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Wednesday, October 5, 2016

Ribasphere Tablets

Dosage Form: tablet, film coated

Rx only

RIBASPHERE (ribavirin, USP) monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication (see WARNINGS).

The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin (see WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Information For Patients, and Pregnancy: Category X).

DESCRIPTION

RIBASPHERE (ribavirin, USP), the Three Rivers Pharmaceuticals brand name for ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:

The molecular formula of ribavirin is C8H12N4O5 and the molecular weight is 244.2. Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.

RIBASPHERE (ribavirin, USP) is available as a blue-colored (shade depending on strength), capsule-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg, 400 mg, or 600 mg of ribavirin and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone K27-33, magnesium stearate, and purified water. The coating of the 200-mg tablet contains partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #2 [indigo carmine aluminum lake], and carnauba wax. The coating of the 400- and 600-mg tablet contains partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #1 [brilliant blue FCF aluminum lake], and carnauba wax.

Mechanism of Action

Ribavirin is a synthetic nucleoside analogue. The mechanism by which the combination of ribavirin and an interferon product exerts its effects against the hepatitis C virus has not been fully established.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight >75 kg) AUC0-12hr was 25,361±7110 ng·hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight >75 kg).

The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Elimination and Metabolism

The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.

Special Populations

Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

Renal Dysfunction

The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with ribavirin (see WARNINGS and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.

Pediatric Patients

Pharmacokinetic evaluations in pediatric patients have not been performed.

Elderly Patients

Pharmacokinetic evaluations in elderly patients have not been performed.

Gender

Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

Drug Interactions

In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes.

Nucleoside Analogues

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine.

In vitro, didanosine or its active metabolite (dideoxyadenosine 5’– triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions).

Drugs Metabolized by Cytochrome P450

There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

Treatment with peginterferon alfa-2a once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC (seePRECAUTIONS: Drug Interactions).

CLINICAL STUDIES

HCV Patients

The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.

In Study NV15801 (described as Study 4 in the PEGASYS®¹ Package Insert), patients were randomized to receive either peginterferon alfa-2a 180 µg sc once weekly (qw) with an oral placebo, peginterferon alfa-2a 180 µg qw with ribavirin 1000 mg po (body weight <75 kg) or 1200 mg po (body weight ≥75 kg) or REBETRON™² (interferon alfa-2b 3 MIU sc tiw plus ribavirin 1000 mg or 1200 mg po). All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (Table 1). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alpha-2a in combination with ribavirin compared to patients with other viral genotypes.

Table 1 Sustained Virologic Response (SVR) to Combination Therapy (Study NV15801*)
	Interferon alfa-2b + Ribavirin 1000 mg or 1200 mg	Peginterferon alfa-2a + placebo	Peginterferon alfa-2a + Ribavirin 1000 mg or 1200 mg
Difference in overall treatment response (Peginterferon alfa-2a /ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3). *Described as Study 4 in the PEGASYS Package Insert.
All Patients	197/444 (44%)	65/224 (29%)	241/453 (53%)
Genotype 1	103/285 (36%)	29/145 (20%)	132/298 (44%)
Genotypes 2–6	94/159 (59%)	36/79 (46%)	109/155 (70%)

In Study NV15942 (described as Study 5 in the PEGASYS Package Insert), all patients received peginterferon alfa-2a 180 µg sc qw and were randomized to treatment for either 24 or 48 weeks and to a ribavirin dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg/≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

HCV Genotypes

HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin.

HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see Table 2).

The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

Table 2 Sustained Virologic Response as a Function of Genotype (Study NV15942*)
	24 Weeks Treatment		48 Weeks Treatment
	Peginterferon alfa‑2a + Ribavirin 800 mg (N=207)	Peginterferon alfa‑2a + Ribavirin 1000 mg or 1200 mg** (N=280)	Peginterferon alfa‑2a + Ribavirin 800 mg (N=361)	Peginterferon alfa‑2a + Ribavirin 1000 mg or 1200 mg** (N=436)
* Described as Study 5 in the PEGASYS Package Insert. **1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg.
Genotype 1	29/101 (29%)	48/118 (41%)	99/250 (40%)	138/271 (51%)
Genotypes 2,3	79/96 (82%)	116/144 (81%)	75/99 (76%)	117/153 (76%)
Genotype 4	0/5 (0%)	7/12 (58%)	5/8 (63%)	9/11 (82%)

Other Treatment Response Predictors

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.

Paired liver biopsies were performed on approximately 20% of patients in studies NV15801 and NV15942. Modest reductions in inflammation compared to baseline were seen in all treatment groups.

In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

INDICATIONS AND USAGE

RIBASPHERE (ribavirin, USP) in combination with peginterferon alfa-2a is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).

CONTRAINDICATIONS

RIBASPHERE (ribavirin, USP) is contraindicated in:

Patients with known hypersensitivity to RIBASPHERE (ribavirin, USP) or to any component of the tablet.

Women who are pregnant.

Men whose female partners are pregnant.

Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a combination therapy is contraindicated in patients with:

Autoimmune hepatitis.

Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment.

WARNINGS

RIBASPHERE (ribavirin, USP) must not be used alone because ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection. The safety and efficacy of ribavirin have only been established when used together with peginterferon alfa-2a, recombinant.

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a should be discontinued in patients who develop evidence of hepatic decompensation during treatment.

There are significant adverse events caused by ribavirin/peginterferon alfa-2a therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. The PEGASYS package insert and MEDICATION GUIDE should be reviewed in their entirety prior to initiation of combination treatment for additional safety information.

