Overview of drugs approved in 2011 dr.devang


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Complilation of FDA approved drugs in 2011,
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  • In 2011 the FDA storylines were innovation, jobs, progressive approval, venture capital drying up, and FDA reform12 of the 30 NMEs were the first drugs approved in their therapeutic classtranslational research typically refers to the translation of non-human research finding, from the laboratory and from animal studies, into therapies for patients. This is often called "bench to bedside"CDER: centre for drug evaluation and research
  • First-in-Class, meaning drugs which, for example, use a new and unique mechanism of action for treating a medical condition. to treat rare or “orphan” diseases that affect 200,000 or fewer Americans. This is significant because patients with rare diseases often have few or no drug treatment options.Examples of rare diseases that now have new effective treatment options include myelofibrosis (Jakafi), hereditary angioedema (Firazyr), and Lennox-Gastaut syndrome (Onfi) Fifteen of the 30 NMEs were designated Priority Review (50%), in which CDER determines the drug to potentially provide a significant advance in medical care and sets a target to review the drug within six months instead of the standard 10 months .Fourteen of the 30 NMEs approved in 2011 (47%) were designated Fast Track approvals, meaning drugs that can treat unmet medical needs; this is the highest number of Fast Track approvals since the program began in 1998. Fast Track speeds new drug reviews; for instance, by increasing the level of communication FDA allocates to developers and by enabling developers to use a “rolling review” process such that CDER can review portions of an application ahead of the submission of the full application FDA’s Accelerated Approval program, which allows early approval of a drug for serious or life-threatening illness that offers a benefit over current treatments. This approval is based on a “surrogate endpoint” (e.g., a laboratory measure) or other clinical measure that FDA considers reasonably likely to predict clinical benefit. After this approval, the drug must undergo additional testing to confirm that benefit-this speeds the availability of the drug.CDER approved most drugs (19 of 30) on the “first cycle” of review (63%), meaning without requests for additional information that would delay approval and lead to another cycle of review.
  • Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.C-AMP relaxes bronchial smoth muscles.Acute bronchospasm: Do not use for the relief of acute bronchospasm
  • strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. Use with inhibitors of CYP3A4 or dual inhibitors of CYP3A4 and CYP1A2 (e.g, erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) will increase roflumilast systemic exposure and may result in increased adverse reactionsTrial 5 randomized a total of 1525 patients (765 on DALIRESP) and Trial 6 randomized a total of 1571 patients (772 on DALIRESP). In 498 both trials, DALIRESP 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo.While DALIRESP is not a bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of DALIRESP on lung function as determined by the difference in FEV1 between DALIRESP and placebo-treated patients (pre-bronchodilator FEV1 measured prior to 515 study drug administration in three of the trials and post-bronchodilator FEV1 measured 30 minutes after administration of 4 puffs of albuterol/salbutamol in one trial) as a co-primary endpoint. In each of these trials DALIRESP 500 mcg once daily demonstrated a statistically significant improvement in FEV1 which averaged approximately 50 mL across the four trials. Table 3 shows FEV1 results from Trials 5 and 6 which had demonstrated a significant reduction in COPD exacerbations
  • iyaroxaban, a factor Xa inhibitor, is the actiye ingredient an orally bio ayailable factor Xa inhibitor that selectively blocks' the active site of , factor Xa and does not require a cofactor (such as Anti-thrombin III) for actiyity. Activation of factor X to factor Xa (FXa) Yia the intrnsic and extrinsic pathways plays a central role in the cascade of blood coagulationDose-dependent inhibition cofactor Xaactiyity was observed in humans and the Neoplastin~ prothrembin--time-EPcT),-aetivated--partial-thremÐeplastin--time--EaP-T+)-and-HepTest~are prolonged dose-dependently. Anti-factor Xa activity is also infiuenced by rivaroxaban.There are no data on the usë of the International Normalized Ratio (INR).
  • The two · ràndomized,double-blind, clinical, studies (RECORD '1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6to 8 hours after wound closure versus enoxaparin 40 mg once daily stared 12 hours preoperatively.VTE: venous thromboembolism
  • therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.
  • The efficacy of POTIGA as adjunctive therapy in partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies in 1,239 adult patients. The primary endpoint consisted of the percent change in seizure frequency from baseline in the double-blind treatment phase.not adequately controlled with 1 to 3 concomitant AEDs, with or without concomitant vagus nerve stimulation. More than 75% of patients were taking 2 or more concomitant AEDs.shows the median percent reduction in 28-day seizure frequency (baseline to double-blind phase) as compared with placebo across all 3 studies. A statistically significant effect was observed with POTIGA at doses of 600 mg/day (Study 1), at 900 mg/day (Studies 1 and 3), and at 1,200 mg/day (Studies 2 and 3).
