

Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, Pediatric Use).

Prescribers should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

With all opioids, the safety of patients using the products is dependent on health care practitioners prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

As with all opioids, dosage should be individualized.

The most important factor to be considered in determining the appropriate dose is the extent of preexisting opioid-tolerance (see BOX WARNING and CONTRAINDICATIONS ).

Initial doses should be reduced in elderly or debilitated patients (see PRECAUTIONS ).

Fentanyl transdermal system should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm.

In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal.

Hair at the application site should be clipped (not shaved) prior to system application.

If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water.

Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics.

Allow the skin to dry completely prior to patch application.

Fentanyl transdermal system should be applied immediately upon removal from the sealed blister package.

Do not use if the seal is broken.

Do not alter the patch (e.g., cut) in any way prior to application and do not use cut or damaged patches.

The transdermal system should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.

If the drug matrix accidentally contacts the skin of the patient or caregiver, the skin should be washed with copious amounts of water.

Do not use soap, alcohol, or other solvents because they may enhance the drug’s ability to penetrate the skin.

Fentanyl transdermal system should be kept out of the reach of children.

Used patches should be folded so that the adhesive side of the patch adheres to itself, then the patch should be flushed down the toilet immediately upon removal.

Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.

Unused patches should be removed from their blisters, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.

Dose Selection Doses must be individualized based upon the status of each patient and should be assessed at regular intervals after fentanyl transdermal system application.

Reduced doses of fentanyl transdermal system are suggested for the elderly and other groups discussed in PRECAUTIONS .

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency.

Use in non-opioid tolerant patients may lead to fatal respiratory depression .

In selecting an initial fentanyl transdermal system dose, attention should be given to 1) the daily dose, potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist-antagonist), 2) the reliability of the relative potency estimates used to calculate the fentanyl transdermal system dose needed (potency estimates may vary with the route of administration), 3) the degree of opioid tolerance, and 4) the general condition and medical status of the patient.

Each patient should be maintained at the lowest dose providing acceptable pain control.

Initial Fentanyl Transdermal System Dose Selection Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose.

There has been no systemic evaluation of fentanyl transdermal system as an initial opioid analgesic in the management of chronic pain, since most patients in the clinical trials were converted to fentanyl transdermal system from other narcotics.

The efficacy of fentanyl transdermal system 12 mcg/hr as an initiating dose has not been determined.

In addition, patients who are not opioid-tolerant have experienced hypoventilation and death during use of fentanyl transdermal system.

Therefore, fentanyl transdermal system should be used only in patients who are opioid-tolerant.

To convert adult and pediatric patients from oral or parenteral opioids to fentanyl transdermal system use TABLE C : Alternatively, for adult and pediatric patients taking opioids or doses not listed in TABLE C , use the following methodology: Calculate the previous 24 hour analgesic requirement.

Convert this amount to the equianalgesic oral morphine dose using TABLE D .

TABLE E displays the range of 24 hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose.

Use this table to find the calculated 24 hour morphine dose and the corresponding fentanyl transdermal system dose.

Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than every 3 days after the initial dose or than every 6 days thereafter) until analgesic efficacy is attained.

The recommended starting dose when converting from other opioids to fentanyl transdermal system is likely too low for 50% of patients.

This starting dose is recommended to minimize the potential for overdosing patients with the first dose.

For delivery rates in excess of 100 mcg/hr, multiple systems may be used.

TABLE C 1 DOSE CONVERSION GUIDELINES Current Analgesic Daily Dosage (mg/d) Oral morphine 60 to 134 135 to 224 225 to 314 315 to 404 IM/IV morphine 10 to 22 23 to 37 38 to 52 53 to 67 Oral oxycodone 30 to 67 67.5 to 112 112.5 to 157 157.5 to 202 IM/IV oxycodone 15 to 33 33.1 to 56 56.1 to 78 78.1 to 101 Oral codeine 150 to 447 448 to 747 748 to 1047 1048 to 1347 Oral hydromorphone 8 to 17 17.1 to 28 28.1 to 39 39.1 to 51 IV hydromorphone 1.5 to 3.4 3.5 to 5.6 5.7 to 7.9 8 to 10 IM meperidine 75 to 165 166 to 278 279 to 390 391 to 503 Oral methadone 20 to 44 45 to 74 75 to 104 105 to 134 IM methadone 10 to 22 23 to 37 38 to 52 53 to 67 ↓ ↓ ↓ ↓ Recommended fentanyl transdermal system dose 25 mcg/hr 50 mcg/hr 75 mcg/hr 100 mcg/hr Alternatively, for adult and pediatric patients taking opioids or doses not listed in TABLE C , use the conversion methodology outlined above with TABLE D .

1 TABLE C should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative.

Use of TABLE C for conversion to other analgesic therapies can overestimate the dose of the new agent.

Overdosage of the new analgesic agent is possible (see , Discontinuation of Fentanyl Transdermal System).

TABLE D TABLE D should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative.

Use of TABLE D for conversion to other analgesic therapies can overestimate the dose of the new agent.

Overdosage of the new analgesic agent is possible (see , Discontinuation of Fentanyl Transdermal System).

All IM and PO doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic effect.

IM denotes intramuscular, PO oral, and PR rectal.

EQUIANALGESIC POTENCY CONVERSION Name Equianalgesic Dose (mg) IM Based on single-dose studies in which an intramuscular dose of each drug listed was compared with morphine to establish the relative potency.

Oral doses are those recommended when changing from parenteral to an oral route.

Reference: Foley, K.M.

(1985) The treatment of cancer pain.

NEJM 313(2):84-95.

, Although controlled studies are not available, in clinical practice it is customary to consider the doses of opioid given IM, IV, or subcutaneously to be equivalent.