General

Treatment with RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a should be administered under the guidance of a qualified physician and may lead to moderate to severe adverse experiences requiring dose reduction, temporary dose cessation or discontinuation of therapy.

Pregnancy

Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. RIBASPHERE (ribavirin, USP) THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO PLANNED INITIATION OF THERAPY. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during RIBASPHERE (ribavirin, USP) therapy and for 6 months after therapy has stopped (see CONTRAINDICATIONS and PRECAUTIONS: Information For Patients and Pregnancy: Category XCONTRAINDICATIONS and PRECAUTIONS: Information For Patients and Pregnancy: Category X).

Anemia

The primary toxicity of ribavirin is hemolytic anemia (hemoglobin <10 g/dL), which was observed in approximately 13% of all ribavirin and peginterferon alfa-2a treated patients in clinical trials (see PRECAUTIONS: Laboratory Tests). The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. BECAUSE THE INITIAL DROP IN HEMOGLOBIN MAY BE SIGNIFICANT, IT IS ADVISED THAT HEMOGLOBIN OR HEMATOCRIT BE OBTAINED PRETREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY OR MORE FREQUENTLY IF CLINICALLY INDICATED. Patients should then be followed as clinically appropriate.

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued (see DOSAGE AND ADMINISTRATION: RIBASPHERE (ribavirin, USP) Dosage Modification Guidelines). Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use RIBASPHERE (ribavirin, USP) (see ADVERSE REACTIONS).

Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. During treatment, patients’ clinical status and hepatic function should be closely monitored, and peginterferon alfa-2a treatment should be immediately discontinued if decompensation (Child-Pugh score ≥6) is observed (see CONTRAINDICATIONS).

Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been rarely reported in the patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy. (see ADVERSE REACTIONS: Postmarketing Experience).

Pulmonary

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and occasional cases of fatal pneumonia, have been reported during therapy with ribavirin and interferon. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored and, if appropriate, combination RIBASPHERE (ribavirin, USP)/peginterferon alfa-2a treatment should be discontinued.

Other

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

RIBASPHERE (ribavirin, USP) should not be used in patients with creatinine clearance <50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).

RIBASPHERE (ribavirin, USP) must be discontinued immediately and appropriate medical therapy instituted if an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops. Transient rashes do not necessitate interruption of treatment.

PRECAUTIONS

The safety and efficacy of RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. RIBASPHERE (ribavirin, USP) should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

The safety and efficacy of RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy have not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C virus infection, patients who are non-responders to interferon therapy or patients coinfected with HBV or HIV and a CD4+ cell count <100 cells/μL.

Information for Patients

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. RIBASPHERE (ribavirin, USP) therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking RIBASPHERE (ribavirin, USP) therapy and for 6 months posttherapy. RIBASPHERE (ribavirin, USP) therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy.

Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during RIBASPHERE (ribavirin, USP) therapy and for 6 months posttherapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy (see CONTRAINDICATIONS and WARNINGS).

The most common adverse event associated with ribavirin is anemia, which may be severe (see ADVERSE REACTIONS). Patients should be advised that laboratory evaluations are required prior to starting RIBASPHERE (ribavirin, USP) therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.

Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

Patients should be informed regarding the potential benefits and risks attendant to the use of RIBASPHERE (ribavirin, USP). Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects.

Patients should be advised to take RIBASPHERE (ribavirin, USP) with food.

Laboratory Tests

Before beginning RIBASPHERE (ribavirin, USP) therapy, standard hematological and biochemical laboratory tests must be conducted for all patients. Pregnancy screening for women of childbearing potential must be done.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. Monthly pregnancy testing should be done during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a combination therapy may be considered as a guideline to acceptable baseline values for initiation of treatment:

Platelet count ≥90,000 cells/mm3 (as low as 75,000 cells/mm3 in patients with cirrhosis)

Absolute neutrophil count (ANC) ≥1500 cells/mm3

TSH and T4 within normal limits or adequately controlled thyroid function

ECG (see WARNINGS)

Hemoglobin ≥12 g/dL for women and ≥13 g/dL for men in CHC monoinfected patients

The maximum drop in hemoglobin usually occurred during the first 8 weeks of initiation of ribavirin therapy. Because of this initial acute drop in hemoglobin, it is advised that a complete blood count should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Additional testing should be performed periodically during therapy. Patients should then be followed as clinically appropriate.

Drug Interactions

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.

Nucleoside Analogues

NRTIs

Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, ribavirin or both should also be considered if worsening toxicities are observed (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION: Dose Modifications).

Didanosine

Co-administration of ribavirin and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions).

Zidovudine

In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs.1%).

Lamivudine, Stavudine, and Zidovudine

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs such as lamivudine, stavudine, and zidovudine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a p53 (+/-) mouse carcinogenicity study and a rat 2-year carcinogenicity study at doses up to the maximum tolerated doses of 100 mg/kg/day and 60 mg/kg/day, respectively, ribavirin was not oncogenic. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended human 24-hour dose of ribavirin.

Mutagenesis

Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.

Impairment of Fertility

In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended human 24-hour dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.

Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive RIBASPHERE (ribavirin, USP) unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (i.e., 15 half-lives of clearance for ribavirin).

No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with RIBASPHERE (ribavirin, USP). However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.

Pregnancy

Pregnancy: Category X (see CONTRAINDICATIONS)

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced.

In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin).

Treatment and Posttreatment: Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

RIBASPHERE (ribavirin, USP) should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive RIBASPHERE (ribavirin, USP) unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months posttherapy.