  • The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine)
  • A major depressive episode (DSM-IV-TR) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attemptVilazodone binds with high affinity to the serotonin reuptake site (Ki= 0.1 nM), but not to the norepinephrine (Ki=56 nM) or dopamine (Ki=37 nM) reuptake sites. Vilazodone potently and selectively inhibits reuptake of serotonin concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Allow at least 14 days after stopping VIIBRYD before starting an MAOI
  • Symptoms of serotonin syndrome were noted in 0.1% of patients treated with VIIBRYD. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.The efficacy of VIIBRYD as a treatment for major depressive disorder was established in two 8-week, multicenter, randomized, double-blind, placebo-controlled studies in adult (18-70 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. In these studies, patients were titrated over 2 weeks to a dose of 40 mg of VIIBRYD with food (n=436) or placebo (n = 433) once daily. VIIBRYD was superior to placebo in the improvement of depressive symptoms as measured by the mean change from baseline to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score
  • belimumab) is a human IgG 1 À monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). BENL YST A is a BLyS-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. BENL YSTA does not bind B cells directly, but by binding BLyS, BENLYSTA inhibits the survival of B cells, including auto reactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells BENL YST A significantly 339 reduced circulating CD19+, CD20+, naïve, and activated B cells, plasmacytoid cells, and the 340 SLE B-cell subset at Week 52. Reductions in naïve and the SLE B-cell subset were observed as early as Week 8 and were sustained to Week 52. Memory cells increased initially and slowly.BENL YSTA led to reductions in IgG and anti-dsDNA, Reconstitute, dilute only in 0.9%NaCl and administer as an intravenous infusion only, over a period of 1 hour Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions
  • >deaths than placebo: Etiologies included infection, cardiovascular disease and suicide.Live vaccines should be avoidedOther biologic therapies should be avoided
  • indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS.a CD30-directed antibody-drug conjugate (ADC) consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10.Brentuximabvedotin is an ADC. The antibody is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule disrupting agent. MMAE is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of ADCETRIS is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells.ADCETRIS (brentuximabvedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidatesSystemic Anaplastic Large Cell Lymphoma
  • The efficacy of ADCETRIS in patients with HL who relapsed after autologous stem cell transplant was evaluated in one open-label, single-arm, multicenter trial. One hundred two patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks. An independent review facility performed efficacy evaluations which included overall response rate (ORR = complete remission [CR] + partial remission [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified) Patients had received a median of 5 prior therapies including autologous stem cell transplant.
  • MOA: CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.a randomized (3:1:1), double-blind, double-dummy study (Study 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 alone
  • included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine.Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.The major efficacy outcome measure was overall survival (OS) in the YERVOY+gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY+gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the study arms, and duration of response.
  • ZELBORAF is not recommended for use in patients with wild-type BRAF melanomaVemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threoninekinase, including BRAFV600E. Vemurafenib also inhibits other kinasesin vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation.Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAFV600E BRAF gene: form protein B-Raf which transfers chemicals from outside to the nucleus of cell.
  • Vandetanib treatment should be continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs.vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinasephosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinasephosphorylation in endothelial cells. In vivo vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer
  • CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) and St. John’s Wort.
  • A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) versus Placebo (n=100 The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared to placebo. Other endpoints included evaluation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator’s assessment, patients were discontinued from blinded study treatment and given the option to receive open-label vandetanib. Nineteen percent (44/231) of the patients initially randomized to vandetanib opted to receive open-label vandetanib after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label vandetanib after disease progression
  • Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteurd’OrigineNantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signalling which can contribute to increased cell proliferation and survival in tumours expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK and c-Met phosphorylation in cell-based assays using tumour cell lines and demonstrated antitumor activity in mice bearing tumorxenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met
  • Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials The use of single-agent XALKORI in the treatment of locally advanced or metastatic ALK-positive NSCLC was investigated in 2 multi-center, single-arm studies (Studies A and B). Patients enrolled into these studies had received prior systemic therapy, with the exception of 15 patients in Study B who had no prior systemic treatment. The primary efficacy endpoint in both studies was Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST)
  • a CYP17 inhibitor indicated for use in combination with prednisolone for the treatment metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxelan androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.
  • Hypertension, hypokalemia (7.2%), and fluid retention due to mineralocorticoid excess Adrenocortical insufficiency
  • A total of 1195 patients were randomized 2:1 to receive either ZYTIGA orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient’s baseline.The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival in patients treated with ZYTIGA compared to patients in the placebo arm (Table 3 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed
  • Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6) Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF patients. Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy subjects and myelofibrosis patients
  • hematologic adverse reactions (incidence > 20%) are thrombocytopenia and anemia. The most common non-hematologic adverse reactions (incidence >10%) are bruising, dizziness and headache.Study 1 was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The median hemoglobin count was 10.5 g/dL and the median platelet count was 251 X 109/L.Patients were dosed with Jakafi or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT
  • ERWINAZE (asparaginaseErwiniachrysanthemi) is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase.ERWINAZE (asparaginaseErwiniachrysanthemi) contains an asparaginase specific enzyme derived from Erwiniachrysanthemi. L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The activity of ERWINAZE is expressed in terms of International Units. AsparaginaseErwiniachrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of ERWINAZE is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparaginesynthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine for their protein metabolism and survival To substitute for a dose of peg aspargase: The recommended dose is 25,000 International Units/m2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargaseTo substitute for a dose of native E. coli asparaginase: The recommended dose is 25,000 International Units/m2 administered intramuscularly for each scheduled dose of native E. coli asparaginase.
  • Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was determination of the proportion of patients who achieved a serum trough asparaginase level greater than or equal to 0.1 International Units/ mL. Serum trough asparaginase activity ≥ 0.1 International Units/ mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 μM) and to serum levels that predict clinical efficacy. Patients received ERWINAZE 25,000 International Units/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in course 1. The median age was 10 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 5% were Hispanic or Latino.
  • Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro
  • Boceprevir is an inhibitor of the HCV NS3/4A protease that is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells. In a biochemical assay, boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression of replicon RNA in cell culture showed additivity of effect without evidence of antagonism
  • RR= relapse rateSVR= sustained viral response
  • Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.
  • RGT= 4 week lead-in then 32 weeks of BOC. Those with RNA negative at wk8 stopped at week 36. Those +8 but negative at week 12 continued with PR to 48 weeks. Null responders (<2log by wk 12) excluded from RESPOND-2
  • Increased risk for developing post-transplant Iymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only. Do not use NULOJIX in transplant recipients who are EBV seronegative or with unknown serostatus.(belatacept), a selective T-cell costimulation blocker, is a soluble fusion protein consisting of the modified extracellular domain of CTLA-4 fused to a portion (hinge-CH2-CH3 . domains) of the Fcdomain of a human immunoglobulin Gl antibody. Belatacept is produced by recombinant DNA technology in a mammalian cell expression system belatacept binds CD80 and CD86 more avidly than abataceptBelatacept, a selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-y, interleukin-4, and TNF-cx. Activated T lymphocytes are thepredominant mediators of immunologic rejection.Belatacept-mediated costimulation blockade results in the inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells Use has not been established for the prophylaxis of organ rejection in transplanted organs other than the kidney.
  • Increased susceptibility to infection and the possible development of malignancies may result from immunosuppressantIn clinical trials, greater reductions in mean immunoglobulin (IgG, IgM, and IgA) concentrations were observed from baseline to Month 6 and Month 12 post-transplant in belatacept-treated patients compared to cyclosporine-treated patient.In Study 1, 666 patients were enrolled, randomized, arid transplanted: 226 to the NULOJIX recommended regimen, 219 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 221 to cyc1osporine control regimen.In Study 1, approximately 87% of patients were EBV seropositive prior to transplant By three years, efficacy failure was 25% in both treatment groups and patient and graft survival was 94% (187/202) in NULOJIX-treated patients compared with 88% (162/184) in cyclosporine treated patients (difference=4.6%, 97.3% CI (-2.1, 11.3)).
  • a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI)Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.
  • Based on the pooled data from the TMC278-C209 and TMC278-C215 trials at 48 weeks of treatment, the mean CD4+ cell count increase from baseline was 192 cells/mm3 for EDURANT-treated subjects and 176 cells/mm3 for efavirenz-treated subjectsAt 192 weeks, 63% (59/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 61% (54/89) of subjects in the control group
  • Fidaxomicin acts locally in the gastrointestinal tract on C. difficile. bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases. A specific mutation (Val-ll43-Gly) in the beta subunit of RNA polymerase is associated with reduced susceptibility to fidaxomicin.
  • presence of either C. difficile toxin A or B in the stool within 48 hours of randomization.Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients Similar rates of clinical response at the end of treatment and proven or suspected CDAD during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients infected with a BI isolate
  • a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction)Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily
  • azilsartanmedoxomil), a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis. An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure
  • In patients with an activated renin-angiotensin system, as by volume- or salt-depletion, renin-angiotensin-aldosterone system (RAAS) blockers such as azilsartanmedoxomil can cause excessive hypotension. Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the second and third trimester hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramniosas monotherapy, was smaller, approximately half, in black patients, who tend to have low renin levels. This has been generally true for other angiotensin II antagonists and ACE inhibitors Two 6-week randomized, double blind studies compared the effect on blood pressure of Edarbi at doses of 40 mg and 80 mg, with placebo and with active comparators. Blood pressure reductions compared to placebo based on clinic blood pressure measurements at trough and 24 hour mean blood pressure by ambulatory blood pressure monitoring (ABPM) are shown in Table 1 for both studies. Edarbi, 80 mg, was statistically superior to placebo and active comparators for both clinic and 24 hour mean blood pressure measurementsEdarbi has about its usual blood pressure lowering effect size when added to a calcium channel blocker (amlodipine) or a thiazide-type diuretic (chlorthalidone).