There may be some differences in pharmacokinetic parameters such as C max and T max .

PO Morphine 10 60 (30) The conversion ratio of 10 mg parenteral morphine = 30 mg oral morphine is based on clinical experience in patients with chronic pain.

The conversion ratio of 10 mg parenteral morphine = 60 mg oral morphine is based on a potency study in acute pain.

Reference: Ashburn and Lipman (1993) Management of pain in the cancer patient.

Anesth Analg 76:402-416.

Hydromorphone (Dilaudid ® ) 1.5 7.5 Methadone (Dolophine ® ) 10 20 Oxycodone 15 30 Levorphanol (Levo-Dromoran ® ) 2 4 Oxymorphone (Numorphan ® ) 1 10 (PR) Meperidine (Demerol ® ) 75 – Codeine 130 200 TABLE E TABLE E should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative.

Use of TABLE E for conversion to other analgesic therapies can overestimate the dose of the new agent.

Overdosage of the new analgesic agent is possible (see , Discontinuation of Fentanyl Transdermal System).

RECOMMENDED INITIAL FENTANYL TRANSDERMAL SYSTEM DOSE BASED UPON DAILY ORAL MORPHINE DOSE Oral 24 hour Morphine (mg/day) Fentanyl Transdermal System Dose (mcg/hr) 60 to 134 25 135 to 224 50 225 to 314 75 315 to 404 100 405 to 494 125 495 to 584 150 585 to 674 175 675 to 764 200 765 to 854 225 855 to 944 250 945 to 1034 275 1035 to 1124 300 NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal system.

The majority of patients are adequately maintained with fentanyl transdermal system administered every 72 hours.

Some patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied every 48 hours rather than every 72 hours.

An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72 hour regimen.

Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.

Because of the increase in serum fentanyl concentration over the first 24 hours following initial system application, the initial evaluation of the maximum analgesic effect of fentanyl transdermal system cannot be made before 24 hours of wearing.

The initial fentanyl transdermal system dose may be increased after 3 days (see , Dose Titration ).

During the initial application of fentanyl transdermal system, patients should use short-acting analgesics as needed until analgesic efficacy with fentanyl transdermal system is attained.

Thereafter, some patients still may require periodic supplemental doses of other short-acting analgesics for “breakthrough” pain.

Dose Titration The recommended initial fentanyl transdermal system dose based upon the daily oral morphine dose is conservative, and 50% of patients are likely to require a dose increase after initial application of fentanyl transdermal system.

The initial fentanyl transdermal system dosage may be increased after 3 days based on the daily dose of supplemental opioid analgesics required by the patient in the second or third day of the initial application.

Physicians are advised that it may take up to 6 days after increasing the dose of fentanyl transdermal system for the patient to reach equilibrium on the new dose (see graph in CLINICAL PHARMACOLOGY ).

Therefore, patients should wear a higher dose through two applications before any further increase in dosage is made on the basis of the average daily use of a supplemental analgesic.

Appropriate dosage increments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/hr increase in fentanyl transdermal system dose.

Discontinuation of Fentanyl Transdermal System To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new analgesic based upon the patient’s report of pain until adequate analgesia has been attained.

Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations.

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion or dose adjustment.

For patients requiring discontinuation of opioids, a gradual downward titration is recommended since it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.

TABLES C, D, and E should not be used to convert from fentanyl transdermal system to other therapies.

Because the conversion of fentanyl transdermal system is conservative, use of TABLES C, D, and E for conversion to other analgesic therapies can overestimate the dose of the new agent.

Overdosage of the new analgesic agent is possible.

Hydrochlorothiazide 12.5 MG Oral Tablet

WARNINGS

Use with caution in severe renal disease.

In patients with renal disease, thiazides may precipitate azotemia.

Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug Interactions ).

DRUG INTERACTIONS

Drug Interactions When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, Barbiturates, Or Narcotics Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs – (Oral Agents And Insulin) Dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive Drugs Additive effect or potentiation.

Cholestyramine And Colestipol Resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH Intensified electrolyte depletion, particularly hypokalemia.

Pressor Amines (e.g., Norepinephrine) Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine) Possible increased responsiveness to the muscle relaxant.

Lithium Generally should not be given with diuretics.

Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide.

Non-Steroidal Anti-Inflammatory Drugs In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.

Therefore, when hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

OVERDOSAGE

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.

If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

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

Emesis should be induced or gastric lavage performed.

Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.

If required, give oxygen or artificial respiration for respiratory impairment.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat.

DESCRIPTION

Hydrochlorothiazide is a diuretic and antihypertensive.

It is the 3,4-dihydro derivative of chlorothiazide.

It is chemically designated as 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula: C 7 H 8 ClN 3 O 4 S 2 Hydrochlorothiazide is a white, or practically white, crystalline powder, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Each tablet for oral administration contains 12.5 mg of hydrochlorothiazide.

In addition, each tablet contains the following inactive ingredients: calcium stearate, corn starch, FD&C yellow #6 (sunset yellow), lactose monohydrate, pregelatinized starch, sodium lauryl sulfate, and stearic acid.

HOW SUPPLIED

Hydrochlorothiazide Tablets, USP are available as follows: 12.5 mg — Each peach, round, tablet imprinted with on one side and 20 on the other side contains 12.5 mg of Hydrochlorothiazide, USP and is supplied in bottles of 30 (NDC 51138-038-30) with a child-resistant closure.

Dispense in a well-closed container as defined in the USP.

Keep container tightly closed.

Protect from light, moisture, and freezing, -20°C (-4°F).