Ribavirin Pregnancy Registry

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.

Animal Toxicology

Long-term study in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum human daily dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

Nursing Mothers

It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with RIBASPHERE (ribavirin, USP), based on the importance of the therapy to the mother.

Pediatric Use

Safety and effectiveness of RIBASPHERE (ribavirin, USP) have not been established in patients below the age of 18.

Geriatric Use

Clinical studies of ribavirin and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. RIBASPHERE (ribavirin, USP) should not be administered to patients with creatinine clearance <50 mL/min. (see CLINICAL PHARMACOLOGY: Special Populations).

Effect of Gender

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.

ADVERSE REACTIONS

Peginterferon alfa-2a in combination with ribavirin causes a broad variety of serious adverse reactions (see BOXED WARNING and WARNINGS).

The most common life-threatening or fatal events induced or aggravated by peginterferon alfa-2a and ribavirin were depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%.

In all studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients receiving peginterferon alfa-2a alone or in combination with ribavirin. The most common serious adverse event (3% in CHC) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of <1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, and thrombotic thrombocytopenic purpura.

Nearly all patients in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus.

Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with ribavirin discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of patients with CHC required modification of peginterferon alfa-2a and/or ribavirin therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC patients was for laboratory abnormalities; neutropenia (20%) and thrombocytopenia (4%). The most common reason for dose modification of ribavirin in CHC patients was anemia (22%).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7% of patients receiving 800 mg ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of patients receiving 1000 mg to1200 mg ribavirin for 48 weeks and in 12% of patients receiving 800 mg ribavirin for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin <10 g/dL (3% vs. 15%), dose modifications of peginterferon alfa-2a (30% vs. 36%) and ribavirin (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg ribavirin. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice.

Table 3 Adverse Reactions Occurring in ≥5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801*)
Body System	CHC Combination Therapy Study NV15801
Body System	Peginterferon alfa-2a 180 µg + 1000 mg or 1200 mg Ribavirin 48 week	Interferon alfa-2b + 1000 mg or 1200 mg Ribavirin 48 week
	N=451	N=443
	%	%
* Described as Study 4 in the PEGASYS Package Insert. ** Severe hematologic abnormalities (lymphocyte <0.5 x 109/L; hemoglobin <10 g/dL; neutrophil <0.75 x 109/L; platelet <50 x 109/L).
Application Site Disorders
Injection site reaction	23	16
Endocrine Disorders
Hypothyroidism	4	5
Flu‑like Symptoms and Signs
Fatigue/Asthenia	65	68
Pyrexia	41	55
Rigors	25	37
Pain	10	9
Gastrointestinal
Nausea/Vomiting	25	29
Diarrhea	11	10
Abdominal pain	8	9
Dry mouth	4	7
Dyspepsia	6	5
Hematologic**
Lymphopenia	14	12
Anemia	11	11
Neutropenia	27	8
Thrombocytopenia

Darvocet-N 100

Generic Name: propoxyphene and acetaminophen (Oral route)

a-seet-a-MIN-oh-fen, proe-POX-i-feen NAP-si-late

Oral route(Tablet)

Accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol, has occurred, and may be fatal within the first hour. Many of the fatalities have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation. The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors leading to enhanced propoxyphene plasma levels; monitor patients closely and adjust dosages if necessary in patients receiving any CYP3A4 inhibitor concomitantly .

Commonly used brand name(s)

In the U.S.

Balacet 325

Darvocet A500

Darvocet-N 100

Darvocet-N 50

Pronap-100

Propoxacet-N

Propoxacet-N 100

Available Dosage Forms:

Tablet

Therapeutic Class: Opioid/Acetaminophen Combination

Chemical Class: Propoxyphene

Uses For Darvocet-N 100

Propoxyphene and acetaminophen combination is used to relieve mild to moderate pain. Propoxyphene belongs to the group of medicines called narcotic analgesics (pain medicines). It acts on the central nervous system (CNS) to relieve pain.

Acetaminophen is used to relieve pain and reduce fever in patients. It does not become habit-forming when taken for a long time. But acetaminophen may cause other unwanted effects when taken in large doses, including liver damage.

When propoxyphene is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

Products containing propoxyphene were withdrawn from the U.S. market starting November 19, 2010.

This medicine was available only with your doctor's prescription.

Before Using Darvocet-N 100

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of propoxyphene and acetaminophen combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of propoxyphene and acetaminophen combination in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving propoxyphene and acetaminophen combination.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Naltrexone

Rasagiline

Selegiline

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Adinazolam

Alfentanil

Alprazolam

Amobarbital

Anileridine

Aprobarbital

Bromazepam

Brotizolam

Buprenorphine

Butabarbital

Butalbital

Butorphanol

Carbamazepine

Carisoprodol

Chloral Hydrate

Chlordiazepoxide

Chlorzoxazone

Clobazam

Clonazepam

Clorazepate

Codeine

Dantrolene

Dezocine

Diazepam

Estazolam

Ethchlorvynol

Fentanyl

Flunitrazepam

Flurazepam

Fospropofol

Halazepam

Hydrocodone

Hydromorphone

Ketazolam

Levorphanol

Lorazepam

Lormetazepam

Medazepam

Meperidine

Mephenesin

Mephobarbital

Meprobamate

Metaxalone

Methocarbamol

Methohexital

Midazolam

Morphine

Morphine Sulfate Liposome

Nalbuphine

Nitrazepam

Nordazepam

Opium

Oxazepam

Oxycodone

Oxymorphone

Pentazocine

Pentobarbital

Phenobarbital

Prazepam

Propoxyphene

Quazepam

Remifentanil

Secobarbital

Sodium Oxybate

Sufentanil

Tapentadol

Temazepam

Thiopental

Triazolam

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acenocoumarol

Carbamazepine

Doxepin

Isoniazid

Metoprolol

Phenytoin

Propranolol

Warfarin

Zidovudine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

Ethanol

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

Cabbage

Proper Use of propoxyphene and acetaminophen

This section provides information on the proper use of a number of products that contain propoxyphene and acetaminophen. It may not be specific to Darvocet-N 100. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of this medicine is taken for a long time, it may become habit-forming (causing mental or physical dependence). Liver damage can occur if large amounts of acetaminophen are taken for a long time.

