Amitiza

Generic Name: lubiprostone

Dosage Form: capsule, gelatin coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Amitiza

Chronic Idiopathic Constipation

Amitiza® is indicated for the treatment of chronic idiopathic constipation in adults.

Irritable Bowel Syndrome with Constipation

Amitiza is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women ≥ 18 years old.

Amitiza Dosage and Administration

 Amitiza should be taken orally with food and water. Physicians and patients should periodically assess the need for continued therapy.

Chronic Idiopathic Constipation

The recommended dose is 24 mcg twice daily orally with food and water.

Reduced dosage in patients with hepatic impairment

For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended dose is 8 mcg twice daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response.

Irritable Bowel Syndrome with Constipation

The recommended dose is 8 mcg twice daily orally with food and water.

Reduced dosage in patients with severe hepatic impairment

For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended dose is 8 mcg once daily. If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response. Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B).

Dosage Forms and Strengths

Amitiza is available as an oval, gelatin capsule containing 8 mcg or 24 mcg of lubiprostone.

• 8-mcg capsules are pink and are printed with "SPI" on one side


• 24-mcg capsules are orange and are printed with "SPI" on one side

Contraindications

Amitiza is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.

Warnings and Precautions

Pregnancy

The safety of Amitiza in pregnancy has not been evaluated in humans. In guinea pigs, lubiprostone has been shown to have the potential to cause fetal loss. Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with Amitiza and should be capable of complying with effective contraceptive measures [see Use in Specific Populations (8.1)].

Nausea

Patients taking Amitiza may experience nausea. If this occurs, concomitant administration of food with Amitiza may reduce symptoms of nausea [see Adverse Reactions (6.1)].

Diarrhea

Amitiza should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Patients should be instructed to inform their physician if severe diarrhea occurs [see Adverse Reactions (6.1)].

Dyspnea

In clinical trials conducted to study Amitiza in treatment of chronic idiopathic constipation and IBS-C there were reports of dyspnea. This was reported at 2.5% of the treated chronic idiopathic constipation population and at 0.4% in the treated IBS-C population. Although not classified as serious adverse events, some patients discontinued treatment on study because of this event. There have been postmarketing reports of dyspnea when using Amitiza 24 mcg. Most have not been characterized as serious adverse events, but some patients have discontinued therapy because of dyspnea. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30–60 minutes after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses.

Bowel Obstruction

In patients with symptoms suggestive of mechanical gastrointestinal obstruction, the treating physician should perform a thorough evaluation to confirm the absence of such an obstruction prior to initiating therapy with Amitiza.

Adverse Reactions

Clinical Studies Experience

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

Chronic Idiopathic Constipation

Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza in 1175 patients with chronic idiopathic constipation (29 at 24 mcg once daily, 1113 at 24 mcg twice daily, and 33 at 24 mcg three times daily) over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤ 4 weeks). The total population (N = 1491) had a mean age of 49.7 (range 19–86) years; was 87.1% female; 84.8% Caucasian, 8.5% African American, 5.0% Hispanic, 0.9% Asian; and 15.5% elderly (≥ 65 years of age). Table 1 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo. In addition, corresponding adverse reaction incidences in patients receiving Amitiza 24 mcg once daily is shown.

Table 1: Percent of Patients with Adverse Reactions (Chronic Idiopathic Constipation)

1Includes only those events associated with treatment (possibly, probably, or definitely related, as assessed by the investigator). 2This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," and "abdominal discomfort."
System/Adverse Reaction1	Placebo N = 316 %	Amitiza 24 mcg Once Daily N = 29 %	Amitiza 24 mcg Twice Daily N = 1113 %
Gastrointestinal disorders
Nausea	3	17	29
Diarrhea	< 1	7	12
Abdominal pain	3	3	8
Abdominal distension	2	-	6
Flatulence	2	3	6
Vomiting	-	-	3
Loose stools	-	-	3
Abdominal discomfort2	< 1	3	2
Dyspepsia	< 1	-	2
Dry mouth	< 1	-	1
Stomach discomfort	< 1	-	1
Nervous system disorders
Headache	5	3	11
Dizziness	< 1	3	3
General disorders and site administration conditions
Edema	< 1	-	3
Fatigue	< 1	-	2
Chest discomfort/pain	-	3	2
Respiratory, thoracic, and mediastinal disorders
Dyspnea	-	3	2

Nausea: Approximately 29% of patients who received Amitiza 24 mcg twice daily experienced an adverse reaction of nausea; 4% of patients had severe nausea while 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Amitiza (any dosage) was substantially lower among male (7%) and elderly patients (18%). Further analysis of the safety data revealed that long-term exposure to Amitiza does not appear to place patients at an elevated risk for experiencing nausea. The incidence of nausea increased in a dose-dependent manner with the lowest overall incidence for nausea reported at the 24 mcg once daily dosage (17%). In open-labeled, long-term studies, patients were allowed to adjust the dosage of Amitiza down to 24 mcg once daily from 24 mcg twice daily if experiencing nausea. Nausea decreased when Amitiza was administered with food. No patients in the clinical studies were hospitalized due to nausea.

Diarrhea: Approximately 12% of patients who received Amitiza 24 mcg twice daily experienced an adverse reaction of diarrhea; 2% of patients had severe diarrhea while 2% of patients discontinued treatment due to diarrhea.

Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving Amitiza.

Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite.

