Clopidogrel

Generic Name: Clopidogrel bisulfate

Dosage Form: Tablets

Clopidogrel Description

Clopidogrel bisulfate is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The empirical formula of Clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and its molecular weight is 419.9.

The structural formula is as follows:

Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.

Clopidogrel Tablets 75 mg for oral administration are provided as reddish-brown, round, unscored, film coated tablets, imprinted "APO" on one side and "CL" over "75" on the other side. The tablets contain 97.875 mg of Clopidogrel bisulfate which is the molar equivalent of 75 mg of Clopidogrel base.

Each tablet contains anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate as inactive ingredients. The reddish-brown film coating contains ferric oxide, hydroxypropyl cellulose, hypromellose 2910 15 CPS, polyethylene glycol 8000 and titanium dioxide.

Clopidogrel - Clinical Pharmacology

Mechanism of Action

Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.

Pharmacodynamic Properties

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of Clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.

Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to Clopidogrel are affected for the remainder of their lifespan.

Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Clopidogrel bisulfate. Repeated doses of 75 mg Clopidogrel bisulfate per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Clopidogrel bisulfate per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

Pharmacokinetics and Metabolism

After repeated 75 mg oral doses of Clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.00025 mg/L) beyond 2 hours after dosing. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it too has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma.

Following an oral dose of 14C-labeled Clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.

Effect of Food

Administration of Clopidogrel bisulfate with meals did not significantly modify the bioavailability of Clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.

Absorption and Distribution

Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg Clopidogrel (base), with peak plasma levels (

Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 µg/mL.

Metabolism and Elimination

In vitro and in vivo, Clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

Special Populations

Geriatric Patients

Plasma concentrations of the main circulating metabolite are significantly higher in elderly (≥75 years) compared to young healthy volunteers but these higher plasma levels were not associated with differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.

Renally Impaired Patients

After repeated doses of 75 mg Clopidogrel bisulfate per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of Clopidogrel bisulfate per day.

Gender

No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.

Race

Pharmacokinetic differences due to race have not been studied.

Clinical Studies

The clinical evidence for the efficacy of Clopidogrel bisulfate is derived from two double-blind trials: the CAPRIE study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events), a comparison of Clopidogrel bisulfate to aspirin, and the CURE study (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events), a comparison of Clopidogrel bisulfate to placebo, both given in combination with aspirin and other standard therapy.

The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing Clopidogrel bisulfate (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) objectively established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).

The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

Table 1: Outcome Events in the CAPRIE Primary Analysis

	Clopidogrel bisulfate	aspirin
Patients	9599	9586
IS (fatal or not)	438 (4.6%)	461 (4.8%)
MI (fatal or not)	275 (2.9%)	333 (3.5%)
Other vascular death	226 (2.4%)	226 (2.4%)
Total	939 (9.8%)	1020 (10.6%)

As shown in the table, Clopidogrel bisulfate was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.8% vs. 10.6%) was 8.7%, P=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the Clopidogrel bisulfate group.

The curves showing the overall event rate are shown in Figure 1. The event curves separated early and continued to diverge over the 3-year follow-up period.

Figure 1: Fatal or Non-Fatal Vascular Events in the CAPRIE Study

Although the statistical significance favoring Clopidogrel bisulfate over aspirin was marginal (P=0.045), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs. placebo) in reducing cardiovascular events in patients with recent myocardial infarction or stroke. Thus, the difference between Clopidogrel bisulfate and placebo, although not measured directly, is substantial.

The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of Clopidogrel bisulfate relative to aspirin was heterogeneous across these randomized subgroups (P=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of Clopidogrel bisulfate over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, Clopidogrel bisulfate was not numerically superior to aspirin.

In the meta-analyses of studies of aspirin vs. placebo in patients similar to those in CAPRIE, aspirin was associated with a reduced incidence of atherothrombotic events. There was a suggestion of heterogeneity in these studies too, with the effect strongest in patients with a history of myocardial infarction, weaker in patients with a history of stroke, and not discernible in patients with a history of peripheral vascular disease. With respect to the inferred comparison of Clopidogrel bisulfate to placebo, there is no indication of heterogeneity.

The CURE study included 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST segment elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age.

Patients were randomized to receive Clopidogrel bisulfate (300 mg loading dose followed by 75 mg/day) or placebo, and were treated for up to one year. Patients also received aspirin (75-325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.30%) in the Clopidogrel bisulfate-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%–28%; p=0.00009) for the Clopidogrel bisulfate-treated group (see Table 2).

At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the Clopidogrel bisulfate-treated group and 1187 (18.83%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%–21%, p=0.0005) for the Clopidogrel bisulfate-treated group (see Table 2).

In the Clopidogrel bisulfate-treated group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo-treated group.

Table 2: Outcome Events in the CURE Primary Analysis

Outcome	Clopidogrel bisulfate (+ aspirin)*	Placebo (+ aspirin)*	Relative Risk Reduction (%) (95% CI)
	(n=6259)	(n=6303)
* Other standard therapies were used as appropriate. † The individual components do not represent a breakdown of the primary and co-primary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
Primary outcome   (Cardiovascular death, MI, Stroke)	582 (9.3%)	719 (11.4%)	20% (10.3, 27.9) P=0.00009
Co-primary outcome   (Cardiovascular death, MI, Stroke,   Refractory Ischemia)	1035 (16.5%)	1187 (18.8%)	14% (6.2, 20.6) P=0.00052
All Individual Outcome Events:†
CV death	318 (5.1%)	345 (5.5%)	7% (-7.7, 20.6)
MI	324 (5.2%)	419 (6.6%)	23% (11.0, 33.4)
Stroke	75 (1.2%)	87 (1.4%)	14% (-17.7, 36.6)
Refractory ischemia	544 (8.7%)	587 (9.3%)	7% (-4.0, 18)

The benefits of Clopidogrel bisulfate were maintained throughout the course of the trial (up to 12 months).

Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study

In CURE, the use of Clopidogrel bisulfate was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with Clopidogrel tablets were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH (low molecular weight heparin), IV glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of Clopidogrel bisulfate was observed independently of the dose of aspirin (75–325 mg once daily). The use of oral anticoagulants, non-study anti-platelet drugs and chronic NSAIDs was not allowed in CURE.

Figure 3. Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study

The use of Clopidogrel bisulfate in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the Clopidogrel bisulfate group, 126 patients [2%] in the placebo group; relative risk reduction of 43%, P=0.0001), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the Clopidogrel bisulfate group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%, P=0.003). The use of Clopidogrel bisulfate in CURE did not impact the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36%] in the Clopidogrel bisulfate group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4%, P=0.1658).

Indications and Usage for Clopidogrel

Clopidogrel bisulfate is indicated for the reduction of atherothrombotic events as follows:

• Recent MI, Recent Stroke or Established Peripheral Arterial Disease
  

  For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, Clopidogrel bisulfate has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

  
  


• Acute Coronary Syndrome
  

  For patients with acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, Clopidogrel bisulfate has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.

  
  

Contraindications

The use of Clopidogrel bisulfate is contraindicated in the following conditions:

• Hypersensitivity to the drug substance or any component of the product.


• Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Warnings

Thrombotic thrombocytopenic purpura (TTP)

TTP has been reported rarely following use of Clopidogrel bisulfate, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. (See ADVERSE REACTIONS.)

Precautions

General

Clopidogrel bisulfate prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, Clopidogrel bisulfate should be discontinued 5 days prior to surgery.

Due to the risk of bleeding and undesirable hematological effects, blood cell count determination and/or other appropriate testing should be promptly considered, whenever such suspected clinical symptoms arise during the course of treatment (see ADVERSE REACTIONS).

In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Clopidogrel bisulfate has not been shown to be more effective than Clopidogrel bisulfate alone, but the combination has been shown to increase major bleeding.

GI Bleeding

In CAPRIE, Clopidogrel bisulfate was associated with a rate of gastrointestinal bleeding of 2%, vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal bleeding was 1.3% vs 0.7% (Clopidogrel bisulfate + aspirin vs. placebo + aspirin, respectively). Clopidogrel bisulfate should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking Clopidogrel bisulfate.