This combination medicine contains acetaminophen (Tylenol®). Carefully check the labels of all other medicines you are using, because they may also contain acetaminophen. It is not safe to use more than 4 grams (4,000 milligrams) of acetaminophen in one day (24 hours).

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (tablets):
- For mild to moderate pain:
  - Adults—One or two tablets every 4 hours as needed. Your doctor may adjust your dose if needed. However, the dose is usually not more than 6 to 12 tablets per day.
  - Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Throw any unused medicine by mixing it with used coffee grounds or kitty litter and place it in a sealable bag, empty can, or container.

Precautions While Using Darvocet-N 100

It is very important that your doctor check your progress while you are taking this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Talk to your doctor first before you stop taking this medicine and changing to another pain medicine.

This medicine can cause changes in heart rhythms, such as conditions called PR, QRS, and QT prolongation. It may change the way your heart beats and cause fainting, dizziness, lightheadedness, or serious side effects in some patients. Contact your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Also, there may be a greater risk of liver damage if you drink three or more alcoholic beverages while you are taking acetaminophen. Do not drink alcoholic beverages, and check with your doctor before taking any of the medicines listed above while you are using this medicine.

This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.

This medicine may make you dizzy, drowsy, or lightheaded. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

If you have been using this medicine regularly for several weeks or longer, do not change your dose or suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.

Using this medicine while you are pregnant may cause serious unwanted effects in your newborn baby. Tell your doctor right away if you think you are pregnant or if you plan to become pregnant while using this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Darvocet-N 100 Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Rare

Abdominal or stomach pain

chills

clay-colored stools

dark urine

dizziness

fever

headache

itching

loss of appetite

nausea

rash

unpleasant breath odor

unusual tiredness or weakness

vomiting of blood

yellow eyes or skin

Incidence not known

Bloating

bloody or black, tarry stools

bloody or cloudy urine

change in consciousness

chest pain or discomfort

confusion

cough

decreased urine output

difficult or troubled breathing

dilated neck veins

drowsiness

extreme fatigue

fainting

fast, slow, pounding, or irregular heartbeat or pulse

fever with or without chills

general feeling of discomfort or illness

hives

hoarseness

irregular, fast, slow, or shallow breathing

itching

joint pain, stiffness, or swelling

light-colored stools

loss of consciousness

low blood pressure or pulse

muscle aches and pains

muscle tremors

pain or discomfort in the arms, jaw, back, or neck

pains in the stomach, side, or abdomen, possibly radiating to the back

pale or blue lips, fingernails, or skin

rapid, deep breathing

redness of the skin

restlessness

right upper stomach pain and fullness

runny nose

severe stomach pain

shakiness and unsteady walk

shivering

shortness of breath

sore throat

stomach cramps

sudden decrease in the amount of urine

sweating

swelling of the eyelids, face, fingers, lips, hands, lower legs, or feet

thoughts of suicide

tightness in the chest

trouble sleeping

troubled breathing or swallowing

unconsciousness

unsteadiness, trembling, or other problems with muscle control or coordination

very slow breathing

very slow heartbeat

vomiting of blood or material that looks like coffee grounds

weight gain

wheezing

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

Agitation

bluish color of the fingernails, lips, skin, palms, or nail beds

convulsion

coughing that sometimes produces a pink frothy sputum

decreased awareness or responsiveness

depression

difficult, fast, or noisy breathing, sometimes with wheezing

dilated pupils

hostility

increased sweating

irritability

lethargy

muscle tremors

muscle twitching

pale skin

pounding or rapid pulse

rapid weight gain

rapid, deep breathing

severe sleepiness

sleepiness or unusual drowsiness

slow to respond

slurred speech

weight loss

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Relaxed and calm feeling

Incidence not known

Abnormal behavior

blurred or loss of vision

constipation

diarrhea

disturbed color perception

double vision

false or unusual sense of well-being

halos around lights

indigestion

muscular pain, tenderness, wasting, or weakness

night blindness

nightmares or unusually vivid dreams

overbright appearance of lights

seeing, hearing, or feeling things that are not there

swelling of the eye

tunnel vision

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Darvocet-N00 side effects (in more detail)

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More Darvocet-N 100 resources

Darvocet-N 100 Side Effects (in more detail)
Darvocet-N 100 Use in Pregnancy & Breastfeeding
Drug Images
Darvocet-N 100 Drug Interactions
Darvocet-N 100 Support Group
37 Reviews for Darvocet-N00 - Add your own review/rating

Darvocet-N 100 MedFacts Consumer Leaflet (Wolters Kluwer)

Darvocet-N 100 Concise Consumer Information (Cerner Multum)

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Pain

Oxcarbazepine

Oxcarbazepine Tablets

Rx only

Prescribing Information

Oxcarbazepine Description

Oxcarbazepine is an antiepileptic drug available as 150 mg, 300 mg and 600 mg film-coated tablets for oral administration. Oxcarbazepine is 10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is

Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27.