Irritable Bowel Syndrome with Constipation

Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 46.5 (range 18–85) years; was 91.6% female; 77.5% Caucasian, 12.9% African American, 8.6% Hispanic, 0.4% Asian; and 8.0% elderly (≥ 65 years of age). Table 2 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 8 mcg twice daily and that occurred more frequently with study drug than placebo.

Table 2: Percent of Patients with Adverse Reactions (IBS-C Studies)

1Includes only those events associated with treatment (possibly or probably related, as assessed by the investigator).
System/Adverse Reaction1	Placebo N = 435 %	Amitiza 8 mcg Twice Daily N = 1011 %
Gastrointestinal disorders
Nausea	4	8
Diarrhea	4	7
Abdominal pain	5	5
Abdominal distension	2	3

Less common adverse reactions: The following adverse reactions (assessed by investigator as probably related to treatment) occurred in less than 1% of patients receiving Amitiza 8 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria.

One open-labeled, long-term clinical study was conducted in patients with IBS-C receiving Amitiza 8 mcg twice daily. This study comprised 476 intent-to-treat patients (mean age 47.5 [range 21–82] years; 93.5% female; 79.2% Caucasian, 11.6% African American, 8.6% Hispanic, 0.2% Asian; 7.8% ≥ 65 years of age) who were treated for an additional 36 weeks following an initial 12–16-week, double-blinded treatment period. The adverse reactions that were reported during this study were similar to those observed in the two double-blinded, controlled studies.

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of Amitiza 24 mcg for the treatment of chronic idiopathic constipation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Voluntary reports of adverse reactions occurring with the use of Amitiza include the following: syncope, allergic-type reactions (including rash, swelling, and throat tightness), malaise, increased heart rate, muscle cramps or muscle spasms, and asthenia.

Drug Interactions

Based upon the results of in vitro human microsome studies, there is low likelihood of drug–drug interactions. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3 [see Clinical Pharmacology (12.3)]. Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. No drug–drug interaction studies have been performed. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic effects: Pregnancy Category C. [See Warnings and Precautions(5.1).]

Teratology studies with lubiprostone have been conducted in rats at oral doses up to 2000 mcg/kg/day (approximately 332 times the recommended human dose, based on body surface area), and in rabbits at oral doses of up to 100 mcg/kg/day (approximately 33 times the recommended human dose, based on body surface area). Lubiprostone was not teratogenic in rats or rabbits. In guinea pigs, lubiprostone caused fetal loss at repeated doses of 10 and 25 mcg/kg/day (approximately 2 and 6 times the highest recommended human dose, respectively, based on body surface area) administered on days 40 to 53 of gestation.

There are no adequate and well-controlled studies in pregnant women. However, during clinical testing of Amitiza, six women became pregnant. Per protocol, Amitiza was discontinued upon pregnancy detection. Four of the six women delivered healthy babies. The fifth woman was monitored for 1 month following discontinuation of study drug, at which time the pregnancy was progressing as expected; the patient was subsequently lost to follow-up. The sixth pregnancy was electively terminated.

Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a woman is or becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been studied.

Geriatric Use

Chronic Idiopathic Constipation

The efficacy of Amitiza in the elderly (≥ 65 years of age) subpopulation was consistent with the efficacy in the overall study population. Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age. Elderly patients taking Amitiza (any dosage) experienced a lower incidence rate of associated nausea compared to the overall study population taking Amitiza (18% vs. 29%, respectively).

Irritable Bowel Syndrome with Constipation

The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.0% were ≥ 65 years of age and 1.8% were ≥ 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

Renal Impairment

No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic drug exposure; therefore, dosing with Amitiza should be modified in these patients [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology (12.3)]. No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

Overdosage

There have been two confirmed reports of overdosage with Amitiza. The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Amitiza and fully recovered. The second report was a study patient who self-administered a total of 96 mcg of Amitiza per day for 8 days. The patient experienced no adverse reactions during this time. Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 healthy volunteers given a single oral dose of 144 mcg of Amitiza (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug. Adverse reactions that occurred in at least 1% of these volunteers included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).

Amitiza Description

Amitiza (lubiprostone) is chemically designated as (–) - 7 - [(2R,4aR,5R,7aR) - 2 - (1,1 - difluoropentyl) - 2 - hydroxy - 6 - oxooctahydrocyclopenta[b]pyran - 5 - yl]heptanoic acid. The molecular formula of lubiprostone is C20H32F2O5 with a molecular weight of 390.46 and a chemical structure as follows:

Lubiprostone drug substance occurs as white, odorless crystals or crystalline powder, is very soluble in ether and ethanol, and is practically insoluble in hexane and water. Amitiza is available as an imprinted, oval, soft gelatin capsule in two strengths. Pink capsules contain 8 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, ferric oxide, titanium dioxide, and purified water. Orange capsules contain 24 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water.

Amitiza - Clinical Pharmacology

Mechanism of Action

Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. Additionally, activation of ClC-2 by lubiprostone has been shown to stimulate recovery of mucosal barrier function via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.

Pharmacodynamics

Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit.

Pharmacokinetics

Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Gender has no effect on the pharmacokinetics of M3 following the oral administration of lubiprostone.

Absorption

Concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL) because lubiprostone has a low systemic availability following oral administration. Peak plasma levels of M3, after a single oral dose with 24 mcg of lubiprostone, occurred at approximately 1.10 hours. The Cmax was 41.5 pg/mL and the mean AUC0–t was 57.1 pg∙hr/mL. The AUC0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone.