Use in Hepatically Impaired Patients

Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Clopidogrel bisulfate should be used with caution in this population.

Use in Renally Impaired Patients

Experience is limited in patients with severe renal impairment. Clopidogrel bisulfate should be used with caution in this population.

Information for Patients

Patients should be told that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they take Clopidogrel bisulfate or Clopidogrel bisulfate combined with aspirin, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking Clopidogrel bisulfate and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.

Drug Interactions

Study of specific drug interactions yielded the following results:

Aspirin

Aspirin did not modify the Clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by Clopidogrel bisulfate. Clopidogrel bisulfate potentiated the effect of aspirin on collagen-induced platelet aggregation. Clopidogrel bisulfate and aspirin have been administered together for up to one year.

Heparin

In a study in healthy volunteers, Clopidogrel bisulfate did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by Clopidogrel bisulfate.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

In healthy volunteers receiving naproxen, concomitant administration of Clopidogrel bisulfate was associated with increased occult gastrointestinal blood loss. NSAIDs and Clopidogrel bisulfate should be coadministered with caution.

Warfarin

Because of the increased risk of bleeding, the concomitant administration of warfarin with Clopidogrel bisulfate should be undertaken with caution. (See PRECAUTIONS–General.)

Other Concomitant Therapy

No clinically significant pharmacodynamic interactions were observed when Clopidogrel bisulfate was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Clopidogrel bisulfate was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of Clopidogrel bisulfate.

At high concentrations in vitro, Clopidogrel inhibits P450 (2C9). Accordingly, Clopidogrel bisulfate may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with Clopidogrel bisulfate.

In addition to the above specific interaction studies, patients entered into clinical trials with Clopidogrel bisulfate received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy, heparins (unfractionated and LMWH) and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. The use of oral anticoagulants, non-study anti-platelet drug and chronic NSAIDs was not allowed in CURE and there are no data on their concomitant use with Clopidogrel.

Drug/Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of tumorigenicity when Clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).

Pregnancy

Pregnancy Category B. Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to Clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Clopidogrel bisulfate should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies in rats have shown that Clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug 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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Geriatric Use

Of the total number of subjects in controlled clinical studies, approximately 50% of patients treated with Clopidogrel bisulfate were 65 years of age and over. Approximately 16% of patients treated with Clopidogrel bisulfate were 75 years of age and over.

The observed difference in risk of thrombotic events with Clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figure 3 (see CLINICAL STUDIES). The observed difference in risk of bleeding events with Clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 3 (see ADVERSE REACTIONS).

Adverse Reactions

Clopidogrel bisulfate has been evaluated for safety in more than 17,500 patients, including over 9,000 patients treated for 1 year or more. The overall tolerability of Clopidogrel bisulfate in CAPRIE was similar to that of aspirin regardless of age, gender and race, with an approximately equal incidence (13%) of patients withdrawing from treatment because of adverse reactions. The clinically important adverse events observed in CAPRIE and CURE are discussed below.

Hemorrhagic: In CAPRIE patients receiving Clopidogrel bisulfate, gastrointestinal hemorrhage occurred at a rate of 2%, and required hospitalization in 0.7%. In patients receiving aspirin, the corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Clopidogrel bisulfate compared to 0.5% for aspirin.

In CURE, Clopidogrel bisulfate use with aspirin was associated with an increase in bleeding compared to placebo with aspirin (see Table 3). There was an excess in major bleeding in patients receiving Clopidogrel bisulfate plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidences of intracranial hemorrhage (0.1%), and fatal bleeding (0.2%), were the same in both groups.

The overall incidence of bleeding is described in Table 3 for patients receiving both Clopidogrel and aspirin in CURE,

Table 3: CURE Incidence of bleeding complications (% patients)

Event	Clopidogrel bisulfate (+ aspirin)*	Placebo (+ aspirin)*	P-value
	(n=6259)	(n=6303)
* Other standard therapies were used as appropriate. † Life threatening and other major bleeding. ‡ Major bleeding event rate for Clopidogrel bisulfate + aspirin was dose-dependent on aspirin: <100 mg=2.6%; 100–200 mg= 3.5%; >200 mg=4.9% Major bleeding event rates for Clopidogrel + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years 5.9% § Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg=2%; 100–200 mg= 2.3%; >200 mg=4% Major bleeding event rates for placebo + aspirin by age were: <65 years = 2.1%, ≥65 to <75 years = 3.1%, ≥75 years 3.6% ¶ Led to interruption of study medication.
Major bleeding †	3.7 ‡	2.7 §	0.001
Life-threatening bleeding	2.2	1.8	0.13
Fatal	0.2	0.2
5 g/dL hemoglobin drop	0.9	0.9
Requiring surgical intervention	0.7	0.7
Hemorrhagic strokes	0.1	0.1
Requiring inotropes	0.5	0.5
Requiring transfusion (≥4 units)	1.2	1
Other major bleeding	1.6	1	0.005
Significantly disabling	0.4	0.3
Intraocular bleeding with significant loss of vision	0.05	0.03
Requiring 2–3 units of blood	1.3	0.9
Minor bleeding ¶	5.1	2.4	<0.001

Ninety-two percent (92%) of the patients in the CURE study received heparin/LMWH, and the rate of bleeding in these patients was similar to the overall results.

There was no excess in major bleeds within seven days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (event rate 4.4% Clopidogrel bisulfate + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for Clopidogrel bisulfate + aspirin, and 6.3% for placebo + aspirin.

Neutropenia/agranulocytosis: Ticlopidine, a drug chemically similar to Clopidogrel bisulfate, is associated with a 0.8% rate of severe neutropenia (less than 450 neutrophils/µL). In CAPRIE severe neutropenia was observed in six patients, four on Clopidogrel bisulfate and two on aspirin. Two of the 9599 patients who received Clopidogrel bisulfate and none of the 9586 patients who received aspirin had neutrophil counts of zero. One of the four Clopidogrel bisulfate patients in CAPRIE was receiving cytotoxic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with Clopidogrel bisulfate. In CURE, the numbers of patients with thrombocytopenia (19 Clopidogrel bisulfate + aspirin vs. 24 placebo + aspirin) or neutropenia (3 vs. 3) were similar.

Although the risk of myelotoxicity with Clopidogrel bisulfate thus appears to be quite low, this possibility should be considered when a patient receiving Clopidogrel bisulfate demonstrates fever or other sign of infection.

Gastrointestinal: Overall, the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving Clopidogrel bisulfate was 27.1%, compared to 29.8% in those receiving aspirin in the CAPRIE trial. In the CURE trial the incidence of these gastrointestinal events for patients receiving Clopidogrel bisulfate + aspirin was 11.7% compared to 12.5% for those receiving placebo + aspirin.

In the CAPRIE trial, the incidence of peptic, gastric or duodenal ulcers was 0.7% for Clopidogrel bisulfate and 1.2% for aspirin. In the CURE trial the incidence of peptic, gastric or duodenal ulcers was 0.4% for Clopidogrel bisulfate + aspirin and 0.3% for placebo + aspirin.

Cases of diarrhea were reported in the CAPRIE trial in 4.5% of patients in the Clopidogrel bisulfate group compared to 3.4% in the aspirin group. However, these were rarely severe (Clopidogrel bisulfate=0.2% and aspirin=0.1%). In the CURE trial, the incidence of diarrhea for patients receiving Clopidogrel bisulfate + aspirin was 2.1% compared to 2.2% for those receiving placebo + aspirin.

In the CAPRIE trial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 3.2% for Clopidogrel bisulfate and 4% for aspirin. In the CURE trial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 0.9% for Clopidogrel bisulfate + aspirin compared with 0.8% for placebo + aspirin.

Rash and Other Skin Disorders: In the CAPRIE trial, the incidence of skin and appendage disorders in patients receiving Clopidogrel bisulfate was 15.8% (0.7% serious); the corresponding rate in aspirin patients was 13.1% (0.5% serious). In the CURE trial the incidence of rash or other skin disorders in patients receiving Clopidogrel bisulfate + aspirin was 4% compared to 3.5% for those receiving placebo + aspirin.