Oxcarbazepine film-coated tablets contain the following inactive ingredients: microcrystalline cellulose, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, talc. Coating: polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, *FD&C Yellow No. 6 aluminum lake, lecithin, FD&C Blue No. 2 aluminum lake, **FD&C Yellow No. 5 aluminum lake. *Contains FD&C Yellow No. 6 as a color additive. **Contains FD&C Yellow No. 5 as a color additive. (See PRECAUTIONS). Allergen Statement: This product contains soy.

Oxcarbazepine - Clinical Pharmacology

Mechanism of Action

The pharmacological activity of Oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of Oxcarbazepine (see Metabolism and Excretion subsection). The precise mechanism by which Oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of Oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.

Pharmacodynamics

Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with Oxcarbazepine or MHD.

Pharmacokinetics

Following oral administration of Oxcarbazepine tablets, Oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half-life of the parent is about two hours, while the half-life of MHD is about nine hours, so that MHD is responsible for most antiepileptic activity.

Based on MHD concentrations, Oxcarbazepine tablets and suspension were shown to have similar bioavailability.

After single-dose administration of Oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours.

In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged Oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.

Effect of Food

Food has no effect on the rate and extent of absorption of Oxcarbazepine from Oxcarbazepine tablets. Therefore, Oxcarbazepine tablets can be taken with or without food.

Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when Oxcarbazepine is given twice a day. At steady-state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day.

Distribution

The apparent volume of distribution of MHD is 49L.

Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

Metabolism and Excretion

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).

Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged Oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and Oxcarbazepine account for 13% of the dose.

Special Populations

Hepatic Impairment

The pharmacokinetics and metabolism of Oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of Oxcarbazepine and MHD. No dose adjustment for Oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of Oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients.

Renal Impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment for Oxcarbazepine is recommended in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

Pediatric Use

Weight-adjusted MHD clearance decreases as age and weight increases approaching that of adults. The mean weight-adjusted clearance in children 2 years-<4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose.The mean weight-adjusted clearance in children 4–12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.

Geriatric Use

Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.

Gender

No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.

Race

No specific studies have been conducted to assess what effect, if any, race may have on the disposition of Oxcarbazepine.

Clinical Studies

The effectiveness of Oxcarbazepine as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials.

The effectiveness of Oxcarbazepine as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.

Oxcarbazepine Monotherapy Trials

Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of Oxcarbazepine as monotherapy. Two trials compared Oxcarbazepine to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of Oxcarbazepine, after substituting Oxcarbazepine 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a BID schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose Oxcarbazepine treatment groups.

One placebo-controlled trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or Oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of Oxcarbazepine (see Figure 1), p=0.0001.

Figure 1: Kaplan-Meier Estimates of Exit Rate by Treatment Group

The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or Oxcarbazepine, initiated at 300 mg BID and titrated to 1200 mg/day (given as 600 mg BID) in six days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of Oxcarbazepine (see Figure 2), p=0.046.

Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group

A third trial substituted Oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this Oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of Oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of Oxcarbazepine or 2400 mg/day Oxcarbazepine. Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between- group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 3), p=0.0001.

Figure 3: Kaplan-Meier Estimates of Exit Rate by Treatment Group

Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs. Patients were randomized to either Oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the Oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the Oxcarbazepine 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 4), p=0.0001.

Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group

A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either Oxcarbazepine 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of Oxcarbazepine therapy. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e. electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting.

Although this study failed to demonstrate an effect of Oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that Oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.

Oxcarbazepine Adjunctive Therapy Trials

The effectiveness of Oxcarbazepine as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of Oxcarbazepine in 128 pediatric patients (1 month to < 4 years of age).

Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of Oxcarbazepine in addition to their other AEDs.

In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14-(pediatrics) or 24-week (adults) maintenance period.

In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of Oxcarbazepine at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 1. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study (see ADVERSE REACTIONS section), an outcome not seen in the monotherapy studies.

Table 1: Summary of Percentage Change in Partial Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials
Trial	Treatment Group	N	Baseline Median Seizure Rate*	Median % Reduction
* = # per 28 days † p=0.0001;
1 (pediatrics)	Oxcarbazepine	136	12.5	34.8†
	Placebo	128	13.1	9.4
2 (adults)	Oxcarbazepine 2400 mg/day	174	10.0	49.9†
	Oxcarbazepine 1200 mg/day	177	9.8	40.2†
	Oxcarbazepine 600 mg/day	168	9.6	26.4†
	Placebo	173	8.6	7.6

Subset analyses of the antiepileptic efficacy of Oxcarbazepine with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed.

The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either Oxcarbazepine 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of Oxcarbazepine 60 mg/kg/day. In this study, there was no evidence that Oxcarbazepine was effective in patients below the age of 2 years (N=75).

Indications and Usage for Oxcarbazepine

Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with epilepsy.

Contraindications

Oxcarbazepine should not be used in patients with a known hypersensitivity to Oxcarbazepine or to any of its components.

Warnings

Hyponatremia

Clinically significant hyponatremia (sodium <125 mmol/L) can develop during Oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of Oxcarbazepine-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first three months of treatment with Oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/L more than one year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their Oxcarbazepine dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with Oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.

Measurement of serum sodium levels should be considered for patients during maintenance treatment with Oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity).

Anaphylactic Reactions and Angioedema

Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).

Patients with a Past History of Hypersensitivity Reaction to Carbamazepine

Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with Oxcarbazepine. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with Oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxcarbazepine should be discontinued immediately (See WARNINGS, Anaphylactic Reactions and Angioedema subsection; see PRECAUTIONS, Multi-Organ Hypersensitivity subsection).

Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with Oxcarbazepine use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. Recurrence of the serious skin reactions following rechallenge with Oxcarbazepine has also been reported.

The reporting rate of TEN and SJS associated with Oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3-to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking Oxcarbazepine, consideration should be given to discontinuing Oxcarbazepine use and prescribing another antiepileptic medication.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Oxcarbazepine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication	Placebo Patients with Events Per 1,000 Patients	Drug Patients with Events Per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Oxcarbazepine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Withdrawal of AEDs

As with all antiepileptic drugs, Oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.

Precautions

FD&C Yellow No. 5 (Tartrazine)

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Cognitive/Neuropsychiatric Adverse Events

Use of Oxcarbazepine has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.

Adult Patients

In one large, fixed-dose study, Oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Oxcarbazepine was added, reduction in Oxcarbazepine dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of Oxcarbazepine on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.

In this trial, 7.1% of Oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on Oxcarbazepine than on placebo. In addition, 26% of Oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on Oxcarbazepine than on placebo. Finally, 28.7% of Oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about seven times greater on Oxcarbazepine than on placebo.

In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of Oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.

In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day Oxcarbazepine, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.

Pediatric Patients

A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which Oxcarbazepine was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as Oxcarbazepine was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for pre-defined weight ranges).

Cognitive adverse events occurred in 5.8% of Oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of Oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.) Finally, 23.2% of Oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) Oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.

Multi-Organ Hypersensitivity

Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of Oxcarbazepine therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, Oxcarbazepine should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).

Information for Patients

Anaphylactic reactions and angioedema may occur during treatment with Oxcarbazepine. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see WARNINGS, Anaphylactic Reactions and Angioedema subsection).

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with Oxcarbazepine. Patients should be advised that if they experience a hypersensitivity reaction while taking Oxcarbazepine they should consult with their physician immediately (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).

Patients should be advised that serious skin reactions have been reported in association with Oxcarbazepine. In the event a skin reaction should occur while taking Oxcarbazepine, patients should consult with their physician immediately (see WARNINGS, Serious Dermatological Reactions subsection).

Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately (see PRECAUTIONS, Multi-Organ Hypersensitivity subsection).

Female patients of childbearing age should be warned that the concurrent use of Oxcarbazepine with hormonal contraceptives may render this method of contraception less effective (see Drug Interactions subsection). Additional non-hormonal forms of contraception are recommended when using Oxcarbazepine.

Patients, their caregivers, and families should be counseled that AEDs, including Oxcarbazepine, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Caution should be exercised if alcohol is taken in combination with Oxcarbazepine therapy, due to a possible additive sedative effect.

Patients should be advised that Oxcarbazepine may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on Oxcarbazepine to gauge whether it adversely affects their ability to drive or operate machinery.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy Category C subsection).

Laboratory Tests

Serum sodium levels below 125 mmol/L have been observed in patients treated with Oxcarbazepine (see WARNINGS section). Experience from clinical trials indicates that serum sodium levels return toward normal when the Oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).

Laboratory data from clinical trials suggest that Oxcarbazepine use was associated with decreases in T4, without changes in T3 or TSH.

Drug Interactions

Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of Oxcarbazepine and MHD.

Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that Oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by Oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by Oxcarbazepine and MHD, however, is clinically relevant (see below).

In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with Oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).

In addition, Oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists and oral contraceptives, resulting in a lower plasma concentration of these drugs.

As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.

Antiepileptic Drugs

Potential interactions between Oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 3.

Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
* nc denotes a mean change of less than 10% † Pediatrics ‡ Mean increase in adults at high Oxcarbazepine doses
Carbamazepine	400-2000	900	nc*	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc*,† up to 40% increase‡ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc*	18% decrease [CI:13% decrease, 40% decrease]

In vivo, the plasma levels of phenytoin increased by up to 40% when Oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of Oxcarbazepine greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with Oxcarbazepine.

Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%).

No autoinduction has been observed with Oxcarbazepine.

Hormonal Contraceptives

Coadministration of Oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study. Therefore, concurrent use of Oxcarbazepine with hormonal contraceptives may render these contraceptives less effective (see Drug Interactions subsection). Studies with other oral or implant contraceptives have not been conducted.

Calcium Antagonists

After repeated coadministration of Oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20-33].

Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD.

Other Drug Interactions

Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of Oxcarbazepine.

Drug/Laboratory Test Interactions

There are no known interactions of Oxcarbazepine with commonly used laboratory tests.

Carcinogenesis/Mutagenesis/Impairment of Fertility

In two-year carcinogenicity studies, Oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at Oxcarbazepine doses ≥70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with Oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the MRHD on a mg/m2 basis), and incidences of hepat

Dabigatran

Generic Name: dabigatran (da BIG a tran)

Brand Names: Pradaxa

What is dabigatran?

Dabigatran keeps the platelets in your blood from coagulating (clotting).

Dabigatran is used to prevent blood clots and to reduce the risk of stroke in people with a certain type of heart rhythm disorder.

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

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

Because dabigatran keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury. Avoid activities that may increase your risk of bleeding or injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

Call your doctor at once if you have any signs of bleeding such as weakness, feeling like you might pass out, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin, pink or brown urine, bloody or tarry stools, coughing up blood, joint pain or swelling, or heavy menstrual bleeding.

If you need surgery, dental work, or any type of medical test or treatment, tell the doctor or dentist ahead of time if you have taken dabigatran within the past 12 hours. You may need to stop taking dabigatran for a short time before you have surgery or other medical procedures.