Distribution

In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Studies in rats given radiolabeled lubiprostone indicate minimal distribution beyond the gastrointestinal tissues. Concentrations of radiolabeled lubiprostone at 48 hours post-administration were minimal in all tissues of the rats.

Metabolism

The results of both human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but rather appear to be mediated by the ubiquitously expressed carbonyl reductase. M3, a metabolite of lubiprostone found in both humans and animals, is formed by the reduction of the carbonyl group at the 15-hydroxy moiety that consists of both α-hydroxy and β-hydroxy epimers. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. This is presumed to be the case in humans as well.

Elimination

Lubiprostone could not be detected in plasma; however, M3 has a t½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces.

Food Effect

A study was conducted with a single 72-mcg dose of 3H-labeled lubiprostone to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that Cmax decreased by 55% while AUC0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials.

Special Populations

Renal Impairment

Sixteen subjects, 34–47 years old (8 severe renally impaired subjects [creatinine clearance (CrCl) < 20 mL/min] who required hemodialysis and 8 control subjects with normal renal function [CrCl > 80 mL/min]), received a single oral 24-mcg dose of Amitiza. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of exposure from previous clinical experience with Amitiza. Thus there is no need for Amitiza dosage adjustment in patients with impaired renal function.

Hepatic Impairment

Twenty-five subjects, 38–78 years old (9 with severe hepatic impairment [Child-Pugh Class C], 8 with moderate impairment [Child-Pugh Class B], and 8 with normal liver function), received either 12 mcg or 24 mcg of Amitiza under fasting conditions. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL) except for two subjects. In moderately and severely impaired subjects, the Cmax and AUC0–t of M3 were increased, as shown in Table 3.

Table 3: Pharmacokinetic Parameters of M3 for Subjects with Normal or Impaired Liver Function following Dosing with Amitiza

Liver Function Status	Mean (SD) AUC0–t (pg•hr/mL)	% Change vs. Normal	Mean (SD) Cmax (pg/mL)	% Change vs. Normal
Normal (n=8)	39.6 (18.7)	n.a.	37.5 (15.9)	n.a.
Child-Pugh Class B (n=8)	119 (104)	+119	70.9 (43.5)	+66
Child-Pugh Class C (n=8)	234 (61.6)	+521	114 (59.4)	+183

These results demonstrate that there is a correlation between increased exposure of M3 and severity of hepatic impairment. In conjunction with the clinical safety results, which demonstrate an increased incidence and severity of adverse events in subjects with greater severity of hepatic impairment, the starting dosage should be reduced in patients with hepatic impairment receiving Amitiza [see Dosage and Administration (2.1, 2.2)]. No dosing adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the highest recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the highest recommended human dose, respectively, based on body surface area) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.

Mutagenesis

Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/–) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 166 times the highest recommended human dose of 48 mcg/day, based on body surface area.

Clinical Studies

Chronic Idiopathic Constipation

Dose-finding Study

A dose-finding, double-blinded, parallel-group, placebo-controlled, Phase 2 study was conducted in patients with chronic idiopathic constipation. Following a 2-week baseline/washout period, patients (N = 127) were randomized to receive placebo (n = 33), Amitiza 24 mcg/day (24 mcg once daily; n = 29), Amitiza 48 mcg/day (24 mcg twice daily; n = 32), or Amitiza 72 mcg/day (24 mcg three times daily; n = 33) for 3 weeks. Patients were chosen for participation based on their need for relief of constipation, which was defined as less than 3 spontaneous bowel movements (SBMs) per week. The primary efficacy variable was the daily average number of SBMs.

The study demonstrated that all patients who took Amitiza experienced a noticeable improvement in clinical response. Based on the efficacy analysis, there was no statistically significant improvement in the clinical response beyond a total daily dose of 24 mcg during treatment weeks 2 and 3 (Figure 1).

Figure 1: Weekly Mean (± Standard Error) Spontaneous Bowel Movements (Dose-finding Study)

Efficacy Studies

Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation. Chronic idiopathic constipation was defined as, on average, less than 3 SBMs per week along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.

Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 [range 20–81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily (48 mcg/day) or placebo twice daily for 4 weeks. The primary endpoint of the studies was SBM frequency. The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients. In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 4).

Table 4: Spontaneous Bowel Movement Frequency Rates1 (Efficacy Studies)

1Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week).
Trial	Study Arm	Baseline Mean ± SD Median	Week 1 Mean ± SD Median	Week 2 Mean ± SD Median	Week 3 Mean ± SD Median	Week 4 Mean ± SD Median	Week 1 Change from Baseline Mean ± SD Median	Week 4 Change from Baseline Mean ± SD Median
	Placebo	1.6 ± 1.3 1.5	3.5 ± 2.3 3.0	3.2 ± 2.5 3.0	2.8 ± 2.2 2.0	2.9 ± 2.4 2.3	1.9 ± 2.2 1.5	1.3 ± 2.5 1.0
Study 1
	Amitiza 24 mcg Twice Daily	1.4 ± 0.8 1.5	5.7 ± 4.4 5.0	5.1 ± 4.1 4.0	5.3 ± 4.9 5.0	5.3 ± 4.7 4.0	4.3 ± 4.3 3.5	3.9 ± 4.6 3.0
	Placebo	1.5 ± 0.8 1.5	4.0 ± 2.7 3.5	3.6 ± 2.7 3.0	3.4 ± 2.8 3.0	3.5 ± 2.9 3.0	2.5 ± 2.6 1.5	1.9 ± 2.7 1.5
Study 2
	Amitiza 24 mcg Twice Daily	1.3 ± 0.9 1.5	5.9 ± 4.0 5.0	5.0 ± 4.2 4.0	5.6 ± 4.6 5.0	5.4 ± 4.8 4.3	4.6 ± 4.1 3.8	4.1 ± 4.8 3.0

In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs. 36.9% in Study 1 and 62.9% vs. 31.9% in Study 2, respectively). Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.

Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age).

Following 4 weeks of treatment with Amitiza 24 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect.

Long-term Studies

Three open-labeled, long-term clinical safety and efficacy studies were conducted in patients with chronic idiopathic constipation receiving Amitiza 24 mcg twice daily. These studies comprised 871 patients (mean age 51.0 [range 19–86] years; 86.1% female; 86.9% Caucasian, 7.3% African American, 4.5% Hispanic, 0.7% Asian; 18.4% ≥ 65 years of age) who were treated for 6–12 months (24–48 weeks). Patients provided regular assessments of abdominal bloating, abdominal discomfort, and constipation severity. These studies demonstrated that Amitiza decreased abdominal bloating, abdominal discomfort, and constipation severity over the 6–12-month treatment periods.

Irritable Bowel Syndrome with Constipation

Efficacy Studies

Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C. IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form. Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) < 3 spontaneous bowel movements per week, 2) > 25% hard stools, and 3) > 25% spontaneous bowel movements associated with straining.

Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 [range 18–85] years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% ≥ 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly utilizing the patient's response to a global symptom relief question based on a 7-point, balanced scale ("significantly worse" to "significantly relieved"): "How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?"

The primary efficacy analysis was a comparison of the proportion of "overall responders" in each arm. A patient was considered an "overall responder" if the criteria for being designated a "monthly responder" were met in at least 2 of the 3 months on study. A "monthly responder" was defined as a patient who had reported "significantly relieved" for at least 2 weeks of the month or at least "moderately relieved" in all 4 weeks of that month. During each monthly evaluation period, patients reporting "moderately worse" or "significantly worse" relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders.

The percentage of patients in Study 1 qualifying as an "overall responder" was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily. In Study 2, 12.1% of patients in the Amitiza 8 mcg group were "overall responders" versus 5.7% of patients in the placebo group. In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.

Results in men: The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women.

Study 1 also assessed the rebound effect from the withdrawal of Amitiza. Following 12 weeks of treatment with Amitiza 8 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect.

How Supplied/Storage and Handling

Amitiza is available as an oval, soft gelatin capsule containing 8 mcg or 24 mcg of lubiprostone with "SPI" printed on one side. Amitiza is available as follows:

8-mcg pink capsule

• Bottles of 60 (NDC 64764-080-60)

24-mcg orange capsule

• Bottles of 60 (NDC 64764-240-60)


• Bottles of 100 (NDC 64764-240-10)

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

PROTECT FROM EXTREME TEMPERATURES.

Patient Counseling Information

Dosing Instructions

Amitiza should be taken twice daily with food and water to reduce potential symptoms of nausea. The capsule should be taken once in the morning and once in the evening daily as prescribed. The capsule should be swallowed whole and should not be broken apart or chewed. Physicians and patients should periodically assess the need for continued therapy.

Patients on treatment who experience severe nausea, diarrhea, or dyspnea should inform their physician. Patients taking Amitiza may experience dyspnea within an hour of the first dose. This symptom generally resol

Synagis

1. Name Of The Medicinal Product

SYNAGIS

2. Qualitative And Quantitative Composition

Each vial contains 50 mg or 100 mg palivizumab*, providing 100 mg/ml of palivizumab when reconstituted as recommended.

*recombinant humanised monoclonal antibody produced by DNA technology in mouse myeloma host cells.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

The powder is a white to off-white cake.

4. Clinical Particulars

4.1 Therapeutic Indications

SYNAGIS is indicated for the prevention of serious lower respiratory tract disease requiring hospitalisation caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease:

• Children born at 35 weeks of gestation or less and less than 6 months of age at the onset of the RSV season.

• Children less than 2 years of age and requiring treatment for bronchopulmonary dysplasia within the last 6 months.

• Children less than 2 years of age and with haemodynamically significant congenital heart disease.

4.2 Posology And Method Of Administration

Recommended dose

The recommended dose of palivizumab is 15 mg/kg of body weight, given once a month during anticipated periods of RSV risk in the community. Where possible, the first dose should be administered prior to commencement of the RSV season. Subsequent doses should be administered monthly throughout the RSV season.

The majority of experience including the pivotal phase III clinical trials with palivizumab has been gained with 5 injections during one season (see section 5.1). Data, although limited, are available on greater than 5 doses (see sections 4.8 and 5.1), therefore the benefit in terms of protection beyond 5 doses has not been established.

To reduce risk of rehospitalisation, it is recommended that children receiving palivizumab who are hospitalised with RSV continue to receive monthly doses of palivizumab for the duration of the RSV season.

For children undergoing cardiac bypass, it is recommended that a 15 mg/kg of body weight injection of palivizumab be administered as soon as stable after surgery to ensure adequate palivizumab serum levels. Subsequent doses should resume monthly through the remainder of the RSV season for children that continue to be at high risk of RSV disease (see section 5.2).