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

Manufactured by: Actavis Elizabeth LLC 200 Elmora Avenue Elizabeth, NJ 07207 USA 40-9079 Revised — January 2008 Repackaged By: Med-Health Pharma, LLC North Las Vegas, NV 89032 SP-60013 Rev01

INDICATIONS AND USAGE

Hydrochlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Hydrochlorothiazide has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

Hydrochlorothiazide is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Use In Pregnancy Routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard.

Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy.

Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (see PRECAUTIONS, Pregnancy ).

Dependent edema in pregnancy, resulting from restriction of venous return by the gravid uterus, is properly treated through elevation of the lower extremities and use of support stockings.

Use of diuretics to lower intravascular volume in this instance is illogical and unnecessary.

During normal pregnancy there is hypervolemia which is not harmful to the fetus or the mother in the absence of cardiovascular disease.

However, it may be associated with edema, rarely generalized edema.

If such edema causes discomfort, increased recumbency will often provide relief.

Rarely this edema may cause extreme discomfort which is not relieved by rest.

In these instances, a short course of diuretic therapy may provide relief and be appropriate.

PEDIATRIC USE

Pediatric Use There are no well-controlled clinical trials in pediatric patients.

Information on dosing in this age group is supported by evidence from empiric use in pediatric patients and published literature regarding the treatment of hypertension in such patients.

(See DOSAGE AND ADMINISTRATION, Infants and Children ).

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy category B : Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects Thiazides cross the placental barrier and appear in cord blood.

There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

NUSRING MOTHERS

Nursing Mothers Thiazides are excreted in breast milk.

Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

DOSAGE AND ADMINISTRATION

Therapy should be individualized according to patient response.

Use the smallest dosage necessary to achieve the required response.

Adults For Edema – The usual adult dosage is 25 to 100 mg daily as a single or divided dose.

Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week.

With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

For Control Of Hypertension – The usual initial dose in adults is 25 mg daily given as a single dose.

The dose may be increased to 50 mg daily, given as a single or two divided doses.

Doses above 50 mg are often associated with marked reductions in serum potassium (see also PRECAUTIONS ).

Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily when used concomitantly with other antihypertensive agents.

Infants And Children For Diuresis And For Control Of Hypertension- The usual pediatric dosage is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age.

In infants less than 6 months of age, doses up to 1.5 mg per pound (3 mg/kg) per day in two divided doses may be required.

(See PRECAUTIONS, Pediatric Use ).

Glyburide 2.5 MG Oral Tablet

WARNINGS

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.

This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes.

The study involved 823 patients who were randomly assigned to one of four treatment groups.

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone.

A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality.

Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning.

The patient should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

DRUG INTERACTIONS

Drug Interactions The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents.

When such drugs are administered to a patient receiving glyburide, the patient should be observed closely for hypoglycemia.

When such drugs are withdrawn from a patient receiving glyburide, the patient should be observed closely for loss of control.

An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan.

Therefore concomitant administration of glyburide and bosentan is contraindicated.

Certain drugs tend to produce hyperglycemia and may lead to loss of control.

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

When such drugs are administered to a patient receiving glyburide, the patient should be closely observed for loss of control.

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

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide.

The mechanism for this interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported.

Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

Metformin: In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and C max were observed, but were highly variable.

The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.

Coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.

Colesevelam: Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and C max of 32% and 47%, respectively.

The reductions in glyburide AUC and C max were 20% and 15%, respectively when administered 1 hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam.

Topiramate: A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day).

There was a 22% decrease in Cmax and a 25% reduction in AUC 24 for glyburide during topiramate administration.

Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively.

The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

OVERDOSAGE

Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia.

Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns.

Close monitoring should continue until the physician is assured that the patient is out of danger.

Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization.

If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution.

This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL.

Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.

DESCRIPTION

Glyburide is an oral blood-glucose-lowering drug of the sulfonylurea class.

Glyburide USP is a white, crystalline compound, formulated as glyburide tablets of 1.25, 2.5, and 5 mg strengths for oral administration.

Inactive ingredients: dibasic calcium phosphate dihydrate, magnesium stearate, microcrystalline cellulose, sodium alginate, and talc.

The chemical name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)-ethyl]phenyl]-sulfonyl]-3-cyclohexylurea and the molecular weight is 493.99.

The structural formula is represented below.

Chemical Structure

HOW SUPPLIED

Glyburide Tablets, USP are supplied as follows: Glyburide Tablets 1.25 mg (White to off white, round, flat, beveled edge tablets with scoreline in between ‘2’ & ‘9’ on one side and ‘A’ debossed on other side.) Bottles of 30 NDC 65862-028-30 (Child Resistant Closure) Bottles of 50 NDC 65862-028-50 (Child Resistant Closure) Bottles of 100 NDC 65862-028-01 (Child Resistant Closure) Glyburide Tablets 2.5 mg (White to off white, round, flat, beveled edge tablets with scoreline in between ‘3’ & ‘0’ on one side and ‘A’ debossed on other side.) Bottles of 30 NDC 65862-029-30 (Child Resistant Closure) Bottles of 100 NDC 65862-029-01 (Child Resistant Closure) Bottles of 100 NDC 65862-029-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-029-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-029-99 (Non Child Resistant Closure) Glyburide Tablets 5 mg (White to off white, round, flat, beveled edge tablets with scoreline in between ‘3’ & ‘1’ on one side and ‘A’ debossed on other side.) Bottles of 30 NDC 65862-030-30 (Child Resistant Closure) Bottles of 100 NDC 65862-030-01 (Child Resistant Closure) Bottles of 100 NDC 65862-030-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-030-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-030-99 (Non Child Resistant Closure) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispensed in well closed containers with safety closures.

Keep container tightly closed.

Distributed by: Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad–500 038, India Revised: 06/2018

GERIATRIC USE

Geriatric Use Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs.

Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS ).

The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION ).

Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia.

Dose selection should include assessment of renal function.

INDICATIONS AND USAGE

Glyburide tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

PEDIATRIC USE

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

PREGNANCY

Pregnancy Teratogenic Effects: Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide.

There are, however, no adequate and well controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible.

Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery.

This has been reported more frequently with the use of agents with prolonged half-lives.

If glyburide is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

NUSRING MOTHERS

Nursing Mothers Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk.

Because the potential for hypoglycemia in nursing infants may exist, 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.

If the drug is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

INFORMATION FOR PATIENTS

Information for Patients: Patients should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy.

They also should be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Primary and secondary failure also should be explained.

Physician Counseling Information for Patients: In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment.

Caloric restriction and weight loss are essential in the obese diabetic patient.

Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia.

The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.

Use of glyburide or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint.

Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of glyburide or other antidiabetic medications.

Maintenance or discontinuation of glyburide or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.

DOSAGE AND ADMINISTRATION

Patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents.

(See PRECAUTIONS ).

There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets.

In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e.

, loss of adequate blood glucose lowering response after an initial period of effectiveness.

Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy.

Short-term administration of glyburide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

Usual Starting Dose The usual starting dose of glyburide tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal.

Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily.

(See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia.

Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy.

Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy: Transfer of patients from other oral antidiabetic regimens to glyburide should be done conservatively and the initial daily dose should be 2.5 to 5 mg.

When transferring patients from oral hypoglycemic agents other than chlorpropamide to glyburide, no transition period and no initial or priming dose are necessary.

When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia.

Patients Receiving Insulin: Some Type II diabetic patients being treated with insulin may respond satisfactorily to glyburide.

If the insulin dose is less than 20 units daily, substitution of glyburide tablets 2.5 to 5 mg as a single daily dose may be tried.

If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets 5 mg daily as a single dose.

If the insulin dose is more than 40 units daily, a transition period is required for conversion to glyburide.

In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started.

Please refer to Titration to Maintenance Dose for further explanation.

Patients Receiving Colesevelam: When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced.

Therefore, glyburide should be administered at least 4 hours prior to colesevelam.

Titration to Maintenance Dose The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (See Dosage Interval section).

Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient’s blood glucose response.

No exact dosage relationship exists between glyburide and the other oral hypoglycemic agents.

Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of glyburide tablets should be observed.

A maintenance dose of 5 mg of glyburide tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide.

When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of glyburide tablets 5 mg concomitantly with a 50% reduction in insulin dose.

Progressive withdrawal of insulin and increase of glyburide in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out.

During this conversion period when both insulin and glyburide are being used, hypoglycemia may occur.

During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician.

The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy.

Concomitant Glyburide and Metformin Therapy Glyburide tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose ).

Refer to metformin package insert.

With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.

However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal.

With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased.

Appropriate precautions should be taken (see PRECAUTIONS section).

Maximum Dose Daily doses of more than 20 mg are not recommended.

Dosage Interval Once-a-day therapy is usually satisfactory.

Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage.

Specific Patient Populations Glyburide is not recommended for use in pregnancy or for use in pediatric patients.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.

(See PRECAUTIONS section.)

Ketamine 50 MG/ML Injectable Solution [Ketalar]

Generic Name: KETAMINE HYDROCHLORIDE

Brand Name: Ketalar

Substance Name(s):
KETAMINE HYDROCHLORIDE

DRUG INTERACTIONS

7 Theophylline or Aminophylline : Do not co-administer with KETALAR as concomitant use may lower the seizure threshold ( 7.1 ).

Sympathomimetics and Vasopressin : Closely monitor vital signs when co-administered with KETALAR.

Consider dose adjustment individualized to the patient’s clinical situation ( 7.2 ).

Benzodiazepines, Opioid Analgesics, or other CNS Depressants : Concomitant use may result in profound sedation, respiratory depression, coma, or death.

Concomitant use of opioid analgesics may prolong recovery time.

( 7.3 ).

7.1 Theophylline or Aminophylline Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold.

Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

7.2 Sympathomimetics and Vasopressin Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine.

Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

7.3 Benzodiazepines, Opioid Analgesics, Or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions ( 5.8 )] .

Opioid analgesics administered concomitantly with KETALAR may prolong time to complete recovery from anesthesia.

OVERDOSAGE

10 Changes in heart rate and blood pressure, respiratory depression, and apnea may occur with overdosage or by a rapid rate of administration of KETALAR.

Monitor patients for clinically relevant changes in heart rate and blood pressure.

Assisted ventilation, including mechanical ventilation, may be required.

In cases of unintentional overdose of KETALAR (up to ten times that usually required), patients had a prolonged but complete recovery.

DESCRIPTION

11 KETALAR (ketamine hydrochloride) injection, for intravenous or intramuscular use, contains ketamine, a nonbarbiturate general anesthetic.

Ketamine hydrochloride, USP is a white crystalline powder and has a molecular formula of C 13 H 16 ClNO•HCl and a molecular weight of 274.19.

The chemical name for ketamine hydrochloride is (±)-2-( o -Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.

The chemical structure of ketamine hydrochloride is: ketamine hydrochloride It is formulated as a slightly acidic (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection.

Each milliliter (mL) of the multiple-dose vials contain either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) and not more than 0.10 mg/mL benzethonium chloride added as a preservative in water for injection.

The 10 mg/mL solution has been made isotonic with 6.60 mg sodium chloride.

ketamine hydrochloride

CLINICAL STUDIES

14 KETALAR has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients in 105 separate studies.

During the course of these studies, KETALAR was administered as the sole general anesthetic, as an induction agent prior to administration of other general anesthetics, or to supplement other anesthetic agents.