In the CAPRIE trial, the overall incidence of patients withdrawing from treatment because of skin and appendage disorders adverse reactions was 1.5% for Clopidogrel bisulfate and 0.8% for aspirin. In the CURE trial, the incidence of patients withdrawing because of skin and appendage disorders adverse reactions was 0.7% for Clopidogrel bisulfate + aspirin compared with 0.3% for placebo + aspirin.

Adverse events occurring in ≥2.5% of patients on Clopidogrel bisulfate in the CAPRIE controlled clinical trial are shown below regardless of relationship to Clopidogrel bisulfate. The median duration of therapy was 20 months, with a maximum of 3 years.

Table 4: Adverse Events Occurring in ≥2.5% of Clopidogrel Bisulfate Patients in CAPRIE

	% Incidence (% Discontinuation)
Body System	Clopidogrel bisulfate	Aspirin
Event	[n=9599]	[n=9586]
Body as a Whole general disorders
Chest Pain	8.3 (0.2)	8.3 (0.3)
Accidental/Inflicted injury	7.9 (0.1)	7.3 (0.1)
Influenza-like symptoms	7.5 (<0.1)	7.0 (<0.1)
Pain	6.4 (0.1)	6.3 (0.1)
Fatigue	3.3 (0.1)	3.4 (0.1)
Cardiovascular disorders, general
Edema	4.1 (<0.1)	4.5 (<0.1)
Hypertension	4.3 (<0.1)	5.1 (<0.1)
Central & peripheral nervous system disorders
Headache	7.6 (0.3)	7.2 (0.2)
Dizziness	6.2 (0.2)	6.7 (0.3)
Gastrointestinal system disorders
Abdominal pain	5.6 (0.7)	7.1 (1.0)
Dyspepsia	5.2 (0.6)	6.1 (0.7)
Diarrhea	4.5 (0.4)	3.4 (0.3)
Nausea	3.4 (0.5)	3.8 (0.4)
Metabolic & nutritional disorders
Hypercholesterolemia	4.0 (0)	4.4 (<0.1)
Musculo-skeletal system disorders
Arthralgia	6.3 (0.1)	6.2 (0.1)
Back Pain	5.8 (0.1)	5.3 (<0.1)
Platelet, bleeding, & clotting disorders
Purpura/Bruise	5.3 (0.3)	3.7 (0.1)
Epistaxis	2.9 (0.2)	2.5 (0.1)
Psychiatric disorders
Depression	3.6 (0.1)	3.9 (0.2)
Respiratory system disorders
Upper resp tract infection	8.7 (<0.1)	8.3 (<0.1)
Dyspnea	4.5 (0.1)	4.7 (0.1)
Rhinitis	4.2 (0.1)	4.2 (<0.1)
Bronchitis	3.7 (0.1)	3.7 (0)
Coughing	3.1 (<0.1)	2.7(<0.1)
Skin & appendage disorders
Rash	4.2 (0.5)	3.5 (0.2)
Pruritus	3.3 (0.3)	1.6 (0.1)
Urinary system disorders
Urinary tract infection	3.1 (0)	3.5 (0.1)

Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses.

Adverse events occurring in ≥2.0% of patients on Clopidogrel bisulfate in the CURE controlled clinical trial are shown below regardless of relationship to Clopidogrel bisulfate.

Table 5: Adverse Events Occurring in ≥2.0% of Clopidogrel Bisulfate Patients in CURE

	% Incidence (% Discontinuation)
Body System	Clopidogrel bisulfate (+ aspirin)*	Placebo (+ aspirin)*
Event	[n=6259]	[n=6303]
* Other standard therapies were used as appropriate.
Body as a Whole– general disorders
Chest Pain	2.7 (<0.1)	2.8 (0.0)
Central & peripheral nervous system disorders
Headache	3.1 (0.1)	3.2 (0.1)
Dizziness	2.4 (0.1)	2 (<0.1)
Gastrointestinal system disorders
Abdominal pain	2.3 (0.3)	2.8 (0.3)
Dyspepsia	2 (0.1)	1.9 (<0.1)
Diarrhea	2.1 (0.1)	2.2 (0.1)

Other adverse experiences of potential importance occurring in 1% to 2.5% of patients receiving Clopidogrel bisulfate in the CAPRIE or CURE controlled clinical trials are listed below regardless of relationship to Clopidogrel bisulfate. In general, the incidence of these events was similar to t

fluoride

Generic Name: fluoride (FLOR ide)

Brand names: Altaflor, Ethedent Chewable, Fluor-A-Day, Fluoritab, Flura-Drops, Flura-Loz, Flura-Tab, Karidium, Lozi-Flur, Luride, Nafrinse, Pharmaflur, Pharmaflur 1.1, ...show all 19 brand names.Pediaflor Drops, Luride-SF, Fluorabon, Fluorodex, Renaf, EPIFLUR

What is fluoride?

Fluoride is a substance that strengthens tooth enamel. This helps to prevent dental cavities.

Fluoride is used as a medication to prevent tooth decay in people that have a low level of fluoride in their drinking water. Fluoride is also used to prevent tooth decay in people who undergo radiation of the head and/or neck, which may cause dryness of the mouth and an increased incidence of tooth decay.

Fluoride may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about fluoride?

You should not use fluoride if the level of fluoride in your drinking water is greater than 0.7 parts per million (ppm).

Before using fluoride, tell your dentist and doctor if you are on a low salt or a salt free diet. You may not be able to use fluoride, or you may need special tests while you are using it.

Do not take fluoride with milk, other dairy products, or calcium supplements. Calcium can make it harder for your body to absorb fluoride.

Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends. Many antacids contain calcium, which can interfere with fluoride absorption.

What should I discuss with my healthcare provider before taking fluoride?

You should not use fluoride if the level of fluoride in your drinking water is greater than 0.7 parts per million (ppm).

Before using fluoride, tell your dentist and doctor if you are on a low salt or a salt free diet. You may not be able to use fluoride, or you may need special tests while you are using it.

Talk to your doctor and dentist before taking fluoride if you are pregnant or could become pregnant during treatment. Talk to your doctor and dentist before taking fluoride if you are breast-feeding. The American Dental Association's Council on Dental Therapeutics recommends the use of fluoride by children up to 13 years of age; the American Academy of Pediatrics recommends fluoride supplementation by children until the age of 16 years of age. Do not give a 1-mg tablet to a child younger than 3 years old, or when your drinking water fluoride content is equal to or greater than 0.3 ppm.

How should I take fluoride?

Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended.

Take this medicine with a full glass of water. Do not take fluoride with milk or other dairy products. Calcium can make it harder for your body to absorb fluoride.

Suck on the fluoride lozenge until it dissolves completely in your mouth. Do not chew the lozenge or swallow it whole.

The chewable forms of fluoride can be chewed, swallowed, dissolved in the mouth, added to drinking water or fruit juice, or added to water for use in infant formula or other food.

The fluoride drops can be taken by mouth undiluted, or mixed with fluid or food.

If you mix fluoride with food or water, drink or eat this mixture right away. Do not save it for later use.

It is important to take fluoride regularly to get the most benefit.

Store fluoride at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include nausea, vomiting, stomach pain, diarrhea, drooling, numbness or tingling, loss of feeling anywhere in your body, muscle stiffness, or seizure (convulsions).

What should I avoid while taking fluoride?

Do not take fluoride with milk, other dairy products, or calcium supplements. Calcium can make it harder for your body to absorb fluoride.

Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends. Many antacids contain calcium, which can interfere with fluoride absorption.

Fluoride side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor if you have any of the following side effects:

• 
  

  discolored teeth;

  
  


• 
  

  weakened tooth enamel; or

  
  


• 
  

  any changes in the appearance of your teeth.

  
  

Less serious side effects may include:

• 
  

  stomach upset;

  
  


• 
  

  headache; or

  
  


• 
  

  weakness.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect fluoride?

There may be other drugs that can interact with fluoride. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More fluoride resources

• Fluoride Use in Pregnancy & Breastfeeding
• Drug Images
• Fluoride Support Group
• 0 Reviews for Fluoride - Add your own review/rating

• Epiflur Prescribing Information (FDA)


• Fluor-A-Day Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Fluor-A-Day Advanced Consumer (Micromedex) - Includes Dosage Information


• Fluor-a-Day Prescribing Information (FDA)


• Fluorides Monograph (AHFS DI)


• Fluoritab Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Lozi-Flur Lozenges MedFacts Consumer Leaflet (Wolters Kluwer)

Compare fluoride with other medications

• Prevention of Dental Caries

Where can I get more information?