  • Short acting beta2 agonists should be used for controlling acute conditions.Indacaterol is a long-acting beta2-adrenergic agonist. When inhaled, indacaterol acts locally in the lung as a bronchodilator. The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenylcyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle
  • in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported In the clinical trials, health care providers observed during clinic visits that an average of 24% of patients experienced a cough on at least 20% of visits following inhalation of the recommended 75 mcg dose of ARCAPTA NEOHALER compared to 7% of patients receiving placeboThe primary efficacy endpoint was 24-hour post-dose trough FEV1 (defined as the average of two FEV1 measurements taken after 23 hours 10 minutes and 23 hours and 45 minutes after the previous dose) after 12 weeks of treatment in all 6 trials.
  • FIRAZYR (icatibant) is a synthetic decapeptide with five non-proteinogenic amino acidsIcatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/ kallikreinproteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE FIRAZYR caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects.Laryngeal attacks: Following treatment of laryngeal attacks with FIRAZYR, advise patients to seek immediate medical attention
  • Injection site bruising, Injection site hematoma, Injection site burning, Injection site erythema, Injection site hypoesthesia, Injection site irritation, Injection site numbness, Injection site edema, Injection site pain, Injection site pressure sensation, Injection site pruritus, Injection site swelling, Injection site urticaria, and Injection site warmthFIRAZYR is a bradykinin B2 receptor antagonist and thereby has the potential to have a pharmacodynamic interaction with ACE inhibitors where FIRAZYR may attenuate the antihypertensive effect of ACE inhibitors. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either FIRAZYR 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label FIRAZYR 30 mg. The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with FIRAZYR (n=43) compared to placebo (n=45) was 2.0 hours [95% CI 1.5, 3.0] versus 19.8 hours [95% CI 6.1, 26.3], respectively (p<0.001).
  • Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron. Approval is based on a reduction in serum ferritin levels. There are no controlled trials demonstrating a direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival
  • The main criterion for chelation failure was serum ferritin >2,500 mcg/L before treatment with Ferriprox. Ferriprox therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥20% decline in serum ferritin within one year of starting therapy.
  • for intravenous use in diagnostic magnetic resonance imaging (MRI) in adults and children (>2 years) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system.Gadavist is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium-based contrast agents, resulting in a lower volume of administration
  • Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk. (5.1) Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations
  • EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration.Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability. Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptorsEYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, following intravitreal administration of EYLEA, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF
  • The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with EYLEA) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 3 initial monthly doses (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered every 4 weeks (EYLEA 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline
  • FDA declined to approve MannKind inhaled insulin Afrezza® and asked for 2 bridging studies and handling of its new device for marketing in comparison with the device used in clinical trials. The March 15 decision was the third refusal by the FDA to approve inhaled insulin.Both the FDA and EMA have provided feedback after BLA and PLA filing by Abbott for the use of Briakinumab in psoriasis. Both agencies require additional studies for approval. Abbott has withdrawn the regulatory applications and may resubmit at a later date. Abbott is the first company to have its BLA/MAA rejected by both the FDA and EMA in January 2011. This unfortunate distinction goes to the mabBriakinumab for Psoriasis.FDA asked Vivus for analysis of existing data about the birth defects due to obesity drug Qnexa® component topiramate. FDA requested that VIVUS assess the feasibility of analyzing existing healthcare databases to determine the historical incidence of oral cleft in offspring of women treated with topiramate for migraine prophylaxis (100 mg)