KETALAR has been evaluated during the following procedures: debridement, dressing changes, and skin grafting in burn patients, as well as other superficial surgical procedures.

neurodiagnostic procedures such as myelograms and lumbar punctures.

diagnostic and operative procedures of the ear, nose, and mouth, including dental extractions.

sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.

extraperitoneal procedures, such as dilatation and curettage.

orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

cardiac catheterization procedures.

HOW SUPPLIED

16 /STORAGE AND HANDLING How Supplied KETALAR injection is a clear, colorless solution supplied as the hydrochloride salt in concentrations equivalent to ketamine base, as follows: Unit of sale Strength NDC 42023-113-10 Unit of 10 200 mg in 20 mL multiple- dose vial (10 mg/mL) 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride) NDC 42023-114-10 Unit of 10 500 mg in 10 mL multiple- dose vial (50 mg/mL) 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) NDC 42023-115-10 Unit of 10 500 mg in 5 mL multiple- dose vial (100 mg/mL) 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride) Storage and Handling KETALAR injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] .

Protect from light.

RECENT MAJOR CHANGES

Warnings and Precautions ( 5.6 ) 8/2020

GERIATRIC USE

8.5 Geriatric Use Clinical studies of ketamine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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.

DOSAGE FORMS AND STRENGTHS

3 KETALAR injection is a clear, colorless, sterile solution available in multiple-dose vials containing either 10 mg ketamine base (equivalent to 11.53 mg ketamine hydrochloride), 50 mg ketamine base (equivalent to 57.67 mg ketamine hydrochloride) or 100 mg ketamine base (equivalent to 115.33 mg ketamine hydrochloride).

200 mg/20 mL (10 mg/mL) 500 mg/10 mL (50 mg/mL) 500 mg/5 mL (100 mg/mL) Injection: 200 mg/20 mL (10 mg/mL), 500 mg/10 mL (50 mg/mL), and 500 mg/5 mL (100 mg/mL) multiple-dose vials ( 3 ).

MECHANISM OF ACTION

12.1 Mechanism of Action KETALAR, a racemic mixture of ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.

The major circulating metabolite of ketamine (norketamine) demonstrated activity at the same receptor with less affinity.

Norketamine is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat.

INDICATIONS AND USAGE

1 KETALAR (ketamine hydrochloride) injection is indicated: as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.

for the induction of anesthesia prior to the administration of other general anesthetic agents.

as a supplement to other anesthetic agents.

KETALAR is a general anesthetic indicated: as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation ( 1 ) for the induction of anesthesia prior to the administration of other general anesthetic agents ( 1 ) as a supplement to other anesthetic agents ( 1 ).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 16 have not been established.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as KETALAR, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 ), and Nonclinical Toxicology ( 13.2 )] .

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of KETALAR in pregnant women.

In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg.

In rabbits, developmental delays and increased fetal resorptions were noted at 0.6 times the human dose.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

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

Clinical Considerations KETALAR use in pregnancy, including obstetrics (either vaginal or abdominal delivery), is not recommended because safe use has not been established [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 ) and Nonclinical Toxicology ( 13.2 )] .

Data Animal Data Pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15.

Ketamine treatment produced an increased incidence of hypoplastic skull, phalanges, and sternebrae in the pups.

Pregnant rabbits were treated intramuscularly with 20 mg/kg ketamine (0.6 times the human dose of 10 mg/kg IM based on body surface area) on either Gestation Days 6 to 10 or Gestation Days 11 to 15.

An increase in resorptions and skeletal hypoplasia of the fetuses were noted.

Additional pregnant rabbits were treated intramuscularly with a single dose 60 mg/kg (1.9 times the human dose of 10 mg/kg IM based on body surface area) on Gestation Day 6 only.

Skeletal hypoplasia was reported in the fetuses.

In a study where pregnant rats were treated intramuscularly with 20 mg/kg ketamine (0.3 times the human dose of 10 mg/kg IM based on body surface area) from Gestation Day 18 to 21.

There was a slight increase in incidence of delayed parturition by one day in treated dams of this group.

No adverse effects on the litters or pups were noted; however, learning and memory assessments were not completed.

Three pregnant beagle dogs were treated intramuscularly with 25 mg/kg ketamine (1.3 times the human dose of 10 mg/kg IM based on body surface area) twice weekly for the three weeks of the first, second, and third trimesters of pregnancy, respectively, without the development of adverse effects in the pups.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 ), and Nonclinical Toxicology ( 13.2 )] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hemodynamic Instability: Monitor vital signs and cardiac function during KETALAR administration.

( 5.1 ) Emergence Reactions: Postoperative confusional states may occur during the recovery period.

Reduce by minimizing verbal, tactile, and visual stimulation of the patient.

( 5.2 ) Risk of Respiratory Depression: May occur with overdosage or too rapid a rate of administration.

Maintain adequate oxygenation and ventilation.

( 5.3 ) Risks of KETALAR alone for Procedures of the Pharynx, Larynx, or Bronchial Tree : Pharyngeal and laryngeal reflexes are not suppressed with KETALAR when it is used alone.Avoid use as a sole anesthetic agent in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree.

Muscle relaxants may be required.

( 5.4 ) Pediatric Neurotoxicity: Long-term cognitive deficits may occur when used for longer than 3 hours in children ≤3 years ( 5.5 ) 5.1 Hemodynamic Instability Transient increases in blood pressure, heart rate, and cardiac index are frequently observed following administration of KETALAR.

Decreases in blood pressure and heart rate, arrhythmias, and cardiac decompensation have also been observed.

Monitor vital signs and cardiac function during KETALAR administration.

KETALAR is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard [see Contraindications ( 4 )] .