• Your pharmacist can provide more information about fluoride.

carbonyl iron

Generic Name: carbonyl iron (car BAH nill I ern)

Brand names: Elemental Iron, Feosol Caplet, Icar, Iron Chews, Ferra-Cap

What is carbonyl iron?

Carbonyl iron is a form of the mineral iron. Iron is important for many functions in the body, especially for the transport of oxygen in the blood.

Carbonyl iron is used as a dietary supplement, and to prevent and to treat iron deficiencies and iron deficiency anemia.

Carbonyl iron may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about carbonyl iron?

Keep this medication out of the reach of children. An accidental overdose of iron by a child can be fatal.

Carbonyl iron may decrease the absorption of other medicines. Talk to your doctor and pharmacist before taking carbonyl iron if you take any other prescription or over-the-counter medicines.

Who should not take carbonyl iron?

Do not take carbonyl iron if you have

• 
  

  hemochromatosis,

  
  


• 
  

  hemosiderosis, or

  
  


• 
  

  hemolytic anemia.

  
  

Carbonyl iron may be dangerous if you have any of the conditions listed above.

If you do not have an iron deficiency, talk to your doctor about the use of carbonyl iron. Generally, carbonyl iron should not be taken chronically by individuals with a normal iron balance.

Talk to your doctor before taking carbonyl iron if you are pregnant. Talk to your doctor before taking carbonyl iron if you are breast-feeding a baby.

How should I take carbonyl iron?

Take carbonyl iron exactly as directed by your doctor, or as directed on the package. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each tablet with a full glass of water. Take carbonyl iron on an empty stomach for best results. If stomach upset occurs, take carbonyl iron with food or following a meal.

Shake the suspension well before measuring a dose. To ensure that you get the correct dose, measure the liquid form of carbonyl iron with a dose measuring cup or spoon, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist where you can get one.

Carbonyl iron may decrease the absorption of other medicines. Talk to your doctor and pharmacist before taking carbonyl iron if you take any other prescription or over-the-counter medicines.

Store carbonyl iron at room temperature, away from moisture and heat. Keep this medication out of the reach of children. An accidental overdose of iron by a child can be fatal.

See also: Carbonyl iron dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time to take next dose, skip the dose you missed and take the next regularly scheduled dose as directed. Do not take a double dose.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a carbonyl iron overdose include decreased energy; nausea; vomiting; abdominal pain; tarry stools; a weak, rapid pulse; fever; coma; seizures; and death.

What should I avoid while taking carbonyl iron?

Keep this medication out of the reach of children. An accidental overdose of iron by a child can be fatal.

Carbonyl iron may decrease the absorption of other medicines. Talk to your doctor and pharmacist before taking carbonyl iron if you take any other prescription or over-the-counter medicines.

Carbonyl iron side effects

If you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives), stop taking carbonyl iron and seek emergency medical attention.

Other less serious side effects are more likely to occur. Continue taking carbonyl iron and talk to your doctor or pharmacist if you experience

• 
  

  stomach upset,

  
  


• 
  

  nausea or vomiting,

  
  


• 
  

  constipation,

  
  


• 
  

  diarrhea,

  
  


• 
  

  black or darker than normal appearing stools, or

  
  


• 
  

  temporary staining of the teeth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Carbonyl iron Dosing Information

Usual Adult Dose for Iron Deficiency Anemia:

50 mg orally three times a day.

Usual Pediatric Dose for Iron Deficiency Anemia:

Premature neonates:
2 to 4 mg elemental iron/kg/day divided every 12 to 24 hours (maximum daily dose = 15 mg).

Infants and children Prophylaxis: 1 to 2 mg elemental iron/kg/day (maximum 15 mg) in 1 to 2 divided doses.

Mild to moderate iron deficiency anemia:
3 mg elemental iron/kg/day in 1 to 2 divided doses.

Severe iron deficiency anemia:
4 to 6 mg elemental iron/kg/day in 3 divided doses.

What other drugs will affect carbonyl iron?

Do not take carbonyl iron within 2 hours of a dose of any of the following medicines

• 
  

  a tetracycline antibiotic such as tetracycline (Achromycin, Sumycin), minocycline (Minocin, Dynacin), doxycycline (Vibramycin, Monodox), demeclocycline (Declomycin), oxytetracycline (Terramycin), or troleandomycin (TAO);

  
  


• 
  

  a fluoroquinolone antibiotic such as ciprofloxacin (Cipro), enoxacin (Penetrex) ofloxacin (Floxin), norfloxacin (Noroxin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), grepafloxacin (Raxar), sparfloxacin (Zagam), or trovafloxacin (Trovan);

  
  


• 
  

  levodopa (Larodopa, Dopar, Sinemet);

  
  


• 
  

  levothyroxine (Synthroid, Levoxyl, others);

  
  


• 
  

  methyldopa (Aldomet); or

  
  


• 
  

  penicillamine (Cuprimine).

  
  

Carbonyl iron may decrease the absorption of the drugs listed above.

Do not take antacids within 2 hours of a dose of carbonyl iron. Antacids may decrease the absorption of carbonyl iron.

Drugs other than those listed here may also interact with carbonyl iron. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines while taking carbonyl iron.

More carbonyl iron resources

• Carbonyl iron Side Effects (in more detail)
• Carbonyl iron Dosage
• Carbonyl iron Use in Pregnancy & Breastfeeding
• Carbonyl iron Drug Interactions
• Carbonyl iron Support Group
• 0 Reviews for Carbonyl iron - Add your own review/rating

• Icar Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Iron Chews Prescribing Information (FDA)

Compare carbonyl iron with other medications

• Iron Deficiency Anemia

Where can I get more information?

• Your pharmacist has additional information about carbonyl iron written for health professionals that you may read.

See also: carbonyl iron side effects (in more detail)

sorbitol

Generic Name: sorbitol (SOR bi tal)

Brand Names:

What is sorbitol?

Sorbitol is a laxative. It is used to treat constipation.

Sorbitol may also be used for purposes not listed in this medication guide.

What is the most important information I should know about sorbitol?

A laxative may be habit forming and should be used only until your bowel habits return to normal. Never share sorbitol with another person, especially someone with a history of eating disorder. Keep the medication in a place where others cannot get to it.

Ask a doctor or pharmacist before taking this medication if you have an allergy, if your bowel habits have changed suddenly in the past 2 weeks, or if you have nausea, vomiting, or stomach pain that has not been checked by a doctor.

Avoid taking other laxatives or stool softeners unless your doctor tells you to.

What should I discuss with my healthcare provider before taking sorbitol?

You should not use sorbitol if you are allergic to it. A laxative may be habit forming and should be used only until your bowel habits return to normal. Never share sorbitol with another person, especially someone with a history of eating disorder. Keep the medication in a place where others cannot get to it.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

• 
  

  any allergy;

  
  


• 
  

  nausea, vomiting, or stomach pain that has not been checked by a doctor;

  
  


• 
  

  if your bowel habits have changed suddenly in the past 2 weeks.

  
  

It is not known whether sorbitol will harm an unborn baby. Do not use this medication without medical advice if you are pregnant. It is not known whether sorbitol passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Older adults may be more sensitive to the effects of this medicine. Do not give this medicine to a child without medical advice.

How should I take sorbitol?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Sorbitol is usually taken only for a short time until your symptoms clear up.

Do not use this medication for longer than 1 week without the advice of your doctor. Store at room temperature away from moisture, heat, and light.

See also: Sorbitol dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include diarrhea and stomach cramps.

What should I avoid while taking sorbitol?

Avoid taking other laxatives or stool softeners unless your doctor tells you to.

Sorbitol side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using sorbitol and call your doctor at once if you have a serious side effect such as:

• 
  

  severe stomach cramps;

  
  


• 
  

  vomiting;

  
  


• 
  

  severe diarrhea;

  
  


• 
  

  rectal bleeding;

  
  


• 
  

  black, bloody, or tarry stools;

  
  


• 
  

  weakness, dizziness; or

  
  


• 
  

  frequent urge to have a bowel movement.

