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PRODUCTS AVAILABLE IN THE UNITED STATES

Please visit our product websites to view complete prescribing information, including a BOXED Warning for Imuran® (AZATHIOPRINE) TABLET, Pexeva® Paroxetine (as mesylate) Tablets, and Ridaura® (Auranofin) Capsules. The product information provided is intended only for residents of the United States.

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SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance.

Click here for Full Prescribing Information and Medication Guide

Click here for Full Prescribing Information and Medication Guide

IMPORTANT SAFETY INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

  • Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), have been shown to increase the risk of suicidal thoughts and behavior in pediatric and young adult patients when used to treat major depressive disorder and other psychiatric disorders. Because BRISDELLE is an SSRI, monitor patients closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.


CONTRAINDICATIONS:
  • Concurrent use with monoamine oxidase inhibitors (MAOIs)
    - or use within 14 days of MAOI use
    - or starting BRISDELLE in a patient who is being treated with linezolid
    - or intravenous methylene blue
    Because of an increased risk of serotonin syndrome.
  • Concomitant use with thioridazine or pimozide due to their increased plasma concentrations and because of the potential of QTc prolongation.
  • Hypersensitivity to any ingredient in BRISDELLE.
  • Pregnancy because BRISDELLE may cause fetal harm.

WARNINGS AND PRECAUTIONS:
  • Suicidality: All patients being treated with BRISDELLE should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of treatment.
  • Serotonin Syndrome: Serotonin syndrome, which is potentially life-threatening, has been reported with concomitant use of serotonergic drugs, and with drugs that impair metabolism of serotonin (in particular, MAOIs). Monitor patients for the emergence of serotonin syndrome. Discontinue BRISDELLE and any concomitant serotonergic agents and initiate supportive treatment.
  • Tamoxifen: Efficacy of tamoxifen may be reduced when administered concomitantly with BRISDELLE.
  • Abnormal Bleeding: SSRIs, including BRISDELLE, may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of BRISDELLE and non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation.
  • Angle Closure Glaucoma: Angle-closure glaucoma has occurred in patients treated with antidepressants with untreated anatomically narrow angles
  • Hyponatremia: may occur as a result of treatment with SSRIs, including BRISDELLE. Elderly patients may be at greater risk and in many cases it can occur in association with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Consider discontinuation of BRISDELLE in patients with symptomatic hyponatremia and institute appropriate medical intervention.
  • Bone fracture: Epidemiological studies have reported an association between SSRI treatment and fractures.
  • Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/ hypomania.
  • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.
  • Akathisia: Can occur, most likely in the first few weeks of treatment. Discontinue treatment with BRISDELLE if akathisia occurs.
  • Cognitive and Motor Impairment: May cause impairment; patients should not operate machinery or motor vehicles until certain that BRISDELLE does not affect them adversely.

ADVERSE REACTIONS:

The most common adverse reactions (≥ 2%) reported in clinical trials were: headache, fatigue, and nausea and vomiting. Of these, nausea occurred primarily within the first 4 weeks of treatment and fatigue occurred primarily within the first week of treatment, and decreased in frequency with continued therapy.

To report SUSPECTED ADVERSE REACTIONS, contact Sebela Pharmaceuticals Inc. at 888-271-4621 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS:

Paroxetine is a strong CYP2D6 inhibitor. Co-administration of BRISDELLE can alter concentrations of other drugs that are metabolized by CYP2D6. Use caution if coadministering BRISDELLE with other drugs that are metabolized by CYP2D6.


INDICATION

BRISDELLE® (paroxetine) is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause.

BRISDELLE is not indicated for the treatment of any psychiatric condition. BRISDELLE contains a lower dose of paroxetine than that used for psychiatric conditions. The safety and efficacy of this lower dose of paroxetine in BRISDELLE have not been established for any psychiatric condition. Patients who require paroxetine for treatment of a psychiatric condition should discontinue BRISDELLE and initiate a paroxetine-containing medication that is indicated for such use.

These are not all the possible side effects of BRISDELLE. Please read the full Prescribing Information including Boxed WARNING and patient Medication Guide.

BRISDELLE® is a registered trademark of Sebela Pharmaceuticals Inc.

Please read the full Prescribing Information including Boxed WARNING and patient Medication Guide.
Motofen

Motofen is now available in pharmacies nationwide.