5.2 Emergence Reactions Emergence delirium (postoperative confusional states or agitation) has occurred in approximately 12% of patients during the recovery period, and the duration is generally a few hours.

The neuropsychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium.

In some cases, these states have been accompanied by confusion, excitement, and irrational behavior, which have been recalled as unpleasant experiences.

No residual psychological effects are known to have resulted from use of KETALAR during induction and maintenance of anesthesia.

Intramuscular administration results in a lower incidence of emergence reactions.

The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using lower recommended dosages of KETALAR in conjunction with an intravenous benzodiazepine during induction and maintenance of anesthesia [see Dosage and Administration ( 2.3 )] .

Also, these reactions may be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period.

This does not preclude the monitoring of vital signs.

5.3 Respiratory Depression Respiratory depression may occur with overdosage or a rapid rate of administration of KETALAR.

Maintain adequate oxygenation and ventilation.

5.4 Risks of Ketalar Alone for Procedures of the Pharynx, Larynx, or Bronchial Tree KETALAR does not suppress pharyngeal and laryngeal reflexes.

Avoid KETALAR administration as a sole anesthetic agent during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx.

Muscle relaxants may be required for successful completion of procedures of the pharynx, larynx, or bronchial tree.

5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Use in Specific Populations ( 8.1 , 8.4 ), Nonclinical Toxicology ( 13.2 )].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.6 Drug-Induced Liver Injury Ketamine administration is associated with hepatobiliary dysfunction (most often a cholestatic pattern), with recurrent use (e.g., misuse/abuse or medically supervised unapproved indications).

Obtain baseline LFTs, including alkaline phosphatase and gamma glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing.

Monitor those receiving recurrent ketamine at periodic intervals during treatment.

5.7 Increase in Cerebrospinal Fluid Pressure An increase in intracranial pressure has been reported following administration of ketamine hydrochloride.

Patients with elevated intracranial pressure should be in a monitored setting with frequent neurologic assessments.

5.8 Drug Interactions Theophylline or Aminophylline : Concomitant administration of KETALAR and theophylline or aminophylline may lower the seizure threshold [see Drug Interactions ( 7.1 )] .

Consider using an alternative to KETALAR in patients receiving theophylline or aminophylline.

Sympathomimetics and Vasopressin : Sympathomimetics and vasopressin may enhance the sympathomimetic effects of ketamine [see Drug Interactions ( 7.2 )] .

Closely monitor vital signs when KETALAR and sympathomimetics or vasopressin are co-administered and consider dose adjustment individualized to the patient’s clinical situation.

Benzodiazepines, Opioid Analgesics, or Other CNS Depressants Concomitant use of ketamine with opioid analgesics, benzodiazepines, or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions ( 7.3 )] .

Closely monitor neurological status and respiratory parameters, including respiratory rate and pulse oximetry, when KETALR and opioid analgesics, benzodiazepines, or other CNS depressants are co-administered.

Consider dose adjustment individualized to the patient’s clinical situation.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions ( 5.5 )] .

Due to the residual anesthetic effects and the potential for drowsiness, advise patients not to drive an automobile, operate hazardous machinery, or engage in hazardous activities within 24 hours of receiving KETALAR.

DOSAGE AND ADMINISTRATION

2 See Full Prescribing Information for important dosage and administration instructions.

( 2 ) Induction of anesthesia: — Intravenous route : Initially, 1 to 4.5 mg/kg administered slowly (over a period of 60 seconds).

Alternatively, administer a dose of 1 to 2 mg/kg at a rate of 0.5 mg/kg/min.

( 2.2 ) — Intramuscular route : Initially, 6.5 to 13 mg/kg.

( 2.2 ) Maintenance of anesthesia: Increments of one-half to the full induction dose may be repeated as needed ( 2.2 ).

Adjust the dose according to the patient’s anesthetic needs and whether an additional anesthetic agent is employed.

( 2.2 ) Supplement to other anesthetic agents : The regimen of a reduced dose of KETALAR supplemented with diazepam can be used to produce balanced anesthesia by combination with other agents.

( 2.2 ) 2.1 Important Dosage and Administration Information KETALAR should be administered by or under the direction of physicians experienced in the administration of general anesthetics, maintenance of a patent airway, and oxygenation and ventilation.

Continuously monitor vital signs in patients receiving KETALAR.

Emergency airway equipment must be immediately available.

Do not administer the 100 mg/mL concentration of KETALAR intravenously without proper dilution [see Dosage and Administration ( 2.3 )] .

Must be used immediately after dilution.

While some degree of airway protection may be afforded due to active laryngeal-pharyngeal reflexes, vomiting and aspiration may occur with KETALAR.

KETALAR is not recommended for use in patients who have not followed nil per os guidelines.

Due to the potential for salivation during KETALAR administration, administer an antisialagogue prior to induction of anesthesia.

In individuals with a history of chronic ketamine use for off-label indications, there have been case reports of genitourinary pain that may be related to the ketamine treatment, not the underlying condition [see Adverse Reactions ( 6 )] .

Consider cessation of ketamine if genitourinary pain continues in the setting of other genitourinary symptoms.

2.2 Recommended Dosage and Administration The KETALAR dosage must be individualized and titrated to the desired clinical effect.

If a longer duration of effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia.

However, a higher total dose will result in a longer time to complete recovery.

Induction of Anesthesia Intravenous Route: The initial dose of KETALAR administered intravenously may range from 1 mg/kg to 4.5 mg/kg.

The average amount required to produce 5 to 10 minutes of surgical anesthesia within 30 seconds following injection is 2 mg/kg.

Administer KETALAR slowly (i.e., over a period of 60 seconds).

Rapid administration may result in respiratory depression and enhanced vasopressor response.