Do not stop taking the medicine without first talking to your doctor. You should not take dabigatran if you are allergic to it, or if you have any active bleeding from a surgery, injury, or other cause. Tell your doctor if you have recently used or received any other medications to treat or prevent blood clots.

Before taking dabigatran, tell your doctor if you have kidney disease, a history of stomach ulcer or bleeding, if you are older than 75, or if you are using a blood thinner such as heparin or warfarin (Coumadin, Jantoven).

Do not crush, chew, break, or open a dabigatran capsule. Swallow the pill whole.

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

You should not take dabigatran if you are allergic to it, or if you have any active bleeding from a surgery, injury, or other cause.

To make sure you can safely take dabigatran, tell your doctor if you have any of these other conditions:

kidney disease;

a history of stomach ulcer or bleeding; or

if you are older than 75.

FDA pregnancy category C. It is not known whether dabigatran will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether dabigatran 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.

How should I take dabigatran?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Because dabigatran keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have any bleeding that will not stop.

Do not stop taking the medicine without first talking to your doctor. Do not crush, chew, break, or open a dabigatran capsule. Swallow the pill whole.

Your kidney function may need to be checked with blood tests before and during treatment with dabigatran. Visit your doctor regularly.

Keep the capsules in their original container or blister pack. Do not put dabigatran capsules into a daily pill box or pill organizer.

If you have received more than a 30-day supply of this medication, do not open more than one bottle at a time. Open a new bottle only after all the capsules in the old bottle are gone.

Store at room temperature, away from moisture and heat. Keep each capsule in the bottle or blister pack until you are ready to take the medicine. Keep the bottle tightly closed when not in use. Throw away any unused capsules if it has been longer than 4 months since you first opened the bottle. Capsules stored in a blister pack should be thrown away after the expiration date on the label has passed.

See also: Dabigatran dosage (in more detail)

What happens if I miss a dose?

If you are less than 6 hours late in taking your medicine, 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.

Try not to miss any doses of dabigatran to best prevent a stroke.

What happens if I overdose?

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

Overdose symptoms may include excessive bleeding or any bleeding that will not stop.

What should I avoid while taking dabigatran?

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth. Avoid drinking alcohol. It may increase your risk of bleeding in your stomach or intestines.

Dabigatran 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 at once if you have a serious side effect such as:

any bleeding that will not stop;

weakness, feeling like you might pass out;

easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

blood in your urine or stools, black or tarry stools;

coughing up blood or vomit that looks like coffee grounds;

pink or brown urine;

joint pain or swelling; or

heavy menstrual bleeding.

Less serious side effects may include:

stomach pain or upset, indigestion, heartburn;

nausea, diarrhea; or

mild skin rash or itching.

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.

Dabigatran Dosing Information

Usual Adult Dose for Prevention of Thromboembolism in Atrial Fibrillation:

To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation:
150 mg orally twice daily

What other drugs will affect dabigatran?

Before you take dabigatran, tell your doctor if you have recently received any other medications to treat or prevent blood clots, such as:

abciximab (ReoPro), anagrelide (Agrylin), cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, Aggrenox), eptifibatide (Integrelin), prasugrel (Effient), ticlopidine (Ticlid), tirofiban (Aggrastat);

heparin or warfarin (Coumadin, Jantoven);

argatroban (Acova), bivalirudin (Angiomax), lepirudin (Refludan);

dalteparin (Fragmin), enoxaparin (Lovenox), fondaparinux (Arixtra), tinzaparin (Innohep); or

alteplase (Activase), tenecteplase (TNKase), urokinase (Abbokinase).

Tell your doctor about all other medications you use, especially:

rifampin (Rifater, Rifadin, Rifamate);

quinidine (Guin-G);

St. John's wort;

antifungal medicine such as itraconazole (Sporanox) or ketoconazole (Nizoral);

aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Motrin, Advil), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), ketoprofen (Actron, Orudis), meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve, Naprosyn), piroxicam (Feldene), and others; or

heart or blood pressure medication such as amiodarone (Cordarone, Pacerone), dronedarone (Multaq), or verapamil (Calan, Covera, Isoptin, Verelan).

This list is not complete and other drugs may interact with dabigatran. 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 dabigatran resources

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

dabigatran Advanced Consumer (Micromedex) - Includes Dosage Information

Dabigatran MedFacts Consumer Leaflet (Wolters Kluwer)

Pradaxa Prescribing Information (FDA)

Pradaxa Consumer Overview

Compare dabigatran with other medications

Prevention of Thromboembolism in Atrial Fibrillation

Where can I get more information?

Your pharmacist can provide more information about dabigatran.

See also: dabigatran side effects (in more detail)

Bimatoprost Drops

Pronunciation: bye-MAT-oh-prost
Generic Name: Bimatoprost
Brand Name: Lumigan

Bimatoprost Drops are used for:

Treating increased pressure in the eye (ocular hypertension) and open-angle glaucoma.

Bimatoprost Drops are a prostaglandin analog. It works to lower pressure in the eye by increasing fluid drainage from the eye.

Do NOT use Bimatoprost Drops if:

you are allergic to any ingredient in Bimatoprost Drops

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

Before using Bimatoprost Drops:

Some medical conditions may interact with Bimatoprost Drops. 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 inflammation, swelling, infection, or injury of the eye

if you do not have a lens in your eye or have had the lens in your eye replaced

if you have other types of glaucoma (eg, narrow-angle, neovascular)

if you will be having eye surgery

Some MEDICINES MAY INTERACT with Bimatoprost Drops. However, no specific interactions with Bimatoprost Drops are known at this time.