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Important Safety Information

INDICATIONS AND USAGE
Motofen® (difenoxin and atropine sulfate tablets) is indicated as adjunctive therapy in the management of acute nonspecific diarrhea and acute exacerbations of chronic functional diarrhea.

CONTRAINDICATIONS
Motofen® is contraindicated in patients with diarrhea associated with organisms that penetrate the intestinal mucosa (toxigenic E. coli, Salmonella species, Shigella) and pseudomembranous colitis associated with broad spectrum antibiotics.

Motofen® is also contraindicated in children under 2 years of age, in patients with known hypersensitivity to difenoxin, atropine, or any of the inactive ingredients, and in patients who are jaundiced.

WARNINGS
Motofen® is not an innocuous drug and dosage recommendations should be strictly adhered to. Accidental overdose may result in severe respiratory depression and coma, possibly leading to permanent brain damage or death.

The use of Motofen® does not preclude the administration of appropriate fluid and electrolyte therapy. Dehydration, particularly in children, may further influence the variability of response to Motofen® and may predispose to delayed difenoxin intoxication. Drug-induced inhibition of peristalsis may result in fluid retention in the colon, and this may further aggravate dehydration and electrolyte imbalance.

Use with caution in patients with ulcerative colitis or liver or kidney disease.

Motofen® may produce drowsiness or dizziness. Use caution when engaging in activities requiring mental alertness, such as driving or operating dangerous machinery.

Keep out of reach of children.

Please click here for full Prescribing Information

Please click here for full Prescribing Information

IMPORTANT SAFETY INFORMATION

Topical corticosteroids are indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. Use may produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression. May cause local adverse reactions including burning, itching, irritation, and dryness.

Pregnancy: Teratogenic Effects: Pregnancy Category C

CLICK HERE FOR FULL PRESCRIBING INFORMATION ABOUT ANALPRAM HC® CREAM 2.5%.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

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PRESCRIBING INFORMATION ABOUT ANALPRAM HC® CREAM 2.5%.

NuLYTELY® and GoLYTELY® are indicated for bowel cleansing prior to colonoscopy. Use is contraindicated in patients with gastrointestinal obstruction, gastric retention, bowel perforation, toxic colitis, toxic megacolon or ileus and patients known to be hypersensitive to any of the components. Use with caution in patients with severe ulcerative colitis. Nausea, abdominal fullness and bloating are the most common adverse reactions. Abdominal cramps, vomiting and anal irritation occur less frequently. Isolated cases of urticaria, rhinorrhea, dermatitis, and (rarely) anaphylactic reaction have been reported which may represent allergic reactions.

Refer to full Prescribing Information for additional information.

Click here for NuLYTELY full Prescribing Information.

Click here for GoLYTELY full Prescribing Information.

NuLYTELY® and GoLYTELY® are indicated for bowel cleansing prior to colonoscopy. Use is contraindicated in patients with gastrointestinal obstruction, gastric retention, bowel perforation, toxic colitis, toxic megacolon or ileus and patients known to be hypersensitive to any of the components. Use with caution in patients with severe ulcerative colitis. Nausea, abdominal fullness and bloating are the most common adverse reactions. Abdominal cramps, vomiting and anal irritation occur less frequently. Isolated cases of urticaria, rhinorrhea, dermatitis, and (rarely) anaphylactic reaction have been reported which may represent allergic reactions.

Refer to full Prescribing Information for additional information.

Click here for NuLYTELY full Prescribing Information.

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INDICATIONS AND USAGE: NAFTIN (Naftifine HCl) GEL 2% is an allylamine antifungal indicated for the treatment of interdigital tinea pedis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum in patients 12 years of age and older.

IMPORTANT SAFETY INFORMATION

ADVERSE REACTIONS: In clinical trials with NAFTIN GEL 2%, the most common adverse reactions (2%) were application site reactions.

WARNINGS AND PRECAUTIONS: If redness or irritation develops with the use of NAFTIN GEL 2%, treatment should be discontinued.

Please click here for full Prescribing Information about NAFTIN GEL 2%.

Please click here for full Prescribing Information about NAFTIN GEL 2%.