  • FDA CRL provided a must do long list for Arena weight loss drug Lorcaserin: a 12 month carcinogen study in female rats, diagnostic criteria for mammary masses and mechanism of action involved in induction of adenocarcinoma in female rats. The mode of action and safety margin for drug induced astrocytoma in male rats. The BLOOM trial showed 6 times higher risk of heart valve damage in the active drug group as compared to a low value in the placebo group. A new risk assessment of heart valve damage in patients was required.The FDA rejected the NDA for Contrave®. A complete response letter was issued to Orexigen for its antiobesity drug Contrave® which was recommended by the FDA expert panel during its meeting on 7 December 2010. The FDA asked for a new clinical study to assess the cardiac safety of the drug  in 60000-100000 patients. Orexigen proposed a trial in 12000-15000 patients. For a small company, running a 100,000 patient trial with uncertain outcome is not feasible.Astra Zeneca has terminated the development of Motavizumab for treatment of RSVand taken a loss of $ 445 million in 2010. This was due to rejection by the FDA expert panel and a Complete Response Letter from the FDA asking for new clinical studies
  • Delcath System NDA to deliver high doses of chemotherapy to the liver to treat metastatic melanoma was rejected by the FDA(refusal to file). FDA asked for inspections of the plants, product/sterilization/safety info and statistical analysis.Salix announced that after discussions with the FDA, a complete response letter is expected from the FDA before the PDUFA due date of 7 March. The drug is currently approved for treatment of E. coli related traveler’s diarrhea.IBS: irritable bowel syndromeRhucin (conestatalfa, Pharming, Santarus) derived from rabbit milk for Hereditary Angioedema (HAE)FDA issued a refusal to file for the incomplete BLA and will issue a CRL. It will delay the approval by a year or more. The drug is approved and marketed as Ruconest in EuropeCladribine  as an oral therapy for relapsing-remitting multiple sclerosis (MS)The FDA concluded that substantial evidence of Cladribine  effectiveness was provided by the CLARITY1 study. However, the FDA has requested the Company provide an improved understanding of safety risks and the overall benefit-risk profile either through additional analyses or by additional studies
  • Overview of drugs approved in 2011 dr.devang

    1. 1. Dr. DevangThursday, August 01, 2013
    2. 2.  FDA reviews each application on its merits and apply best judgment with regard to the data, the science and the regulations  Decrease in submission of “me-too” drugs  Bench to bedside transition time decreased to <1.5 years
    3. 3. 1. Brentuximab vedotin 2. Belimumab 3. Roflumilast 4. Icatibant 5. Ruxolitinib 6. Belatacept 7. Ezogabine 8. Boceprevir 9. Crizotinib 10.Ipilimumab 11.Vemburanfenib 12.Alberaterone First in-class drugs Orphan drug approvals 1. Brentuximab vedotin 2. Vandetanib 3. Erwinia L- asparaginase 4. Deferiprone 5. Icatibant 6. Ruxolitinib 7. Belatacept 8. Clobazam 9. Crizotinib 10.Ipilimumab 11.Vemburanfenib
    4. 4.  Daliresp tablet  Selective phosphodiesterase 4 (PDE4) inhibitors  Indication: To reduce the risk of COPD exacerbations in patients with severe COPD and chronic bronchitis  MOA:As PDE4, a major cyclic AMP metabolizing enzyme is inhibited, accumulation of intracellular cyclicAMP -> bronchial smooth muscle relaxation  Dose: 500 mcg /day orally  t1/2: 30 hours (3 active metabolites)
    5. 5.  ADR: in ≥ 2% diarrhoea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness and decreased appetite.  C.I.: liver impairment Acute bronchospasm Psychiatric disorders  Avoid CYP3A4 inducers and CYP3A4 inhibitors  Evidence: it reduced 15-18 % exacerbations compared to placebo in patients with severe COPD  Also showed 18-41% improvement in FEV1 after 6 months therapy.
    6. 6.  Xarelto tablet  Factor Xa inhibitor  Indication: Prophylaxis of deep vein thrombosis (DVT) in patients undergoing knee or hip replacement  Dose: 10 mg/day orally 12-35 days  Warning: Spinal/epidural hematoma, risk of bleeding
    7. 7.  ADR: bleeding in >5%  Muscle spasms, joint pain, pruritus, agranulocytosis, hypersensitivity  Epidural/ spinal hematoma  Evidence:(RECORD 1 and 2 studies) In patients undergoing elective THR surgery compared Rivaroxaban 10 mg OD starting 6 to 8 hours after wound closure versus enoxaparin 40 mg OD stared 12 hours preoperatively. Showed 71-78 % relative risk reduction and 87-91 % reduction in majorVTE episodes.
    8. 8.  Advantage: • In vitro studies indicate that Rivaroxaban neither inhibits the cytochrome P450 enzymes nor induces them. • In vitro data also indicates a low inhibitory potential for P-gp. • No carcinogenicity or teratogenicity in animal studies
    9. 9.  Potiga tablet  A potassium channel opener ?  Indication: partial-onset seizures  MOA: Enhances potassium currents and stabilizes resting membrane potential and reduce brain excitability  Augmentation of GABA mediated currents?  Dose: start at 100 mgTDS with other anticonvulsant Increase up to 200-400 mgTDS • Dose adjustment in hepatic and renal disease • Increase dose when used with Carbamezapines, phenytoin