Ask your health care provider if Bimatoprost Drops 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 Bimatoprost Drops:

Use Bimatoprost Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Use Bimatoprost Drops in the evening unless your doctor tells you otherwise.

Soft contact lenses may absorb a chemical in Bimatoprost Drops. Remove contact lenses before you use Bimatoprost Drops; lenses may be placed back in the eyes 15 minutes after use of Bimatoprost Drops.

Wash your hands before and after using Bimatoprost Drops.

Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eyelid for 1 to 2 minutes. Do not blink. Remove excess medicine around your eye with a clean, dry tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them.

To prevent waste of Bimatoprost Drops, do not squeeze the bottle. Turn the bottle upright immediately after a drop is released.

To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including the eye. Keep the container tightly closed.

Use Bimatoprost Drops at least 5 minutes apart from any other medicine that you put in your eye.

Continue to use Bimatoprost Drops even if you feel well. Do not miss any doses.

If you miss a dose of Bimatoprost Drops, use 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 use 2 doses at once.

Ask your health care provider any questions you may have about how to use Bimatoprost Drops.

Important safety information:

Bimatoprost Drops are for use in the eye only. Do not get it in your nose or mouth.

Bimatoprost Drops may make your eyes more sensitive to light. Use Bimatoprost Drops with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it. If your eyes become sensitive to light, wearing sunglasses may help.

Bimatoprost Drops may cause the colored part of your eye (iris) to turn brown. This change may be permanent. It may not be noticeable for several months to years. If it occurs, you will need to have regular eye examinations. Discuss any questions or concerns with your doctor.

Bimatoprost Drops may cause the whites of your eyes and your eyelids to darken. It may also cause changes in the way that your eyelashes grow (eg, length, thickness, number of lashes). These effects usually go away after you stop using Bimatoprost Drops. Discuss any questions or concerns with your doctor.

Do NOT use more than the recommended dose without checking with your doctor.

If you will be having eye surgery, tell your doctor that you use Bimatoprost Drops.

Lab tests, including eye pressure, may be performed while you use Bimatoprost Drops. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.

Bimatoprost Drops should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Bimatoprost Drops while you are pregnant. It is not known if Bimatoprost Drops are found in breast milk. If you are or will be breast-feeding while you use Bimatoprost Drops, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Bimatoprost Drops:

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:

Changes in eyelash growth; cold symptoms; eye burning, dryness, itching, or redness; feeling of having something in your eye; headache; increased tear production.

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); darkening of the eyelid, eye color, or whites of the eyes; eye or eyelid discharge, inflammation, irritation, pain, or swelling; severe or persistent eye fatigue; vision changes.

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.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Bimatoprost Drops:

Store Bimatoprost Drops between 36 and 77 degrees F (2 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Bimatoprost Drops out of the reach of children and away from pets.

General information:

If you have any questions about Bimatoprost Drops, please talk with your doctor, pharmacist, or other health care provider.

Bimatoprost Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.

Do not use Bimatoprost Drops for other health conditions.

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

This information is a summary only. It does not contain all information about Bimatoprost Drops. 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

More Bimatoprost resources

Bimatoprost Use in Pregnancy & Breastfeeding
Bimatoprost Drug Interactions
Bimatoprost Support Group
4 Reviews for Bimatoprost - Add your own review/rating

Compare Bimatoprost with other medications

Glaucoma, Open Angle
Intraocular Hypertension

Wednesday, October 5, 2016

Ribasphere Tablets

DESCRIPTION

Mechanism of Action

CLINICAL PHARMACOLOGY

Pharmacokinetics

Special Populations

Drug Interactions

CLINICAL STUDIES

HCV Patients

HCV Genotypes

Other Treatment Response Predictors

INDICATIONS AND USAGE

CONTRAINDICATIONS

WARNINGS

General

Pregnancy

Anemia

Hepatic Failure

Hypersensitivity

Pulmonary

Other

PRECAUTIONS

Information for Patients

Laboratory Tests

Drug Interactions

NRTIs

Didanosine

Zidovudine

Lamivudine, Stavudine, and Zidovudine

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Nursing Mothers

Pediatric Use

Geriatric Use

Effect of Gender

ADVERSE REACTIONS

Darvocet-N 100

Commonly used brand name(s)

Uses For Darvocet-N 100

Before Using Darvocet-N 100

Allergies

Pediatric

Geriatric

Pregnancy

Breast Feeding

Interactions with Medicines

Interactions with Food/Tobacco/Alcohol

Other Medical Problems

Proper Use of propoxyphene and acetaminophen

Dosing

Missed Dose

Storage

Precautions While Using Darvocet-N 100

Darvocet-N 100 Side Effects

More Darvocet-N 100 resources

Compare Darvocet-N 100 with other medications

Oxcarbazepine

Oxcarbazepine Description

Oxcarbazepine - Clinical Pharmacology

Mechanism of Action

Pharmacodynamics

Pharmacokinetics

Distribution

Metabolism and Excretion

Special Populations

Clinical Studies

Oxcarbazepine Monotherapy Trials

Oxcarbazepine Adjunctive Therapy Trials

Indications and Usage for Oxcarbazepine

Contraindications

Warnings

Hyponatremia

Anaphylactic Reactions and Angioedema

Patients with a Past History of Hypersensitivity Reaction to Carbamazepine

Serious Dermatological Reactions

Suicidal Behavior and Ideation

Withdrawal of AEDs

Precautions

FD&C Yellow No. 5 (Tartrazine)