INDICATIONS AND USAGE

LOTRONEX is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and not responded adequately to conventional therapy. Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. Because of infrequent but serious gastrointestinal adverse reactions associated with LOTRONEX, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable. Clinical studies have not been performed to adequately confirm the benefits of LOTRONEX in men.

IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS GASTROINTESTINAL ADVERSE REACTIONS

Infrequent but serious gastrointestinal adverse reactions have been reported with the use of LOTRONEX. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death.

  • LOTRONEX is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy.
  • LOTRONEX should be discontinued immediately in patients who develop constipation or symptoms of ischemic colitis. Patients should immediately report constipation or symptoms of ischemic colitis to their prescriber. LOTRONEX should not be resumed in patients who develop ischemic colitis. Patients who have constipation should immediately contact their prescriber if the constipation does not resolve after LOTRONEX is discontinued. Patients with resolved constipation should resume LOTRONEX only on the advice of their treating prescriber.

CONTRAINDICATIONS
  • Do not initiate in patients with constipation
  • History of chronic or severe constipation or sequelae from constipation; intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions; ischemic colitis; impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; Crohn’s disease or ulcerative colitis; diverticulitis; severe hepatic impairment
  • Concomitant use of fluvoxamine

WARNINGS AND PRECAUTIONS
  • Serious Complications of Constipation: May occur in some patients without warning. Include obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia and in rare cases perforation and death have been reported. Risk is increased in patients who are elderly, debilitated, or taking medications that decrease bowel motility. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either LOTRONEX or placebo.
  • Discontinue LOTRONEX immediately if constipation occurs.
  • Ischemic colitis: May occur in some patients without warning. Promptly evaluate patients with signs of ischemic colitis (e.g., rectal bleeding, bloody diarrhea, new or worsening abdominal pain). In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving LOTRONEX was 0.2% (2 per 1,000 patients, 95% confidence interval 1 to 3) through 3 months and was 0.3% (3 per 1,000 patients, 95% confidence interval 1 to 4) through 6 months.
  • Discontinue LOTRONEX immediately if signs of ischemic colitis occur, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain.

ADVERSE REACTIONS
Most common adverse reactions (incidence >2% and >placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea, and gastrointestinal discomfort and pain.

Please see the complete prescribing information for LOTRONEX, including Boxed Warning and Medication Guide.
Please see the complete prescribing information for LOTRONEX, including Boxed Warning and Medication Guide.

IMPORTANT SAFETY INFORMATION Pramosone® Lotion 2.5% (Hydrocortisone Acetate 2.5% and Pramoxine HCl 1%) is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. Use may produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression. May cause local adverse reactions including burning, itching, irritation and dryness.

PLEASE SEE FULL PRESCRIBING INFORMATION HERE

PLEASE SEE FULL PRESCRIBING INFORMATION HERE
Imuran

Full Prescribing Information

See new NDC number below.

WARNING - MALIGNANCY
Chronic immunosuppression with IMURAN, a purine antimetabolite increases risk of malignancy in humans. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. Physicians should inform patients of the risk of malignancy with IMURAN. See WARNINGS.

DESCRIPTION:

   IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid.

   Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of azathioprine is:

   It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound.

   Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide.

CLINICAL PHARMACOLOGY:

   Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE.

   Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites (See Metabolism Scheme in Figure 1). The cytotoxicity of azathgopfline is due, in part, to the incorporation of 6-TGN into DNA.

   6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorpism.1, 2, 3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN.4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN toxicity.2, 3, 7, 8, 9 Accurate phenolyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See WARNINGS, PRECAUTIONS: Drug Interactions, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections.

Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA.

GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: lnosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU Thiouric acid; XO: Xanthine oxidase (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.)

   Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) in form 6-thiouric acid.

   The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function.

   Homograft Survival: The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses.

   Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal.

   Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine.

   The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued.

INDICATIONS AND USAGE:

   IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.

   Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of IMURAN on these variables has not been tested in controlled trials.

   Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended.

CONTRAINDICATIONS:

   IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with IMURAN.

WARNINGS:

Malignancy

   Patients receiving immunosuppressants, including IMURAN, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with IMURAN. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant

   Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including IMURAN. Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.

Rheumatoid Arthritis

   Information is available on the risk of malignancy with the use of IMURAN in rheumatoid arthritis (see ADVERSE REACTIONS). It has not been possible to define the precise risk of malignancy due to IMURAN. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received IMURAN.