    10. 10.  ADR: • Hypotension, Urine retention, dizziness, somnolence, blurred vision, gait disturbance, QT prolongation
    11. 11.  Natroba  Topical suspension 1 %  Indication: topical treatment of head lice infestations  MOA: causes neuronal excitation in insects. After periods of hyper excitation, lice become paralyzed and die.  Repeat treatment if live lice are seen 7 days after first treatment  Not recommended in age less than 6 months; potential for increased systemic absorption
    12. 12.  Adverse events: • Application site erythema seen in 1% • Lesser adverse reactions than Permethrin • Gasping syndrome  Evidence Proportion of subjects free of live lice 14 days after treatment Study 1 `Study 2 Spinosad 1% N=91 Permethrin 1% N=89 Spinosad 1% N=83 Permethrin 1% N=84 77(84.6%) 40 (44.9%) 72 (86.7%) 36 (42.9%)
    13. 13.  Vibryd tablet  Indication: Major depressive disorder (MDD)  MOA: not fully understood -Enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. -Also a partial agonist at 5-HT1A receptors  Dose: 10-40 mg/day  Gradual dose reduction is recommended  Drug interaction: MAO inhibitors
    14. 14.  ADR: diarrhea, nausea, vomiting, and insomnia, palpitation, dry mouth, arthralgia • Decreased libido (>2% ) • Neuroleptic malignant syndrome (NMS) like reactions (0.1%) • Seizures • Abnormal bleeding(when used with NSAIDs) Montgomery-Asberg Depression Rating Scale
    15. 15.  Benlysta (120/400 mg vial)  A human IgG 1A monoclonal antibody specific for human B lymphocyte stimulator protein (BLyS )  Indication: Active autoantibody-positive SLE  MOA: Inhibits BLyS: B cells survival factor - Inhibits B cell differentiation  Dose: 10 mg/kg at 2-week intervals for first 3 doses and at 4-week intervals thereafter  Efficacy has not been evaluated in patients with severe active lupus nephritis nor with IV cyclophosphamide
    16. 16.  ADR: (6%) • Serious infection, Pneumonia, URTI, UTI, cellulitis • Anaphylaxis(0.6%) • Infusion reactions(17%) • Depression, Suicide (4%)  Immunogenicity (4.8%)  Safety in pregnant and nursing mothers?  Studies showed 41-51 % improvement in SRI compared to placebo after 52 weeks of Belimumab(10mg/kg)
    17. 17.  Adcetris injection  A CD30-directed antibody-drug conjugate  Indication: Hodgkin’s lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy • Systemic anaplastic large cell lymphoma after failure of multi-agent chemotherapy  Approval was based on response rate  Dose: 1.8 mg/kg IV infusion over 30 min every 3 weeks • Continue until a maximum of 16 cycles, disease progression or unacceptable toxicity
    18. 18.  ADR: (>20%)Peripheral neuropathy, fatigue, anemia, URTI, diarrhoea, thrombocytopenia, vomiting, infusion reactions and anaphylaxis, tumor lyses pattern, SJ syndrome  Teratogenicity  Immunogenicity The efficacy of Brentuximab in patients with HL who relapsed after autologous stem cell transplant
    19. 19.  Yervoy  A recombinant, human cytotoxicT-lymphocyte antigen 4 (CTLA-4)-blocking monoclonal antibody, an IgG1 kappa immunoglobulin  Indication: Unresectable or metastatic melanoma  MOA:T-cell activation is required for anti tumor response • CTLA-4 is inhibitor ofT-cell activation  Dose: 3 mg/kg IV over 1 hour once in 3 week cycle
    20. 20.  ADR: (>5%) • Fatigue, diarrhoea, pruritus, rash, and colitis T cell activation and proliferation • Immune-mediated hepatitis and enterocolitis, endocrinopathies (0.2%) • Nephritis, pneumonitis, meningitis and hemolytic anemia (<1%) Immunogenicity (6.9%)
    21. 21. Ipilimumab A randomized double blind study showing 5.7% increased response in Ipilimumab+gp100 arm with mean increase in survival rate of 11.5 months.
    22. 22.  Zelboraf 240 mg tablets  A BRAF serine threonine kinase inhibitor  Indication: Unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA- approved test  Dose: 960 mg BD orally
    23. 23.  ADR: (≥ 30%) • Arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea • Cutaneous squamous cell carcinomas (24%) • SJ syndrome, toxic epidermal necrolysis  Evidence: • A study showed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in theVemurafenib arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the Dacarbazine arm. • 2 complete response and 104 partial response
    24. 24.  Vandetanib tablets  A tyrosine kinase inhibitor  Indication: Medullary thyroid cancer: unresectable locally advanced or metastatic  MOA: inhibits endothelial cell migration, proliferation, survival and new blood vessel formation by inhibiting EGFR,VECG receptors by preventing phosphorylation of tyrosine kinase  Dose: 300mg/day orally (t1/2= 19 hours)
    25. 25.  ADR: (>20%) • Diarrhoea, rash, acne, nausea, headache, fatigue and abdominal pain • Decreased calcium, increased ALT, hypoglycemia and hypothyroidism • QT prolongetion(4.3%),Torsades de pointes, ventricular tachycardia and sudden deaths • SJ syndrome, hypertension and hemorrhage(1%)  CYP 3A4 inducers: reduce drug levels  CYP3A4 inhibitors: increaseADRs.