Method of administration

Palivizumab is administered in a dose of 15 mg/kg of body weight once a month intramuscularly, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve. The injection should be given using standard aseptic technique. Injection volumes over 1 ml should be given as a divided dose.

For information on reconstituting SYNAGIS, see section 6.6.

4.3 Contraindications

Known hypersensitivity to the active substance or to any of the excipients (see section 6.1), or other humanised monoclonal antibodies.

4.4 Special Warnings And Precautions For Use

Allergic reactions including very rare cases of anaphylaxis have been reported following palivizumab administration (see section 4.8).

Medicinal products for the treatment of severe hypersensitivity reactions, including anaphylaxis, should be available for immediate use following administration of palivizumab.

A moderate to severe acute infection or febrile illness may warrant delaying the use of palivizumab, unless, in the opinion of the physician, withholding palivizumab entails a greater risk. A mild febrile illness, such as mild upper respiratory infection, is not usually reason to defer administration of palivizumab.

As with any intramuscular injection, palivizumab should be given with caution to patients with thrombocytopaenia or any coagulation disorder.

The efficacy of palivizumab when administered to patients as a second course of treatment during an ensuing RSV season has not been formally investigated in a study performed with this objective. The possible risk of enhanced RSV infection in the season following the season in which the patients were treated with palivizumab has not been conclusively ruled out by studies performed aiming at this particular point.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal interactions studies with other medicinal products were conducted, however no interactions have been described to date. In the phase III IMpact-RSV study in the premature and bronchopulmonary dysplasia paediatric populations, the proportions of patients in the placebo and palivizumab groups who received routine childhood vaccines, influenza vaccine, bronchodilators or corticosteroids were similar and no incremental increase in adverse reactions was observed among patients receiving these agents.

Since the monoclonal antibody is specific for RSV, palivizumab is not expected to interfere with the immune response to vaccines.

4.6 Pregnancy And Lactation

Not relevant. SYNAGIS is not indicated for use in adults. Data on pregnancy and lactation are not available.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Adverse drug reactions (ADRs) reported in the prophylactic paediatric studies were similar in the placebo and palivizumab groups. The majority of ADRs were transient and mild to moderate in severity.

Adverse events at least possibly causally-related to palivizumab, both clinical and laboratory, are displayed by system organ class and frequency (common

Within each frequency grouping, adverse reactions have been presented in order of decreasing seriousness.

Table 1 Undesirable effects in prophylactic clinical studies with premature and bronchopulmonary dysplasia paediatric populations
Infections and infestations	Uncommon	Viral infection Upper respiratory infection
Blood and lymphatic system disorders	Uncommon	Leucopaenia
Psychiatric disorders	Common	Nervousness
Respiratory, thoracic and mediastinal disorders	Uncommon	Wheeze Rhinitis Cough
Gastrointestinal disorders	Common   Uncommon	Diarrhoea   Vomiting
Skin and subcutaneous tissue disorders	Uncommon	Rash
General disorders and administration site conditions	Common   Uncommon	Fever Injection site reaction Pain
Investigations	Uncommon	AST increase ALT increase Abnormal liver function test

No medically important differences were observed during the prophylactic studies carried out in the premature and bronchopulmonary dysplasia paediatric populations in ADRs by body system or when evaluated in subgroups of children by clinical category, gender, age, gestational age, country, race/ethnicity or quartile serum palivizumab concentration. No significant difference in safety profile was observed between children without active RSV infection and those hospitalised for RSV. Permanent discontinuation of palivizumab due to ADRs was rare (0.2%). Deaths were balanced between the integrated placebo and palivizumab groups and were not drug-related.

Table 2 Undesirable effects in the prophylactic paediatric congenital heart disease clinical study
Infections and infestations	Uncommon	Gastroenteritis Upper respiratory infection
Psychiatric disorders	Uncommon	Nervousness
Nervous system disorders	Uncommon	Somnolence Hyperkinesia
Vascular disorders	Uncommon	Haemorrhage
Respiratory, thoracic and mediastinal disorders	Uncommon	Rhinitis
Gastrointestinal disorders	Uncommon	Vomiting Diarrhoea Constipation
Skin and subcutaneous tissue disorders	Uncommon	Rash Eczema
General disorders and administration site conditions	Common   Uncommon	Fever Injection site reaction Asthenia

In the congenital heart disease study no medically important differences were observed in ADRs by body system or when evaluated in subgroups of children by clinical category. The incidence of serious adverse events was significantly lower in the palivizumab group compared to the placebo group. No serious adverse events related to palivizumab were reported. The incidences of cardiac surgeries classified as planned, earlier than planned or urgent were balanced between the groups. Deaths associated with RSV infection occurred in 2 patients in the palivizumab group and 4 patients in the placebo group and were not drug-related.

Post-marketing experience:

The following events were reported during post-marketing experience of palivizumab. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to palivizumab exposure.

Blood and lymphatic system disorders: thrombocytopenia

Immune system disorders: anaphylaxis

Nervous system disorders: convulsion

Respiratory, thoracic and mediastinal disorders: apnoea

Skin and subcutaneous tissue disorders: urticaria

Post-marketing serious spontaneous adverse events reported during palivizumab treatment between 1998 and 2002 covering four RSV seasons were evaluated. A total of 1,291 serious reports were received where palivizumab had been administered as indicated and the duration of therapy was within one season. The onset of the adverse event occurred after the sixth or greater dose in only 22 of these reports (15 after the sixth dose, 6 after the seventh doses and 1 after the eight dose). These events are similar in character to those after the initial five doses.