  
  

Less serious side effects may include:

• 
  

  gas, mild nausea or stomach cramps; or

  
  


• 
  

  rectal irritation.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Sorbitol Dosing Information

Usual Adult Dose for Constipation:

Oral: 30 to 150 mL (70% solution) once.

Rectal: 120 mL (25% to 30% solution) as a rectal enema once.

Usual Pediatric Dose for Constipation:

2 to 11 years:
Oral: 2 mL/kg (70% solution) once.
Rectal: 30 to 60 mL (25% to 30% solution) as a rectal enema once.

Greater than or equal to 12 years:
Oral: 30 to 150 mL (70% solution) once.
Rectal: 120 mL (25% to 30% solution) as a rectal enema once.

What other drugs will affect sorbitol?

Tell your doctor about all other medicines you use, especially other laxatives, stool softeners, or sodium polystyrene sulfonate.

This list is not complete and other drugs may interact with sorbitol. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More sorbitol resources

• Sorbitol Dosage
• Sorbitol Use in Pregnancy & Breastfeeding
• Sorbitol Drug Interactions
• Sorbitol Support Group
• 0 Reviews for Sorbitol - Add your own review/rating

• Sorbitol Prescribing Information (FDA)


• Sorbitol Irrigation Solution MedFacts Consumer Leaflet (Wolters Kluwer)

Compare sorbitol with other medications

• Constipation

Where can I get more information?

• Your pharmacist can provide more information about sorbitol.

Miraphen PE Controlled-Release Tablets

Pronunciation: gwye-FEN-e-sin/fen-il-EF-rin
Generic Name: Guaifenesin/Phenylephrine
Brand Name: Examples include Lusonex and Miraphen PE

Miraphen PE Controlled-Release Tablets are used for:

Relieving symptoms of congestion, cough, and throat and airway irritation due to colds, flu, or hay fever. It may also be used for other conditions as determined by your doctor.

Miraphen PE Controlled-Release Tablets are a decongestant and expectorant combination. It works by constricting blood vessels and shrinking swollen and congested nasal tissues (mucous membranes) and by thinning and loosening mucus in the airway. This allows you to breathe more easily and makes coughs more productive.

Do NOT use Miraphen PE Controlled-Release Tablets if:

• you are allergic to any ingredient in Miraphen PE Controlled-Release Tablets


• you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, or severe heart problems


• you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Miraphen PE Controlled-Release Tablets:

Some medical conditions may interact with Miraphen PE Controlled-Release Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a fast, slow, or irregular heartbeat


• if you have a history of adrenal gland problems (eg, tumor), heart problems, high blood pressure, diabetes, heart blood vessel problems, stroke, glaucoma, an enlarged prostate, seizures, or an overactive thyroid


• if you have chronic cough

Some MEDICINES MAY INTERACT with Miraphen PE Controlled-Release Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), furazolidone, indomethacin, MAOIs (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Miraphen PE Controlled-Release Tablets's side effects


• Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased


• Bromocriptine because the risk of its side effects may be increased by Miraphen PE Controlled-Release Tablets


• Guanethidine, guanadrel, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Miraphen PE Controlled-Release Tablets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Miraphen PE Controlled-Release Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Miraphen PE Controlled-Release Tablets:

Use Miraphen PE Controlled-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Miraphen PE Controlled-Release Tablets by mouth with or without food.


• Take Miraphen PE Controlled-Release Tablets with a full glass of water (8 oz/240 mL) unless your doctor directs otherwise.


• Swallow Miraphen PE Controlled-Release Tablets whole. Do not break, crush, or chew before swallowing. Some brands of Miraphen PE Controlled-Release Tablets may be broken in half before taking. If you have difficulty swallowing the whole tablet, ask your pharmacist if your brand of medicine may be broken in half.


• If you miss a dose of Miraphen PE Controlled-Release Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Miraphen PE Controlled-Release Tablets.

Important safety information:

• Miraphen PE Controlled-Release Tablets may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Miraphen PE Controlled-Release Tablets with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not take diet or appetite control medicines while you are taking Miraphen PE Controlled-Release Tablets without checking with you doctor.


• Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• If your symptoms do not get better within 5 to 7 days or if they get worse, check with your doctor.


• Miraphen PE Controlled-Release Tablets may interfere with certain lab tests. Be sure your doctor and lab personnel know you are taking Miraphen PE Controlled-Release Tablets.


• Tell your doctor or dentist that you take Miraphen PE Controlled-Release Tablets before you receive any medical or dental care, emergency care, or surgery.


• Use Miraphen PE Controlled-Release Tablets with caution in the ELDERLY; they may be more sensitive to its effects.


• Caution is advised when using Miraphen PE Controlled-Release Tablets in CHILDREN; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Miraphen PE Controlled-Release Tablets while you are pregnant. It is not known if Miraphen PE Controlled-Release Tablets are found in breast milk. Do not breast-feed while taking Miraphen PE Controlled-Release Tablets.

Possible side effects of Miraphen PE Controlled-Release Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Dizziness; excitability; headache; nausea; nervousness or anxiety; trouble sleeping; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, lightheadedness, or headache; tremor.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Miraphen PE side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org), or emergency room immediately. Symptoms may include blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Miraphen PE Controlled-Release Tablets:

Store Miraphen PE Controlled-Release Tablets at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Miraphen PE Controlled-Release Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Miraphen PE Controlled-Release Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Miraphen PE Controlled-Release Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Miraphen PE Controlled-Release Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Miraphen PE resources

• Miraphen PE Side Effects (in more detail)
• Miraphen PE Use in Pregnancy & Breastfeeding
• Miraphen PE Drug Interactions
• Miraphen PE Support Group
• 0 Reviews for Miraphen PE - Add your own review/rating

Compare Miraphen PE with other medications

• Cough and Nasal Congestion
• Sinus Symptoms

Zanamivir

Class: Neuraminidase Inhibitors
VA Class: AM800
Chemical Name: 5-Acetamido-2,6-anhydro-3,4,5-trideoxy-4-guanidino-d-glycero-d-g
CAS Number: 139110-80-8
Brands: Relenza

Introduction

Antiviral; neuraminidase inhibitor; sialic acid analog.^{1 9}

Uses for Zanamivir

Treatment of Seasonal Influenza A and B Virus Infections

Symptomatic treatment of uncomplicated acute illness caused by influenza A or B virus in adults, adolescents, and children ≥7 years of age who have been symptomatic for ≤2 days.^{1 3 4 5 6 14 116 149}

Efficacy of zanamivir for treatment of influenza is not established in patients with underlying airways disease (e.g., asthma, COPD).¹ Also not recommended for those with underlying airways disease because of risk of serious bronchospasm.¹ (See Individuals with Asthma or COPD under Cautions.) Treatment with zanamivir has not been shown to reduce the risk of transmission of influenza to others.¹

CDC, AAP, and IDSA recommend treatment of influenza illness in all individuals with suspected or confirmed influenza who require hospitalization (regardless of vaccination status or underlying illness)^{116 137 149} and in individuals with suspected or confirmed influenza who are at high risk of developing complications (regardless of vaccination status or influenza severity).^{116 149} Early empiric treatment also should be considered for individuals with suspected or confirmed influenza who are at increased risk for influenza-related complications, including children <2 years of age, adults ≥65 years of age, pregnant women and women up to 2 weeks postpartum (including following pregnancy loss), individuals of any age with certain chronic medical or immunosuppressive conditions, individuals <19 years of age who are receiving long-term aspirin therapy, and residents of any age in nursing homes or other long-term care facilities.^{116 137} If indicated, initiate treatment as early as possible since benefit is greatest if started within 48 hours of symptom onset;^{116 137 149} do not delay initiation of treatment while waiting for laboratory confirmation.^{137 149}

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.^{116 137 149} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,^{116 144} and emergence of zanamivir-resistant influenza virus may decrease effectiveness of the drug.¹ When treatment of seasonal influenza is indicated, oseltamivir or zanamivir usually is recommended.^{137 149} If viral surveillance indicates that influenza strains resistant to oseltamivir are circulating and treatment is indicated, zanamivir should be used.¹³⁷

CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season.¹⁴⁴ Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .

Prevention of Seasonal Influenza A and B Virus Infections

Prophylaxis of influenza in adults, adolescents, and children ≥5 years of age.^{1 2 17 18 116 149}

Has been effective for prophylaxis of influenza in household settings and during community outbreaks;^{1 2 17 18} efficacy is not established for prophylaxis of influenza in nursing home settings.¹

Not recommended for those with underlying airways disease (e.g., asthma, COPD) because of risk of serious bronchospasm.¹ (See Individuals with Asthma or COPD under Cautions.)

Annual vaccination with seasonal influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.^{116 144 149 161} Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza.^{1 144 161}

When seasonal influenza viruses are circulating in the community, postexposure prophylaxis with oseltamivir or zanamivir can be considered for certain individuals, including those at high risk of developing influenza complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals).^{116 137 149} Other possible candidates for antiviral prophylaxis include unvaccinated health care personnel, public health workers, and first responders with unprotected, close-contact exposure to a patient with confirmed, probable, or suspected influenza during the time when the patient was infectious.^{137 149} Also consider antiviral prophylaxis for controlling influenza outbreaks in nursing and long-term care facilities or other closed or semi-closed settings with large numbers of individuals at high risk for influenza complications.^{116 137 149} In individuals at high risk of influenza complications who receive parenteral inactivated influenza vaccine, use of prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.^{116 149} (See Influenza Virus Vaccines under Interactions.)

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for prophylaxis of influenza.^{137 149} The most appropriate antiviral for prevention of influenza is based on the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.^{137 144} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,^{137 144} and the possibility that emergence of zanamivir-resistant influenza virus may decrease effectiveness of the drug should be considered.¹

CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.¹⁴⁴ Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .

Avian Influenza A Virus Infections

No clinical data to date regarding use for treatment of avian influenza A virus infections.¹⁰⁴ Drug of choice for treatment of strongly suspected or clinically confirmed cases of avian influenza A (H5N1) infection is oseltamivir.^{68 94 104}

May be an alternative to oseltamivir for prophylaxis of avian influenza A infections^{28 94} since in vitro studies indicate some avian influenza A (H5N1) strains resistant to oseltamivir are susceptible to zanamivir.^{28 32}

Pandemic Influenza

Treatment or prevention of pandemic influenza† caused by susceptible strains of influenza virus.^{52 151}

Influenza viruses can cause pandemics, during which rates of illness and death from influenza-related complications can increase dramatically worldwide.^{52 109 161} Most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain.^{52 134 144 151}

On June 11, 2009, the WHO declared that the first global influenza pandemic in 41 years was occurring and issued a phase 6 pandemic alert regarding 2009 influenza A (H1N1).¹³⁴ A phase 6 pandemic is characterized by human-to-human spread of an animal or human-animal reassortant virus and sustained community level outbreaks of the virus in at least 2 countries in a single WHO region and sustained community level outbreaks in at least one other country in a different WHO region.¹³⁵ Cases of human infection with 2009 influenza A (H1N1) virus were first reported in Mexico and other countries (including the US) beginning in March and April 2009.^{114 117 118 119 132 134 144} In the US, the pandemic was characterized by a substantial increase in influenza activity that peaked in late October and early November 2009 and returned to seasonal baseline levels by January 2010.^{117 144} During that time, more than 99% of influenza viruses circulating in the US were the 2009 pandemic influenza A (H1N1) virus.^{117 144} As of August 2010, the WHO declared that the world was in a post-pandemic period;¹⁴⁸ however, the 2009 influenza A (H1N1) virus is expected to continue to circulate during the 2010–2011 influenza season.^{144 162}

The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asia and other countries that was identified in 2003 represents a potential future pandemic threat.^{28 50 54 55 56 77 144 147}

Zanamivir Dosage and Administration

Administration

Administer commercially available powder for inhalation only by oral inhalation using the inhaler (Diskhaler) provided by the manufacturer.¹ Do not administer using a nebulizer or mechanical ventilator.¹⁴¹

Zanamivir has been administered IV†;^{158 159 160} but a parenteral dosage form of the drug is not commercially available in the US.

Oral Inhalation

Zanamivir powder for inhalation is commercially available in a disk containing 4 foil blisters of the drug (Rotadisk) and is provided with an inhaler (Diskhaler) that is used to deliver the drug to the respiratory tract.¹

Do not remove zanamivir powder for inhalation from its foil blister packaging.¹⁴¹ Do not attempt to dissolve or reconstitute the powder for inhalation in any liquid.¹⁴¹ Do not attempt to administer using a nebulizer or mechanical ventilator.¹⁴¹ (See Administration Precautions under Cautions.)

Consult the manufacturer's instructions for information on how to load the Rotadisk onto the drug delivery system (Diskhaler) and how to use the Diskhaler to administer the drug.¹

Patients should be instructed in the safe and effective use of the Diskhaler;¹ instructions should include a demonstration whenever possible.¹

Patients scheduled to use an inhaled bronchodilator at the same time as zanamivir should use the bronchodilator first.¹

Dosage

Pediatric Patients

Treatment of Seasonal Influenza A and B Virus Infections

Oral Inhalation

Adolescents and children ≥7 years of age: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days.¹

Whenever possible, the first day of treatment should include 2 doses provided there is at least 2 hours between doses; on subsequent days, doses should be given about 12 hours apart (morning and evening) at approximately the same time each day.¹

Initiate zanamivir treatment within 2 days after onset of symptoms.¹ Although efficacy not established,¹ antiviral treatment initiated >48 hours after onset of symptoms may still be beneficial in those with moderate to severe or progressive influenza.^{116 137 149} In addition, although usual duration of antiviral treatment is 5 days, patients hospitalized with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) may require >5 days of antiviral treatment.¹³⁷

Prevention of Seasonal Influenza A and B Virus Infections

Household Setting

Oral Inhalation

Adolescents and children ≥5 years of age: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 10 days.¹

Administer at approximately the same time each day.¹ Efficacy in household settings not established if zanamivir prophylaxis initiated >1.5 days after onset of symptoms in the index case.¹

Community Outbreak

Oral Inhalation

Adolescents: 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 28 days.¹ Administer at approximately the same time each day.¹

Efficacy in community outbreaks not established if zanamivir prophylaxis initiated >5 days after the outbreak is identified in the community.¹ Safety and efficacy of prophylaxis given for >28 days not evaluated.¹

Adults

Treatment of Seasonal Influenza A and B Virus Infections

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days.¹

Whenever possible, the first day of treatment should include 2 doses provided there is at least 2 hours between doses; on subsequent days, doses should be given about 12 hours apart (morning and evening) at approximately the same time each day.¹

Initiate zanamivir treatment within 2 days after onset of symptoms.¹ Although efficacy not established,¹ antiviral treatment initiated >48 hours after onset of symptoms may still be beneficial in those with moderate to severe or progressive influenza.^{116 137 149} In addition, although usual duration of antiviral treatment is 5 days, patients hospitalized with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) may require >5 days of antiviral treatment.¹³⁷

Prevention of Seasonal Influenza A and B Virus Infections

Household Setting

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 10 days.¹ Administer at approximately the same time each day.¹

Efficacy in household settings not established if zanamivir prophylaxis initiated >1.5 days after onset of symptoms in the index case.¹

Community Outbreak

Oral Inhalation

2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) once daily for 28 days.¹ Administer at approximately the same time each day.¹

Efficacy in community outbreaks not established if zanamivir prophylaxis initiated >5 days after the outbreak is identified in the community.¹ Safety and efficacy of prophylaxis given for >28 days not evaluated.¹

Special Populations

Renal Impairment

Dosage adjustment not needed in patients with renal impairment.¹

Cautions for Zanamivir

Contraindications

• 
  

  History of hypersensitivity reaction to zanamivir or any ingredient in the formulation (e.g., lactose).¹

  
  

Warnings/Precautions

Respiratory Effects

Serious bronchospasm, including fatalities, reported when used in patients with or without underlying airways disease.¹ (See Individuals with Asthma or COPD under Cautions.) Many such cases were reported during postmarketing surveillance and causality to the drug difficult to assess.¹

Some patients without prior respiratory disease also may have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase vulnerability to adverse drug reactions.¹

Discontinue use if bronchospasm develops or respiratory function declines;¹ immediate treatment and hospitalization may be required.¹

Individuals with Asthma or COPD

Not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (e.g., asthma, COPD) because of risk of serious bronchospasm.¹ (See Respiratory Effects under Cautions.)