    26. 26. A double-blind, placebo-controlled study in patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg(n=231)Vs Placebo (n=100). (HR=0.35, p<0.0001) Vandetanib
    27. 27.  Xalkori Capsules  A tyrosine kinase inhibitor  Indication: Locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA- approved test.  Dose: 250 mg BD until response continues  indication is based on response rate (no data available demonstrating improvement in patient outcomes or survival)
    28. 28.  ADR: (≥25%) are vision disorder, nausea, diarrhoea, vomiting, edema, constipation • Pneumonitis, QT prolongation, bradycardia • Teratogenicity, carcinogenicity
    29. 29.  Zytiga tablets  A 17 alfa-hydroxylase/C17,20-lyase (CYP17) inhibitor  Indication: metastatic resistant prostate cancer who have received prior chemotherapy containing Docetaxel  99 % protein binding: t1/2: 12+/- 4 hours  AUC increase up to 10 fold with meals  Dose: 1 gm administered orally once daily with Prednisolone 5 mg BD
    30. 30.  ADR: (≥ 5%) • Joint swelling or discomfort, muscle discomfort, hot flush, diarrhoea, UTI, cough, hypertension, arrhythmia, dyspepsia • Hypokalemia (7.2%), fluid retention • Hepatotoxicity (2.3%)  C.I.: in severe hepatic impairment, pregnancy  Avoid CYP2D6 inhibitor
    31. 31.  Jakafi tablets  A kinase (JAK1,2) inhibitor  Indication: Intermediate or high-risk myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis)  Dose: 20 mg BD (maintain acc.To response & thrombocytopenia)
    32. 32.  ADR: Hematologic adverse reactions (> 20%) • Thrombocytopenia and anaemia. • Bruising, dizziness and headache (>10%)
    33. 33.  Erwinaze injection  An asparagine specific enzyme  Indication: as a component of a multi-agent chemotherapy for acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derivedAsparaginase  Dose: 25ooo IU/m2 IM 3 times in week for each dose of Asparaginase
    34. 34.  ADR: Serious hypersensitivity reactions(5%) • Including anaphylaxis • Severe hemorrhagic pancreatitis(4%) • Irreversible glucose intolerance(2%) • Hemorrhage, vomiting, fever (>23%)
    35. 35.  Tradjenta tablet  Inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme  Indication: Type 2 DM  MOA: Increases incretin GLP-1 ->insulinotropic  t1/2: 12 hours  Dose: 5 mg BD  ADR: Nasopharingitis(5%), hypoglycemia(when used with sulfonylurea)
    36. 36.  Victrelis  A hepatitisC virus (HCV) NS3/4 protease inhibitor  Indication: chronic hepatitisC (CHC) genotype 1 infection in combination with peg-interferon alfa and Ribavirin  MOA: Reversibly binds and inhibits HCV protease -> inhibits viral replication  Dose: 800 mg orallyTDS in combination with peg- interferon alfa and Ribavirin
    37. 37. ADR: Teratogenicity, Neutropenia, Fatigue, anemia, nausea, headache Boceprevir- REALIZE-2
    38. 38.  Incivek  A hepatitisC virus (HCV) NS3/4A protease inhibitor  Indication: chronic hepatitisC genotype 1 infection in combination with peg-interferon alfa and Ribavirin  MOA: Reversibly binds and inhibits HCV protease -> inhibits viral replication  Dose: 750 mg orallyTDS
    39. 39.  ADR:Teratogenicity  Neutropenia  Fatigue, anemia, nause a, headache and dysgeusia  C.I.: CYP3Ainducers and inhibitors Telaprevir- REALIZE 21 78
    40. 40.  Nulojix  A selective T.cell co-stimulation (CTLA-4) blocker  Indication: Prophylaxis of organ rejection in adult patients receiving a kidney transplant in combination with basiliximab, mycophenolate mofetil and corticosteroids.  Warning: Post. Transplant lymphoproliferative disorder, other malignancies and serious infections  Use in EBV seropositive patients only  Dose: 10 mg/kg IV over 30 min. infusion prior to implant, after 5 days f/b week 2,4,8 and then 4 weekly
    41. 41.  ADR: (20%) Anaemia, diarrhoea, UTI, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, vomiting, hypo/hyper kalemia, leukopenia  Infection and malignancies
    42. 42.  Edurant tablet  Novel NNRTI specific for HIV-1  Indication: HIV-1 infection  MOA: Non-competitive inhibition of HIV-1 reverse transcriptase  To be used with other ART (but not NNRTI)  Cross resistance with other NNRTIs  Less effective in severe viremia  Dose: 25 mg OD
    43. 43.  ADR: (2%) • Depression, insomnia, headache, rash, diarrhoea  At 48 weeks, Rilpivirine+BR and Efavirenz+BR treament showed CD4+ cell raise of 192 and 176 cells/mm3 respectively.(p<0.001)  At 2 years, 63% (59/93) of subjects who received Rilpivirine achieved HIV RNA <50 copies/ml compared to 51% (46/89) of subjects in the control group
    44. 44.  Dificide  A macrolide antibacterial drug  Indication: Clostridium difficile-associated diarrhoea in adults  It should not be used for systemic infections.  Active metabolite: OP-1118  Not dependent on CYP450 enzymes  High frequency of resistance  Dose: 200 mg orally BD x 10 days  Post antibiotic effect lasts for 6-10 hours
    45. 45.  ADR: Nausea % vomiting (11%), abdominal pain (6%), gastrointestinal haemorrhage (4%), anemia and neutropenia