Inflammatory Bowel Disease

   Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with IMURAN. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn‘s disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with IMURAN as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis. The safety and efficacy of IMURAN for the treatment of Crohn's disease and ulcerative colitis have not been established.

Cytopenias

   Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with IMURAN. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing IMURAN toxicity.2-9 (See PRECAUTIONS: Laboratory Tests). Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing relection. It is suggested that patients on IMURAN have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count.

Serious infections

   Patients receiving immunosuppressants, including Imuran, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal, outcomes.

Progressive Multifocal Leukoencephalopathy

   Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Imuran. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft.

Effect on Sperm in Animals

   IMURAN has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose;10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg.11

Pregnancy: Pregnancy Category D. IMURAN can cause fetal harm when administered to a pregnant woman. IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.12

   IMURAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies.11

   Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. In a detailed case report,13 documented lymphopenia, diminished lgG and lgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily.14 There have been two published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy.15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy.

   Benefit versus risk must be weighed carefully before use of IMURAN in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.

PRECAUTIONS:

   General: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with IMURAN and are reversible upon discontinuation of the drug. The reaction can recur within hours after re-challenge with a single dose of IMURAN.

   Information for Patients: Patients being started on IMURAN should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving IMURAN and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when IMURAN is being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of IMURAN during pregnancy and during the nursing period. The increased risk of malignancy following therapy with IMURAN should be explained to the patient.

   Laboratory Tests: Complete Blood Count (CBC) Monitoring: Patients on IMURAN should haye complete blood counts. including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary.

   TPMT Testing: It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT*2, TPMT*3A and TPMT*3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections.

   Drug Interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections.

   Use with Aminosalicylates: There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution.

   Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

   Use with Angintensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and seyere leukopenia.

   Use with Warfarin: IMURAN may inhibit the anticoagulant effect of warfarin.

   Use with ribavirin: The use of ribavirin for hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine- related myelotoxicity. lnosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6- methylthioionosine monophosphate (6-MTITP], which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary.

   Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section.

   Pregnancy: Terategenic Effects: Pregnancy Category D. See WARNINGS section.

   Nursing Mothers: The use of IMURAN in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low leyels, both transplacentally and in breast milk.17,18,19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

   Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established.

ADVERSE REACTIONS:

   The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

*Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of Iymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.

   Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Anemias, including macrocytic anemia and/or bleeding have been reported.

   TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS: Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.6,20

   Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity parrcreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis.21,22,23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno—occlusive disease is clinically suspected, IMURAN should be permanently withdrawn.

   Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma (see Warnings — Malignancy), and Sweet’s Syndrome (acute febrile neutrophilic dermatosis).

OVERDOSAGE:

   The oral LD50s for single doses of IMURAN in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of IMURAN is bound to serum proteins, but approximately 45% is removed during an 8 hour hemodialysis.24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg IMURAN. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.

DOSAGE AND ADMINISTRATION:

   TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD DOUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from IMURAN if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). IMURAN should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction.

   Renal Homotransplantation: The dose of IMURAN required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of IMURAN should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.

   Rheumatoid Arthritis: IMURAN is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. IMURAN may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.

   Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible.

   Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

   Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

   HOW SUPPLIED: 50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “IMURAN” and “50” on each tablet; bottle of 100 (NDC 54766-590-10).

   Store at 20-25 °C (USP Controlled Room Temperature) (68° to 77°F) in a dry place and protect from light.

REFERENCES:

1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992; 43:329-339.

2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001; 29:601-605.

3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus — implications for clinical pharmaeogenomics. Pharmacogenomics. 2002; 3:89-98.

4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine — an enzyme deficiency caused by a common genetic polymorphism: a review. JR Soc Med. 1992; 85:752-756.

5.. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:1858-1866.

6. Data on file, Sebela Ireland Ltd.

7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basisfor azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614.

8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998; 129:716-718.

9. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology. 2004; 43:13-18.

10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99.

11. Data on file. Sebela Ireland Ltd.

12.Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes.

13. Cote' CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974; 85:324-328.

14. DeWitte DB, Buick MK, Cyran SE, at al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr 1984; 105:625-628.

15. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol. 1981; 58:247-250.