Palivizumab treatment schedule and adverse events were monitored in a group of nearly 20,000 infants tracked through a patient compliance registry between 1998 and 2000. Of this group 1,250 enrolled infants had 6 injections, 183 infants had 7 injections, and 27 infants had either 8 or 9 injections. Adverse events observed in patients after a sixth or greater dose were similar in character and frequency to those after the initial 5 doses.

Human anti-human antibody (HAHA) response:

Antibody to palivizumab was observed in approximately 1% of patients in the IMpact-RSV during the first course of therapy. This was transient, low titre, resolved despite continued use (first and second season), and could not be detected in 55/56 infants during the second season (including 2 with titres during the first season). Therefore, HAHA responses appear to be of no clinical relevance.

Immunogenicity was not studied in the congenital heart disease study.

4.9 Overdose

In clinical studies, three children received an overdose of more than 15 mg/kg. These doses were 20.25 mg/kg, 21.1 mg/kg and 22.27 mg/kg. No medical consequences were identified in these instances.

From the post-marketing experience, overdoses as high as 60 mg/kg have been reported without any untoward medical events.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: specific immunoglobulins; ATC Code: J06BB16

Palivizumab is a humanised IgG_1κ monoclonal antibody directed to an epitope in the A antigenic site of the fusion protein of respiratory syncytial virus (RSV). This humanised monoclonal antibody is composed of human (95%) and murine (5%) antibody sequences. It has potent neutralising and fusion-inhibitory activity against both RSV subtype A and B strains.

Palivizumab serum concentrations of approximately 30 μg/ml have been shown to produce a 99% reduction in pulmonary RSV replication in the cotton rat model.

Clinical studies

In a placebo-controlled trial of RSV disease prophylaxis in (IMpact-RSV trial) 1502 high-risk children (1002 SYNAGIS; 500 placebo), 5 monthly doses of 15 mg/kg reduced the incidence of RSV related hospitalisation by 55% (p = < 0.001). The RSV hospitalisation rate was 10.6% in the placebo group. On this basis, the absolute risk reduction is 5.8% which means the number needed to treat is 17 to prevent one hospitalisation. The severity of RSV disease in children hospitalised despite prophylaxis with palivizumab in terms of days in ICU stay per 100 children and days of mechanical ventilation per 100 children was not affected.

A total of 222 children were enrolled in two separate studies to examine the safety of palivizumab when it is administered for a second RSV season. One hundred and three (103) children received monthly palivizumab injections for the first time, and 119 children received palivizumab for two consecutive seasons. No difference between groups regarding immunogenicity was observed in either study. However, as the efficacy of palivizumab when administered to patients as a second course of treatment during an ensuing RSV season has not been formally investigated in a study performed with this objective, the relevance of these data in terms of efficacy is unknown.

In an open label prospective trial designed to evaluate pharmacokinetics, safety and immunogenicity after administration of 7 doses of palivizumab within a single RSV season, pharmacokinetic data indicated that adequate mean palivizumab levels were achieved in all 18 children enrolled. Transient, low levels of antipalivizumab antibody were observed in one child after the second dose of palivizumab that dropped to undetectable levels at the fifth and seventh dose.

In a placebo-controlled trial in 1,287 patients

5.2 Pharmacokinetic Properties

In studies in adult volunteers, palivizumab had a pharmacokinetic profile similar to a human IgG₁ antibody with regard to volume of distribution (mean 57 ml/kg) and half-life (mean 18 days). In prophylactic studies in premature and bronchopulmonary dysplasia paediatric populations, the mean half-life of palivizumab was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean 30 day trough serum active substance concentrations of approximately 40 μg/ml after the first injection, approximately 60 μg/ml after the second injection, approximately 70 μg/ml after the third injection and fourth injection. In the congenital heart disease study, monthly intramuscular doses of 15 mg/kg achieved mean 30 day trough serum active substance concentrations of approximately 55 µg/ml after the first injection and approximately 90 µg/ml after the fourth injection.

Among 139 children in the congenital heart disease study receiving palivizumab who had cardio

5.3 Preclinical Safety Data

Single dose toxicology studies have been conducted in cynomolgus monkeys (maximum dose 30 mg/kg), rabbits (maximum dose 50 mg/kg) and rats (maximum dose 840 mg/kg). No significant findings were observed.

Studies carried out in rodents gave no indication of enhancement of RSV replication, or RSV-induced pathology or generation of virus escape mutants in the presence of palivizumab under the chosen experimental conditions.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder:

Histidine

Glycine

Mannitol (E421)

Solvent:

Water for injections

6.2 Incompatibilities

Palivizumab should not be mixed with any medicinal products or diluents other than water for injections.

6.3 Shelf Life

3 years.

After reconstitution, the product should be used immediately. However in-use stability has been demonstrated for 3 hours at 20 - 24^oC.

6.4 Special Precautions For Storage

Store in a refrigerator (2ºC to 8ºC).

Do not freeze.

Store in the original container.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

50 mg of powder in a 4 ml vial (Type I glass) with a stopper (bromobutyl rubber) and a flip-off seal (aluminium).