When tested in patients with mild or moderate asthma (but without acute influenza-like illness), bronchospasm documented in 1/13 patients.¹ When used in patients with acute influenza-like illness superimposed on underlying asthma or COPD, a >20% decline in FEV₁ occurred in more patients receiving the drug than in those receiving placebo.¹

The benefits and risks should be considered carefully if use of zanamivir is considered in patients with underlying airways disease.¹ If a decision is made to use the drug in such patients, monitor respiratory function carefully and have appropriate supportive care available, including short-acting β-adrenergic bronchodilators.^{1 15}

Sensitivity Reactions

Hypersensitivity Reactions

Bronchospasm and allergic-like reactions (e.g., oropharyngeal edema, serious skin rash) reported.¹

Discontinue immediately and initiate appropriate treatment if an allergic reaction occurs or is suspected.¹

Neuropsychiatric Events

Postmarketing reports of delirium and abnormal behavior leading to self-injury reported mainly in Japanese children receiving neuraminidase inhibitors, including zanamivir.¹ Role of zanamivir not determined.¹

Influenza itself can be associated with a variety of neurologic and behavioral symptoms (e.g., seizures, hallucinations, delirium, abnormal behavior) and fatalities can occur.¹ Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.¹

Closely monitor patients with influenza for signs of abnormal behavior.¹ If neuropsychiatric symptoms develop, consider risks versus benefits of continued therapy.¹

Concomitant Illness

Safety and efficacy for treatment or prophylaxis of influenza not established in patients with high-risk underlying medical conditions.¹ (See Individuals with Asthma or COPD under Cautions.)

No data available regarding use in patients with severe or unstable medical conditions that may require inpatient care.¹

Differential Diagnosis

When making treatment decisions in patients with suspected influenza, consider the possibility of primary or concomitant bacterial infection for which zanamivir would be ineffective.^{1 15}

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.¹ No evidence that zanamivir prevents such complications.¹

No evidence of efficacy in illness caused by any organisms other than influenza A or B.¹

Administration Precautions

Administer zanamivir powder for inhalation using only the inhaler (Diskhaler) provided by the manufacturer.^{1 141} Do not remove the powder from its foil blister packaging (Rotadisk).¹⁴¹ Do not attempt to reconstitute or solubilize the powder in liquid;¹⁴¹ do not attempt to administer in a nebulizer or mechanical ventilator.¹⁴¹

Safety and efficacy have not been established for administration by nebulization or mechanical ventilation.¹⁴¹ Lactose in the formulation may obstruct or interfere with proper functioning of mechanical ventilator equipment.^{140 141} At least 1 death has been reported when a patient received the drug by mechanical ventilation after solubilization in a liquid.^{140 141}

Patients should be instructed in the safe and effective use of the drug delivery system (Diskhaler) provided by the manufacturer.¹ Instructions on use of the inhaler should include a demonstration whenever possible.¹

Some geriatric patients may need assistance with the inhaler.¹

Children should be under adult supervision with close attention to use of the inhaler.¹ (See Pediatric Use under Cautions.)

Prior Use

No data available regarding safety and efficacy of repeated courses of zanamivir for treatment of influenza.¹

Influenza Vaccination

Zanamivir is not a substitute for annual vaccination with seasonal influenza virus vaccine inactivated or seasonal influenza virus vaccine live intranasal.^{1 144}

Antiviral agents used for treatment or prevention of influenza may be used concomitantly with parenteral inactivated seasonal influenza virus vaccine if indicated.^{1 144}

Intranasal live seasonal influenza virus vaccine should not be administered until at least 48 hours after influenza antiviral agents are discontinued and these antiviral agents should not be administered until at least 2 weeks after administration of live intranasal influenza vaccine, unless medically indicated.^{1 144} (See Influenza Virus Vaccines under Interactions.)

Specific Populations

Pregnancy

Category C.¹

Pregnant women are at increased risk for severe complications and death from influenza.¹⁴⁴

CDC states that pregnancy should not be considered a contraindication to use of zanamivir for the treatment or prevention of influenza; zanamivir regimens recommended for such infections in pregnant women are the same as those for other adults.^{127 137 142}

Because of its systemic absorption, CDC states that oseltamivir may be preferred when a neuraminidase inhibitor is indicated for treatment of influenza in a pregnant woman, but the drug of choice for prophylaxis of these infections is less clear.^{127 142} Zanamivir may be preferred for prophylaxis in pregnant women because of its limited systemic absorption; however, respiratory complications that may be associated with zanamivir because of its route of administration should be considered, especially in women at risk for respiratory problems.^{127 142}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use with caution.¹

CDC states that antiviral treatment or prophylaxis is not a contraindication for breastfeeding.¹²⁷

Pediatric Use

Safety and efficacy for treatment of influenza not established in children <7 years of age.^{1 14}

Safety and efficacy for prophylaxis of influenza not established in children <5 years of age.¹

Safety and efficacy in adolescents and children ≥7 years of age for treatment of influenza and safety and efficacy in adolescents and children ≥5 years of age for prophylaxis of influenza similar to adults.¹

Some young children may have suboptimal inspiratory flow rates through the drug delivery system (Diskhaler).¹ When considering use of zanamivir in pediatric patients, clinicians should carefully evaluate the ability of the child to use the inhaler.¹

Children should receive zanamivir only under adult supervision and with close attention to proper use of the inhaler.¹ The supervising adult should be instructed on proper use of the inhaler.¹

Geriatric Use

Safety and efficacy for treatment of influenza in those ≥65 years of age similar to younger adults.¹

Safety and efficacy for prophylaxis of influenza in those ≥65 years of age in household or community settings similar to younger adults.¹ Efficacy not established for prophylaxis in geriatric individuals in nursing home settings.¹

Possibility exists of greater sensitivity to the drug in some older individuals.¹

Some geriatric patients may need assistance with the drug delivery system (Diskhaler).¹

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.¹

Renal Impairment

Safety and efficacy not documented in patients with severe renal impairment, but systemic exposure is limited after oral inhalation.¹ Consider potential for drug accumulation.¹

Common Adverse Effects

Diarrhea, nausea, vomiting, headache, dizziness, nasal signs and symptoms, bronchitis, sinusitis, cough, and ear, nose, and throat infections.¹ Some adverse effects may be related to lactose vehicle contained in the powder for oral inhalation.¹

Interactions for Zanamivir

Zanamivir not metabolized by and does not affect CYP enzymes, including CYP1A1, 1A2, 2A6, 2C9, 2C18, 2D6, 2E1, or 3A4.¹ Drug interactions with drugs that are substrates or inhibitors of these enzymes unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Influenza virus vaccines	Parenteral inactivated influenza vaccine: No evidence of interference with the antibody response to the vaccine1 10 Intranasal live influenza vaccine: Potential interference with antibody response to the vaccine; no specific studies1	Parenteral inactivated influenza vaccine: May be administered concomitantly with or at any interval before or after zanamivir144 Intranasal live influenza vaccine: Do not administer the live intranasal vaccine until at least 48 hours after zanamivir is discontinued; do not administer zanamivir until at least 2 weeks after administration of the live intranasal vaccine, unless medically indicated;1 144 repeat vaccination if influenza antiviral is given 2 days before to 14 days after the vaccine144

Zanamivir Pharmacokinetics

Absorption

Bioavailability

Following oral inhalation of zanamivir, approximately 4–17% of the inhaled dose is absorbed systemically.¹

Absolute bioavailability averages 2% following oral inhalation;³ peak serum concentrations attained within 1–2 hours.^{1 3}

Special Populations

In pediatric patients <12 years of age with signs and symptoms of respiratory illness, zanamivir serum concentrations may be low or undetectable following oral inhalation because of inadequate or absent inspiratory flow rates.¹ (See Pediatric Use under Cautions.)