The induction dose may be administered as an intravenous infusion at a rate of 0.5 mg/kg/min.

Intramuscular Route : The initial dose of KETALAR administered intramuscularly may range from 6.5 to 13 mg/kg.

A dose of 9 to 13 mg/kg usually produces surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Administer a benzodiazepine, if clinically indicated, for the prevention of neuropsychological manifestations during emergence from anesthesia.

Maintenance of Anesthesia Adjust the maintenance dose according to the patient’s anesthetic needs and whether an additional anesthetic agent is administered.

Repeat increments of one-half to the full induction dose as needed for maintenance of anesthesia.

Purposeless and tonic-clonic movements of extremities may occur during the course of ketamine anesthesia.

These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.

KETALAR given by slow microdrip infusion technique at a dose of 0.1 to 0.5 mg/minute will maintain general anesthesia in adult patients induced with KETALAR.

Augment KETALAR with an intravenous benzodiazepine for the prevention of neuropsychological manifestations during emergence.

Supplement to Other Anesthetic Agents KETALAR can be administered to supplement other general and local anesthetic agents.

Continuously monitor patients for changes in respiratory and hemodynamic parameters.

A reduced dose of KETALAR can be used to produce balanced anesthesia when used in combination with other anesthetic agents.

2.3 Preparation of Dilution KETALAR is a clear, colorless sterile solution.

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

Discard if product is discolored or contains particulate matter.

Induction of Anesthesia : Do not intravenously inject the 100 mg/mL concentration of KETALAR without proper dilution.

Dilute KETALAR with an equal volume of either Sterile Water for injection, USP, 0.9% Sodium Chloride Injection, USP (Normal Saline), or 5% Dextrose in Water.

Use immediately after dilution.

Maintenance of Anesthesia : To prepare a dilute solution containing 1 mg of ketamine per mL, aseptically transfer 10 mL from a 50 mg per mL vial or 5 mL from a 100 mg per mL vial to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (Normal Saline) and mix well.

The resultant solution will contain 1 mg of ketamine per mL.

Use immediately after dilution.

When fluid restriction is required, KETALAR can be added to a 250 mL infusion as described above to provide a KETALAR concentration of 2 mg/mL.

KETALAR 10 mg/mL vials are not recommended for dilution.

nifedipine 30 MG Osmotic 24 HR Extended Release Oral Tablet

Generic Name: NIFEDIPINE

Brand Name: Nifedipine

Substance Name(s):
NIFEDIPINE

WARNINGS

Excessive Hypotension Although in most angina patients the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension.

These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant beta blockers.

Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia.

The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out.

In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and if the patient’s condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.

The following information should be taken into account in those patients who are being treated for hypertension as well as angina: Increased Angina and/or Myocardial Infarction Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase.

The mechanism of this effect is not established.

Beta Blocker Withdrawal It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine.

Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines.

Initiation of nifedipine treatment will not prevent this occurrence and on occasion has been reported to increase it.

Congestive Heart Failure Rarely, patients, usually receiving a beta blocker, have developed heart failure after beginning nifedipine.

Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit, owing to the fixed impedance to flow across the aortic valve in these patients.

Gastointestinal Obstruction Requiring Surgery There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of Nifedipine Extended-release Tablets.

Bezoars can occur in very rare cases and may require surgical intervention.

Cases of serious gastrointestinal obstruction have been identified in patients with no known gastrointestinal disease, including the need for hospitalization and surgical intervention.

Risk factors for a gastrointestinal obstruction identified from post-marketing reports of Nifedipine Extended-release Tablets include alteration in gastrointestinal anatomy (e.g., severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and inflammatory bowel disease), hypomotility disorders (e.g., constipation, gastroesophageal reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications (e.g., H 2 -histamine blockers, opiates, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents).

Gastrointestinal Ulcers Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

DRUG INTERACTIONS

Drug Interactions Beta-adrenergic blocking agents (see INDICATIONS AND USAGE and WARNINGS .) Experience in over 1400 patients with nifedipine capsules in a noncomparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina.

Long-acting Nitrates Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

Digitalis Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers.

The average increase was 45%.

Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease.

In an uncontrolled study of over two hundred patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed.

Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization.

Coumarin Anticoagulants There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered.

However, the relationship to nifedipine therapy is uncertain.

Cimetidine A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%), after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day.

Ranitidine produced smaller, non-significant increases.

The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine.

If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.

Nifedipine is metabolized by CYP3A4.

Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%.

Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy.

CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir may result in increased exposure to nifedipine when co-administered.

Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications.

OVERDOSAGE

Experience with nifedipine overdosage is limited.

Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support, including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents, and fluids.

Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function.

Since nifedipine is highly protein-bound, dialysis is not likely to be of any benefit.

There has been one reported case of massive overdosage with Nifedipine Extended-release Tablets.

The main effects of ingestion of approximately 4800 mg of Nifedipine Extended-release Tablets in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness.

Within several hours of ingestion, nausea, vomiting, and generalized edema developed.

No significant hypotension was apparent at presentation, 18 hours post-ingestion.

Electrolyte abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT.

Vital signs remained stable, no electrocardiographic abnormalities were noted, and renal function returned to normal within 24 to 48 hours with routine supportive measures alone.

No prolonged sequelae were observed.

The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient also on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement.

A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block.

These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously.

Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment.

A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids.

No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.

DESCRIPTION

Nifedipine is a drug belonging to a class of pharmacological agents known as the calcium channel blockers.

Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, C 17 H 18 N 2 O 6, and has the structural formula: Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol.

It has a molecular weight of 346.33.

Nifedipine Extended-release Tablet is formulated as a once-a-day extended-release tablet for oral administration designed to deliver 30, 60, or 90 mg of nifedipine.