100 mg of powder in a 10 ml vial (Type I glass) with a stopper (bromobutyl rubber) and a flip-off seal (aluminium).

1ml of water for injections in an ampoule (type I glass).

Pack size of 1.

6.6 Special Precautions For Disposal And Other Handling

SLOWLY add 0.6 ml of water for injections for the 50 mg vial or 1.0 ml of water for injections for the 100 mg vial along the inside wall of the vial to minimise foaming. After the water is added, tilt the vial slightly and gently rotate the vial for 30 seconds. DO NOT SHAKE THE VIAL. Palivizumab solution should stand at room temperature for a minimum of 20 minutes until the solution clarifies. Palivizumab solution does not contain a preservative and should be administered within 3 hours of preparation.

When reconstituted as recommended, the final concentration is 100 mg/ml.

The appearance of the reconstituted solution is clear to slightly opalescent.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Abbott Laboratories Limited

Abbott House,

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

8. Marketing Authorisation Number(S)

50 mg vial: EU/1/99/117/001

100 mg vial: EU/1/99/117/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 13 August 1999

Date of latest renewal: 13 August 2009

10. Date Of Revision Of The Text

23 December 2009

Isosorbide Dinitrate

Isosorbide Dinitrate Tablets, USP (Oral)

Isosorbide Dinitrate Description

Isosorbide Dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is:

The organic nitrates are vasodilators, active on both arteries and veins.

Isosorbide Dinitrate is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of 70°C and has an optical rotation of +134° (c=1, alcohol, 20°C). Isosorbide Dinitrate is freely soluble in organic solvents such as acetone, alcohol, and ether, but is only sparingly soluble in water.

Isosorbide Dinitrate is available as 5 mg, 10 mg, and 20 mg tablets for oral administration. Inactive ingredients: lactose (monohydrate), magnesium stearate, microcrystalline cellulose. The 5 mg also contains FD & C Red #40 Aluminum Lake. The 20 mg also contains D & C Yellow #10 Aluminum Lake, FD & C Blue #1 Aluminum Lake, and FD & C Yellow #6 Aluminum Lake.

Isosorbide Dinitrate - Clinical Pharmacology

The principal pharmacological action of Isosorbide Dinitrate is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored.

Pharmacokinetics

Absorption of Isosorbide Dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. Serum levels reach their maxima about an hour after ingestion. The average bioavailability of ISDN is about 25%; most studies have observed progressive increases in bioavailability during chronic therapy.

Once absorbed, the volume of distribution of Isosorbide Dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN’s half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur. Clearance is affected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).

Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours.

The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN and its active metabolites.

Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.

Clinical Trials

In clinical trials, immediate-release oral Isosorbide Dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg. Controlled trials of single oral doses of Isosorbide Dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours. Anti-anginal activity is present about 1 hour after dosing.

Most controlled trials of multiple-dose oral ISDN taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing. Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400, and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above. The effects of the second and later doses have been smaller and shorter-lasting than the effect of the first.

From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from Isosorbide Dinitrate is about 12 hours. No dosing regimen for Isosorbide Dinitrate, however, has ever actually been shown to achieve this duration of effect. One study of 8 patients, who were administered a pretitrated dose (average 27.5 mg) of immediate-release ISDN at 0800, 1300, and 1800 hours for 2 weeks, revealed that significant anti-anginal effectiveness was discontinuous and totaled about 6 hours in a 24 hour period.

Indications and Usage for Isosorbide Dinitrate

Isosorbide Dinitrate tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of immediate-release oral Isosorbide Dinitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

Contraindications

Allergic reactions to organic nitrates are extremely rare, but they do occur. Isosorbide Dinitrate tablets are contraindicated in patients who are allergic to Isosorbide Dinitrate or any of its other ingredients.

Warnings

Amplification of the vasodilatory effects of Isosorbide Dinitrate by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of immediate release oral Isosorbide Dinitrate in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use Isosorbide Dinitrate in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects of oral Isosorbide Dinitrate are so difficult to terminate rapidly, this formulation is not recommended in these settings.

Precautions

General

Severe hypotension, particularly with upright posture, may occur with even small doses of Isosorbide Dinitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by Isosorbide Dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

As tolerance to Isosorbide Dinitrate develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the daily dose-free interval in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. The importance of these observations to the routine, clinical use of immediate-release oral Isosorbide Dinitrate is not known.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Information for Patients

Patients should be told that the anti-anginal efficacy of Isosorbide Dinitrate is strongly related to its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches sometimes accompany treatment with Isosorbide Dinitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with Isosorbide Dinitrate, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve Isosorbide Dinitrate-induced headaches with no deleterious effect on Isosorbide Dinitrate’s anti-anginal efficacy.

Treatment with Isosorbide Dinitrate may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

Drug Interactions

The vasodilating effects of Isosorbide Dinitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of Isosorbide Dinitrate. In a modified two-litter reproduction study there was no remarkable gross pathology and no altered fertility or gestation among rats fed Isosorbide Dinitrate at 25 or 100 mg/kg/day.

Pregnancy

Pregnancy Category C

At oral doses 35 and 150 times the maximum recommended human daily dose, Isosorbide Dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant women. Isosorbide Dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Isosorbide Dinitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Isosorbide Dinitrate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Isosorbide Dinitrate 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.

Adverse Reactions

Adverse reactions to Isosorbide Dinitrate are generally dose-related, and almost all of these reactions are the result of Isosorbide Dinitrate’s activity as a vasodilator. Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each daily dose, especially at higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been reported but are uncommon.

Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see OVERDOSAGE).

Data are not available to allow estimation of the frequency of adverse reactions during treatment with Isosorbide Dinitrate tablets.

Overdosage

Hemodynamic Effects

The ill effects of Isosorbide Dinitrate overdose are generally the results of Isosorbide Dinitrate’s capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death.

Laboratory determinations of serum levels of Isosorbide Dinitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Isosorbide Dinitrate overdose.

There are no data suggesting what dose of Isosorbide Dinitrate is likely to be life-threatening in humans. In rats, the median acute lethal dose (LD50) was found to be 1100 mg/kg.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Isosorbide Dinitrate and its active metabolites. Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis.

No specific antagonist to the vasodilator effects of Isosorbide Dinitrate is known, and no intervention has been subject to controlled studies as a therapy for Isosorbide Dinitrate overdose. Because the hypotension associated with Isosorbide Dinitrate overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of Isosorbide Dinitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Nitrate ions liberated during metabolism of Isosorbide Dinitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of Isosorbide Dinitrate are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of Isosorbide Dinitrate should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of Isosorbide Dinitrate. In one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 to 6.9 mg of bioavailable Isosorbide Dinitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.

Isosorbide Dinitrate Dosage and Administration

As noted under CLINICAL PHARMACOLOGY, multiple-dose studies with ISDN and other nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every dosing regimen for Isosorbide Dinitrate tablets must provide a daily dose-free interval to minimize the development of this tolerance. With immediate-release ISDN, it appears that one daily dose-free interval must be at least 14 hours long.

As also noted under CLINICAL PHARMACOLOGY, the effects of the second and later doses have been smaller and shorter-lasting than the effects of the first.

Large controlled studies with other nitrates suggest that no dosing regimen with Isosorbide Dinitrate tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day.

As with all titratable drugs, it is important to administer the minimum dose which produces the desired clinical effect. The usual starting dose of Isosorbide Dinitrate is 5 mg to 20 mg, two or three times daily. For maintenance therapy, 10 mg to 40 mg, two or three times daily is recommended. Some patients may require higher doses. A daily dose-free interval of at least 14 hours is advisable to minimize tolerance. The optimal interval will vary with the individual patient, dose and regimen.

How is Isosorbide Dinitrate Supplied

Isosorbide Dinitrate tablets, USP are supplied as:

5 mg: Round, pink, scored tablets, debossed GG 259 on one side and plain on the reverse side, and supplied as:

NDC 0781-1635-01 bottles of 100

NDC 0781-1635-10 bottles of 1000

NDC 0781-1635-13 unit dose packages of 100

10 mg: Round, white, scored tablets, debossed GG 26 on one side and plain on the reverse side, and supplied as:

NDC 0781-1556-01 bottles of 100

NDC 0781-1556-05 bottles of 500

NDC 0781-1556-10 bottles of 1000

NDC 0781-1556-13 unit dose packages of 100

20 mg: Round, green, scored tablets, debossed GG 227 on one side and plain on the reverse side, and supplied as:

NDC 0781-1695-01 bottles of 100

NDC 0781-1695-10 bottles of 1000

NDC 0781-1695-13 unit dose packages of 100

Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container.

12-2007M

7185

Sandoz Inc.

Princeton, NJ 08540

mg Label

NDC 0781-1635-01

Isosorbide

Dinitrate

Tablets, USP

5 mg ORAL

Rx only

100 Tablets

SANDOZ

mg Label

NDC 0781-1556-01

Isosorbide

Dinitrate

Tablets, USP

10 mg ORAL

Rx only

100 Tablets

SANDOZ

mg Label

NDC 0781-1695-01

Isosorbide

Dinitrate

Tablets, USP

20 mg ORAL

Rx only

100 Tablets

SANDOZ

Isosorbide Dinitrate  Isosorbide Dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-1635 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isosorbide Dinitrate (ISOSORBIDE) Isosorbide Dinitrate 5 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   FD&C RED NO. 40   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color PINK Score 2 pieces Shape ROUND Size 8mm Flavor Imprint Code GG259 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-1635-10 1000 TABLET In 1 BOTTLE None 2 0781-1635-01 100 TABLET In 1 BOTTLE None 3 0781-1635-13 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK 3 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0781-1635-13)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA086221	01/07/1988

Isosorbide Dinitrate  Isosorbide Dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-1556 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isosorbide Dinitrate (ISOSORBIDE) Isosorbide Dinitrate 10 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 8mm Flavor Imprint Code GG26 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-1556-13 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0781-1556-13) 2 0781-1556-01 100 TABLET In 1 BOTTLE None 3 0781-1556-05 500 TABLET In 1 BOTTLE None 4 0781-1556-10 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA086223	01/07/1988

Isosorbide Dinitrate  Isosorbide Dinitrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-1695 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isosorbide Dinitrate (ISOSORBIDE) Isosorbide Dinitrate 20 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   D&C YELLOW NO. 10   FD&C BLUE NO. 1   FD&C YELLOW NO. 6   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE

Product Characteristics Color GREEN Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code GG227 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-1695-13 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0781-1695-13) 2 0781-1695-10 1000 TABLET In 1 BOTTLE None 3 0781-1695-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA089367	04/07/1988

Labeler - Sandoz Inc (110342024)

Revised: 01/2012Sandoz Inc