16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 1970; 211:1854-1855.

17. Data on file, Sebeia Ireland Ltd.

18. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106.

19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982; 14: 605-609.

20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine- induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436.

21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic veno- occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655.

22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology 1986; 90:446-454.

23. Weitz H, Gokel JM, Loeshke K, et al. Veno— occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982: 385:245-258.

24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302.

25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621.

26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590-1592.

27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428.

29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263.

30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049.

31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm. 1996; 43:1193-1204.


IMURAN and ZYLOPRIM are registered trademarks of Sebela International Ltd.


Distributed by: Sebela Pharmaceuticals Inc.
645 Hembree Parkway, Suite I
Roswell, Georgia 30076
www.sebelapharma.com

Toll Free 1-844-732-3521

© 2016 Sebela Pharmaceuticals Inc. All rights reserved.


Revised September 2016                                    PI 59010 0916

Indications for PEXEVA

PEXEVA (paroxetine mesylate) is indicated for the treatment of major depressive disorder (MDD), obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD).

IMPORTANT SAFETY INFORMATION

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of paroxetine mesylate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PEXEVA (paroxetine mesylate) is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)


Contraindications:

Concomitant use of PEXEVA in patients taking monoamine oxidase inhibitors (MAOIs) (or within 14 days of use of MAOIs), thioridazine, or pimozide is contraindicated and can become life threatening. PEXEVA is also contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in PEXEVA tablets.

Warnings and Precautions:

Clinical Worsening and Suicide Risk: All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

Families and caregivers of patients being treated with PEXEVA should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

PEXEVA is not approved for use in bipolar depression. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine the risk of them having bipolar disorder, since PEXEVA may activate mania or hypomania.

Potential for Interaction with Monoamine Oxidase Inhibitors:

In patients receiving SSRIs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling a potentially life-threatening Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS). Paroxetine should not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI.

Potentially life-threatening Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions have been reported with SNRIs and SSRIs alone, including PEXEVA, but particularly with concomitant use of serotonergic drugs, including triptans, with drugs that impair the metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. If concomitant use with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Concomitant use of PEXEVA with serotonin precursors (such as tryptophan) is not recommended.

Thioridazine with PEXEVA is contraindicated because elevated blood levels of thioridazine can prolong QTc interval and contribute to arrhythmias and sudden death.

Usage in Pregnancy: Teratogenic Effect:

Infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations; ventricular septal defects (VSDs), atrial septal defects (ASDs), and right ventricular outflow tract obstructions.

Neonates exposed to PEXEVA late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying have been known to occur. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).

For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options.

Discontinuation of Treatment with PEXEVA:

Patients should be monitored for symptoms when discontinuing PEXEVA. Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania have been seen to occur. A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible.

Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality may be reduced when co-prescribed with paroxetine as a result of paroxetine's irreversible inhibition of CYP2D6. However other studies have failed to show such a risk. When Tamoxifen is used for the treatment or prevention of breast cancer, alternative antidepressants with little or no CYP2D6 inhibition should be considered.

Akathisia, hyponatremia, abnormal bleeding have been known to occur. Discontinuation of PEXEVA should be considered in patients with symptomatic hyponatremia. Patients should be cautioned about the concomitant use of PEXEVA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Patients should be advised that taking Pexeva can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

As with all antidepressants, PEXEVA should be used cautiously in patients with a history or family history of mania or hypomania, or with a history of seizure disorder.

Adverse Reactions

The most common side effects (incidence of 5% or greater and incidence for paroxetine at least twice that of placebo) that have been reported with PEXEVA include nausea, dry mouth, constipation, decreased appetite, infection, drowsiness, tremor, sweating, muscle weakness, trouble sleeping, abnormal ejaculation, impotence, and other male genital disorders and female genital disorders.