Distribution

Extent

Delivered to epithelial lining of the respiratory tract following oral inhalation.²² Amount of drug in respiratory tract depends on patient factors such as inspiratory flow rate.¹ May be present in sputum and nasal washings for at least 12 hours after a dose.²²

Crosses the placenta in animals.¹

Distributed into milk in animals;¹ not known whether distributed into human milk.¹

Plasma Protein Binding

<10% bound to plasma proteins.¹

Elimination

Metabolism

Not metabolized.¹

Not a substrate for and does not affect CYP isoenzymes.¹

Elimination Route

Following oral inhalation, absorbed drug is excreted unchanged in urine within 24 hours;¹ unabsorbed drug excreted in feces.¹

Half-life

Serum half-life following oral inhalation is 2.5–5.1 hours.^{1 23}

Special Populations

Half-life prolonged in those with renal impairment;¹ studies using IV zanamivir indicate half-life is 4.7 hours if mild to moderate impairment and 18.5 hours if severe impairment.¹

Stability

Storage

Oral Inhalation

Powder for Inhalation

25°C (may be exposed to 15–30°C).¹

ActionsActions and Spectrum

• 
  

  Zanamivir is a potent selective competitive inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication; possibly alters virus particle aggregation and release.^{1 2 3 4 5 6 9}

  
  


• 
  

  Active against influenza A and B viruses, including amantadine- and rimantadine-resistant isolates.^{1 2 3 4 5 6} Active in vitro against avian influenza A viruses (including H5N1, H6N1, N7N7, H9N2).²⁴

  
  


• 
  

  Active against some influenza strains resistant to oseltamivir.¹⁵³ To date, isolates of 2009 pandemic influenza A (H1N1) virus, including some oseltamivir-resistant strains, have been susceptible to zanamivir.^{117 124 144 162} Some isolates of influenza A (H5N1) with reduced susceptibility or resistance to oseltamivir remain susceptible to zanamivir.³²

  
  


• 
  

  Influenza viruses with reduced susceptibility to zanamivir have been produced in vitro.^{1 7 10} Resistance reported rarely in clinical isolates of influenza A or B,^{1 7 153} but risk of emergence of resistant isolates with clinical use has not been quantified.¹

  
  


• 
  

  Influenza strains cross-resistant to zanamivir and oseltamivir have been generated in cell culture;^{1 21} only limited data available regarding possible emergence of clinical isolates with cross-resistance to both drugs.^{1 21}

  
  

Advice to Patients

• 
  

  Importance of understanding proper inhalation technique and use of the drug delivery system (Diskhaler);¹ importance of reading patient instructions for use.¹

  
  


• 
  

  Importance of initiating zanamivir treatment as soon as possible after appearance of influenza symptoms (within 2 days after symptom onset);^{1 11} efficacy not established if treatment begins after 48 hours of symptoms.¹

  
  


• 
  

  Advise patients that zanamivir treatment does not reduce the risk of transmission of influenza virus to others.¹

  
  


• 
  

  Advise patients of the possible risk of bronchospasm, especially in those with underlying respiratory disease; importance of patients with asthma or COPD having a short-acting inhaled β-adrenergic bronchodilator readily available.¹

  
  


• 
  

  Advise patients using an inhaled bronchodilator at the same time as zanamivir of the importance of using the bronchodilator first.¹

  
  


• 
  

  Importance of discontinuing zanamivir and promptly contacting clinician if there is an increase in respiratory symptoms (e.g., wheezing, dyspnea, signs or symptoms of bronchospasm) or if symptoms of an allergic reaction occur.¹

  
  


• 
  

  Importance of immediately contacting a clinician if patient demonstrates signs of unusual behavior.¹ Influenza patients, particularly children and adolescents, may be at increased risk of seizures, confusion, or abnormal behavior early in their illness and should be closely observed for signs of unusual behavior.¹ Such events are uncommon, but may occur after starting zanamivir treatment or when influenza is not treated and can result in accidental injury to the patient.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Zanamivir

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation	Powder for inhalation (contained in Rotadisk foil pack)	5 mg per inhalation	Relenza (with Diskhaler)	GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Relenza Diskhaler 5MG/BLISTER Aerosol (GLAXO SMITH KLINE): 20/$75.73 or 60/$204.14

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. GlaxoSmithKline. Relenza (zanamivir) for inhalation prescribing information. Research Triangle Park, NC; 2010 Mar.

2. Monto AS, Robinson DP, Herlocher ML et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999; 282:31-5. [IDIS 427990] [PubMed 10404908]

3. Hayden FG, Osterhaus ADME, Treanor JJ et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med. 1997; 337:874-80. [IDIS 391783] [PubMed 9302301]

4. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet. 1998; 352:1877-81. [IDIS 418344] [PubMed 9863784]

5. Calfee DP, Hayden FG. New approaches to influenza chemotherapy: neuraminidase inhibitors. Drugs. 1998; 56:537-53. [PubMed 9806102]

6. Aoki FY, Hayden FG. Zanamivir: a potent and selective inhibitor of influenza A and B viruses. Clin Pharmacokinet. 1999; 36(Suppl 1):v-ix. [PubMed 10429834]

7. Gubareva LV, Matrosivich MN, Brenner MK et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998; 178:1257-62. [IDIS 418530] [PubMed 9780244]

9. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008; 57(RR-7):1-60.

10. Webster A, Boyce M, Edmundson S. Coadministration of orally inhaled zanamivir with inactivated trivalent influenza virus vaccine does not adversely affect the production of antihaemagglutinin antibodies in the serum of healthy volunteers. Clin Pharmacokinet. 1999; 36(Suppl 1):51-8. [PubMed 10429840]

11. Glaxo Wellcome, Research Triangle Park, NC: Personal communication.

12. Shilling M, Povinelli L, Krause P et al. Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks. Vaccine. 1998; 16:1771-4. [PubMed 9778755]

14. Hedrick JA, Barzilai A, Behre U et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J. 2000; 19:410-7. [IDIS 447594] [PubMed 10819336]

15. Lumpkin MM. Food and Drug Administration. Dear healthcare provider letter regarding safe and appropriate use of influenza drugs. Rockville, MD; 2000 Jan 12. From FDA website.

17. Hayden FG, Gubareva LV, Monto AS et al. Inhaled zanamivir for the prevention of influenza in families. N Engl J Med. 2000; 343:1282-9. [IDIS 454760] [PubMed 11058672]

18. Kaiser L, Henry D, Flack NP et al. Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study. Clin Infect Dis. 2000; 30:587-9. [IDIS 444643] [PubMed 10722450]

19. Hedrick JA, Barzilai A, Behre U et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J. 2000; 19:410-7. [IDIS 447594] [PubMed 10819336]

21. Genentech USA, Inc. Tamiflu (oseltamivir phosphate) capsules and for oral suspension prescribing information. South San Franciso: 2010 Sep.

22. Peng AW, Milleri S, Stein DS. Direct measurement of the anti-influenza agent zanamivir in the respiratory tract following inhalation. Antimicrob Agents Chemother. 2000; 44:1974-6. [IDIS 448903] [PubMed 10858364]

23. Cass LM, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet. 1999; 36(Suppl 1):1-11. [PubMed 10429835]

24. Govorkova EA, Leneva IA, Goloubeva OG et al. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother. 2001;45:2723-32.

26. Nuzzo J. Federal advisory groups recommend priorities for vaccination and antivirals during a pandemic. CBN Weekly Bulletin. 2005 Aug 2.

28. Hayden FG. Pandemic influenza: is an antiviral response realistic? Pediatr Infect Dis J. 2004; 23(Suppl):S262-9.

29. American Academy of Pediatrics. 2009 Red Book. Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

30. Koopmans M, Wilbrink B, Conyn M et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet. 2004; 363:587-93. [PubMed 14987882]

31. Leneva IA, Goloubeva O, Fenton RJ et al. Efficacy of zanamivir against avian influenza A viruses that possess genes encoding H5N1 internal proteins and are pathogenic in mammals. Antimicrob Agents Chemother. 2001;45:1216-24.