Inert ingredients in the formulations are: black iron oxide; cellulose acetate; colloidal silicon dioxide; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polyethylene oxide; polysorbate; povidone; propylene glycol; red ferric oxide; sodium chloride; titanium dioxide; triacetin.

Chemical Structure System Components and Performance Nifedipine Extended-release Tablet is similar in appearance to a conventional tablet.

It consists, however, of a semipermeable membrane surrounding an osmotically active drug core.

As water from the gastrointestinal tract enters the tablet, pressure increases in the core of the tablet, releasing drug through the precision laser-drilled tablet orifice in the one side of the tablet.

Nifedipine Extended-release Tablet is designed to provide nifedipine at an approximately constant rate over 24 hours.

This controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility.

Nifedipine Extended-release Tablet depends for its action on the existence of an osmotic gradient between the contents of the tablet core and fluid in the gastrointestinal tract.

Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero.

Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

USP Drug Release Test 5.

HOW SUPPLIED

Nifedipine Extended-release Tablets 30 mg are round, biconvex, pink coated tablets imprinted with “KU 260” in black ink.

They are supplied as follows: Bottles of 30 Tablets NDC 68645-512-54 Nifedipine Extended-release Tablets 60 mg are round, biconvex, pink coated tablets imprinted with “KU 261” in black ink.

They are supplied as follows: Bottles of 30 Tablets NDC 68645-513-54 Store at 20°-25°C (68°-77°F) (See USP Controlled Room Temperature).

Protect from moisture, humidity, and light.

For Medical Information Contact: Medical Affairs Department Phone: 1-844-834-0530 Distributed by: Lannett Company, Inc.

Philadelphia, PA 19136 Distributed By: Wal-Mart Bentonville, AR 72716 Packaged By: Legacy Pharmaceutical Packaging LLC Earth City, MO 63045 CIA70797K Rev.

03/19

MECHANISM OF ACTION

Mechanism of Action A) Angina The precise mechanisms by which inhibition of calcium influx relieves angina has not been fully determined, but includes at least the following two mechanisms: 1) Relaxation and Prevention of Coronary Artery Spasm Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced.

This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of nifedipine in vasospastic (Prinzmetal’s or variant) angina.

Whether this effect plays any role in classical angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization.

This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.

2) Reduction of Oxygen Utilization Nifedipine regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral vascular resistance (afterload) against which the heart works.

This unloading of the heart reduces myocardial energy consumption and oxygen requirements, and probably accounts for the effectiveness of nifedipine in chronic stable angina.

B) Hypertension The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance.

The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle.

Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium.

Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle.

The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels.

Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur.

The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.

INDICATIONS AND USAGE

Vasospastic Angina Nifedipine Extended-release Tablet is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm.

In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied.

Nifedipine Extended-release Tablet may also be used where the clinical presentation suggests a possible vasospastic component, but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion, or in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm, or when angina is refractory to nitrates and/or adequate doses of beta-blockers.

II.

Chronic Stable Angina (Classical Effort-Associated Angina) Nifedipine Extended-release Tablet is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents.

In chronic stable angina (effort-associated angina), nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients is incomplete.

Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities.

When introducing such concomitant therapy, care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs (see WARNINGS ).

III.

Hypertension Nifedipine Extended-release Tablet is indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including Nifedipine Extended-release Tablet.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Nifedipine Extended-release Tablet may be used alone or in combination with other antihypertensive agents.

PEDIATRIC USE

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

PREGNANCY

Pregnancy Pregnancy Category C Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin.

Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species).

On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (5 to 50 times) than the maximum recommended human dose of 120 mg/day.

On a mg/m 2 basis, some doses were higher and some were lower than the maximum recommended human dose, but all are within an order of magnitude of it.

The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on a mg/m 2 basis.

There are no adequate and well-controlled studies in pregnant women.

Nifedipine Extended-release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk.

INFORMATION FOR PATIENTS

Information for Patients Nifedipine Extended-release Tablets should be swallowed whole.

Do not chew, divide or crush tablets.

Do not be concerned if you occasionally notice in your stool something that looks like a tablet.

In Nifedipine Extended-release Tablets, the medication is contained within a nonabsorbable shell that has been specially designed to slowly release the drug for your body to absorb.

When this process is completed, the empty tablet is eliminated from your body.

DOSAGE AND ADMINISTRATION

Dosage must be adjusted according to each patient’s needs.

Therapy for either hypertension or angina should be initiated with 30 or 60 mg once daily.

Nifedipine Extended-release Tablets should be swallowed whole and should not be bitten or divided.

In general, titration should proceed over a 7-14 day period so that the physician can fully assess the response to each dose level and monitor blood pressure before proceeding to higher doses.

Since steady-state plasma levels are achieved on the second day of dosing, titration may proceed more rapidly, if symptoms so warrant, provided the patient is assessed frequently.

Titration to doses above 120 mg are not recommended.

Angina patients controlled on nifedipine capsules alone or in combination with other antianginal medications may be safely switched to Nifedipine Extended-release Tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d.

of nifedipine capsules may be changed to 90 mg once daily of Nifedipine Extended-release Tablets).

Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted.

Experience with doses greater than 90 mg in patients with angina is limited.

Therefore, doses greater than 90 mg should be used with caution and only when clinically warranted.

Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Other Interactions ).

No “rebound effect” has been observed upon discontinuation of Nifedipine Extended-release Tablets.

However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision.

Care should be taken when dispensing Nifedipine Extended-release Tablets to assure that the extended release dosage form has been prescribed.

Co-Administration with Other Antianginal Drugs Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration.

See PRECAUTIONS, Drug Interactions , for information on co-administration of nifedipine with beta blockers or long-acting nitrates.