    46. 46.  Brilinta  A P2Y12 platelet inhibitor  Indication: reduce thrombotic CVS events in patients with acute coronary syndrome  MOA: Inhibits platelet activation by preventing signal transduction  Dose: load with 180 mg f/b 90 mg BD withAspirin (75-100 mg/day)
    47. 47.  ADR: 3% higher than Clopidogrel  Bleeding, dysapnea, headache, cough, diarrhea  C.I. : Intracranial hemorrhage, pathological bleeding, hepatic impairment  Strong CYP3A inhibitors or CYP3A inducers
    48. 48.  Edarbi (prodrug)  A selective angiotensin II receptor antagonist  Indication:Treatment of hypertension  MOA: blocks the vasoconstrictor and aldosterone- secreting effects of angiotensin II  Dose: starting dose of 40 mg/day • Increase up to 80 mg daily
    49. 49.  ADR: Diarrhea (2%). • Sudden hypotension (activated RAS) • Oligohydramnios • Teratogenecity, fetal loss
    50. 50.  Arcapta Neohaler  A long-acting beta2-adrenergic agonist  Indication: maintenance bronchodilator treatment of chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema  NOT indicated to treat acute bronchospasm of COPD/ asthma  Dose: 75 mcg inhaled every day via neohaler
    51. 51.  ADR: (<2 %) • Cough, oropharyngeal pain, nasopharingitis, headache, tachycardia • Prolonged use: URTI, hyperglycemia, muscular pain, peripheral edema Advantage: •No tolerance developed after 12 weeks therapy •33 % reduction in use of rescue Salbutamol in study group
    52. 52.  Firazyr injection (10 mg/ml)  A bradykinin B2 receptor antagonist  Indication: Acute attacks of hereditary angio- edema (HAE) caused by an absence or dysfunction of C1-esterase-inhibitor, thus more bradykinin  Dose: 30 mg injected s.c., repeat after 6 hours if needed
    53. 53.  ADR: Pyrexia, transaminase increase, dizziness, rash  Injection site reactions in 97 %  C.I.: ACE inhibitor use The median time to 50% reduction in symptoms with cutaneous or abdominal attacks treated with Icatibant (n=43) compared to placebo (n=45) was 2.0 hours [95% CI] versus 19.8 hours [95% CI] (p<0.001).
    54. 54.  Ferbiprox tablets  An iron chelator  Indication:Transfusion iron overload due to thalassemia syndromes when current chelation therapy is inadequate.  Approval is based on a reduction in serum ferritin levels.There are no controlled trials demonstrating a direct treatment benefit  Dose: 25-33 mg/kgTDS
    55. 55.  ADR: (≥ 5%) • Nausea, vomiting,abdominal pain, arthralgia , neutropenia and agranulocytosis  In clinical studies, the endpoint of at least 20% reduction in serum ferritin was met in 50% (of 236 subjects) within 1 year
    56. 56.  Gadavist  a gadolinium-based contrast agent  Highly water soluble, extremely hydrophilic compound  Indication: IV use in diagnostic MRI in patients to detect and visualize areas with disrupted blood brain barrier or abnormal vascularity of the central nervous system.  Dose: Gadobutrol concentration is 1 mmol/mL (equivalent to 604.72 mg gadobutrol/mL)  Give IV bolus of 0.1 ml/kgbw (0.1 mmol/kgbw)
    57. 57.  ADR: (4%) headache, nausea, feeling hot • (<0.1%) Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination • Hypersensitivity: anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations  Advantage over other Gadolinium based contrast agents (Gadoteridol): 1. Higher concentration leads to lesser volume of administration 2. Faster elimination (t1/2 <2 hours), so less side effects
    58. 58.  Eylea injection  A recombinantVEGF fusion protein  Indication: Neovascular (wet) age-related macular degeneration (AMD)  MOA:VEGF recepror stimulation: neovascularization increase permeability  Dose: 2 mg (0.05 ml) once monthly • Intravitreal injection only
    59. 59.  ADR: Ocular or periocular infection • Hypersensitivity • Raised IOP, retinal detachment • Conjunctival haemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and IOP
    60. 60.  Afreezza: Inhaled insulin by Mankind • FDA asked for bridging study for inhaler used in trials  Briakinumab for psoriasis by Abbott • FDA & EMA asked for additional safety studies  Qnexa:Topiramate as Obesity pill byVivus • FDA asked for analysis of data for birth defects by topiramate
    61. 61.  Lorcaserin: Obesity pill by Arena • FDA asked for 12 month carcinogen study and risk assessment of adenocarcinoma and heart valve damage in patients  Numax: Motavizumab by Astra Zeneca for RSV • FDA asked for complete revised clinical studies • AZ terminated further research  Liprotamase: Pancreatic enzyme replacement therapy by Lilly for exocrine pancreatic insufficiency associated with CF, chronic pancreatitis and pancreatectomy
    62. 62.  Xifaxan: Rifaximin for IBS by Salix • Approved for E.Coli traveler’s diarrhea  Rhucin: Conestat alfa for Hereditary angioedema • Incomplete safety data • Currently approved in Europe  Cladribine: for MS by Merck • FDA asked to provide benefit-risk & safety profile through additional analysis
    63. 63. To get this slides : http://tinyurl.com/2011drugsdpp OR Mail me at: dr.dp@in.com