Indication

Ridaura® (auranofin) is indicated in the management of adults with active classical or definite rheumatoid arthritis (ARA criteria) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of full doses of one or more nonsteroidal anti-inflammatory drugs. 1Ridaura® should be added to a comprehensive baseline program, including nondrug therapies. 1

RIDAURA® (auranofin) contains gold and, like other gold-containing drugs, can cause gold toxicity, signs of which include: fall in hemoglobin, leukopenia below 4,000 WBC/cu mm, granulocytes below 1,500/cu mm, decrease in platelets below 150,000/cu mm, proteinuria, hematuria, pruritus, rash, stomatitis or persistent diarrhea. Therefore, the results of recommended laboratory work (See PRECAUTIONS) should be reviewed before writing each RIDAURA prescription. Like other gold preparations, RIDAURA is only indicated for use in selected patients with active rheumatoid arthritis. Physicians planning to use RIDAURA should be experienced with chrysotherapy and should thoroughly familiarize themselves with the toxicity and benefits of RIDAURA.

In addition, the following precautions should be routinely employed:
1. The possibility of adverse reactions should be explained to patients before starting therapy.
2. Patients should be advised to report promptly any symptoms suggesting toxicity.
(See PRECAUTIONS—Information for Patients.)


Description

Ridaura® contains 29% gold.1 Like other gold compounds, Ridaura® is classified as a disease-modifying antirheumatic drug (DMARD). The mechanism of action of Ridaura® is not understood.

Ridaura® Therapeutic Effect1

The greatest potential benefit of treatment with Ridaura® occurs in patients with active synovitis, particularly in its early stage. Unlike anti-inflammatory drugs, Ridaura® does not produce an immediate response.

  • Therapeutic effect may be achieved after three to four months of treatment.
  • Six months of treatment may be necessary for some patients.

Flexible Dosing1 Ridaura® can be given as a 3 mg dose twice daily or a 6 mg dose once daily. The dose may be increased to 9 mg daily (three doses of 3 mg each) if an adequate response is not achieved after six months. If response remains inadequate after a three-month trial of 9 mg daily, Ridaura® therapy should be discontinued

Important Safety Information1 Contraindications

Ridaura® is contraindicated in patients with a history of any of the following gold-induced disorders: anaphylactic reactions, necrotizing enterocolitis, pulmonary fibrosis, exfoliative dermatitis, bone marrow aplasia or other severe hematologic disorders.

Potential Benefits vs Risks

The potential benefits of using Ridaura® in patients with progressive renal disease, significant hepatocellular disease, inflammatory bowel disease, skin rash or history of bone marrow depression should be weighed against 1) the potential risks of gold toxicity on organ systems previously compromised or with decreased reserve, and 2) the difficulty in quickly detecting and correctly attributing the toxic effect.

Use With Other Agents

The safety of concomitant use of Ridaura® with injectable gold, hydroxychloroquine, penicillamine, immunosuppressive agents or high doses of corticosteroids has not been established.

Recommended Monitoring and Potential Adverse Events

Blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.

A precipitous decline in platelets or a platelet count less than 100,000/cu mm or signs and symptoms suggestive of thrombocytopenia indicates a need to immediately suspend Ridaura® and other therapies with the potential to cause thrombocytopenia until the thrombocytopenia resolves and further studies show it was not due to gold therapy.

It is important to perform urinalysis regularly and to discontinue treatment promptly if proteinuria or hematuria develops.

The most common reaction to Ridaura® is diarrhea/loose stools reported in approximately 50% of patients. Ulcerative colitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.

Use in Specific Populations

Use of Ridaura® by pregnant women is not recommended. Women of childbearing potential should be warned of the potential risks of RIDAURA therapy during pregnancy. Nursing during Ridaura® therapy is not recommended.

Ridaura® is not recommended for use in pediatric patients because its safety and effectiveness have not been established in this population.

1. Ridaura® (auranofin) Capsules [prescribing information]. Roswell, GA: Sebela Pharmaceuticals Inc; 2017.

The NDC # for Imuran changed to 54766-590-10 effective 1/1/18. Please call 678-736-5206 if you have any challenges getting Imuran at your retail pharmacy.

The NDC #’s for Pexeva changed in November 2017. Please call 678-736-5206 if you have challenges getting Pexeva at your retail pharmacy.

  • Pexeva 10mg = 54766-201-01
  • Pexeva 20mg = 54766-202-01
  • Pexeva 30mg = 54766-203-01
  • Pexeva 40mg = 54766-204-01

The NDC # for Ridaura changed to 54766-093-06 in March 2017. Please contact Hikma Customer Service at 1-800-631-2174 if you have challenges getting Ridaura at your retail pharmacy.