Jamie D. Croxtall

Fulvestrant: A Review of its Use in the Management of Hormone Receptor-Positive Metastatic Breast Cancer in Postmenopausal Women

Fulvestrant (Faslodex®) is an intramuscularly administered steroidal estrogen receptor antagonist that is devoid of any known estrogen agonist effects. It is indicated as second-line therapy for the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer who have progressed following prior endocrine therapy. In well designed, randomized clinical trials, regimens of fulvestrant 250 and 500 mg provided effective second-line therapy for postmenopausal women with advanced breast cancer who had progressed following prior endocrine therapy. Moreover, fulvestrant 250 mg monthly (with or without a loading dose) was as effective as aromatase inhibitor therapy. However, fulvestrant is absorbed slowly, and greater steady-state concentrations are achieved more rapidly when using a higher dosage with a loading dose regimen. Consequently, a regimen of fulvestrant 500 mg monthly with a loading dose was significantly more effective than a regimen of 250 mg monthly in postmenopausal women with disease progression. Limited data also indicate a potential role for the fulvestrant 500 mg regimen as first-line therapy. Fulvestrant is generally well tolerated with no additional adverse events noted with the high-dose regimen compared with the 250 mg regimens. Furthermore, the incidence of joint disorders was shown to be significantly lower with fulvestrant 250 mg monthly than with anastrozole. Treatment with fulvestrant is not associated with any clinically significant effects on endometrial thickening, bone-specific turnover markers or sex hormone levels. In conclusion, a monthly regimen of intramuscular fulvestrant 500 mg with a loading dose provides effective and well tolerated second-line therapy for postmenopausal women with advanced breast cancer who have progressed following prior endocrine therapy and is now the approved optimal dose.

Pneumococcal polysaccharide protein D-conjugate vaccine (Synflorix; PHiD-CV).

Abstract▲ The pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix™) contains ten capsular polysaccharide serotypes from the bacterium Streptococcus pneumoniae, eight of which are conjugated to a nonlipidated cell-surface liporotein (protein D) of non-typeable Haemophilus influenzae (NTHi) and two of which are conjugated to either tetanus or diphtheria toxoid.▲ In a three-dose primary vaccination schedule in infants aged <6 months, PHiD-CV elicited high immune responses against all pneumococcal serotypes contained in the vaccine and was non-inferior to an approved 7-valent pneumococcal conjugate vaccine (7vCRM) for eight of the ten serotypes (five of the seven common to both vaccines). Moreover, functional antibodies were elicited against all vaccine serotypes in an opsonophagocytic activity (OPA) assay.▲ A fourth booster dose of PHiD-CV during the second year of life elicited an anamnestic response against all ten pneumococcal serotypes, as determined by both antibody concentrations and OPA titers.▲ There were no clinically relevant changes in the immunogenicity of PHiD-CV when coadministered with meningococcal serogroup C conjugate or pentavalent whole cell pertussis combination vaccines, and polio vaccines using two different primary vaccination schedules.▲ 11Pn-PD, an 11-valent prototype of PHiD-CV, demonstrated protection against episodes of acute otitis media (AOM) caused by S. pneumoniae and NTHi in infants aged <27 months. The first occurrence of an episode of AOM caused by pneumococcal vaccine serotypes was reduced by 52.6% in 11Pn-PD vaccinees compared with recipients of a control vaccine (primary endpoint).▲ The tolerability profile of PHiD-CV was generally similar to that of 7vCRM.

Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients.

Raltegravir (Isentress), an integrase inhibitor, inhibits the insertion of HIV-1 complementary DNA into the host genome. It is indicated in combination with other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple ART agents. It is the first of a new class of ART agents to be approved that, as a result of a different mechanism of action to other ART agents, has good activity against multidrug-resistant HIV-1 strains. In clinical trials in treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of oral raltegravir to an optimized background therapy (OBT) regimen improved virological and immunological responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Raltegravir therapy was generally well tolerated, with a similar incidence of mild to moderate adverse events in the treatment and placebo arms. The introduction of integrase inhibitors extends the options available for managing treatment-experienced patients with multiple-drug-resistant HIV-1 infection. Results to date suggest that the combination of raltegravir and OBT will be a valuable treatment option for this difficult-to-treat patient group.

Meningococcal Quadrivalent (Serogroups A, C, W135 and Y) Tetanus Toxoid Conjugate Vaccine (Nimenrix™)

Nimenrix™ (MenACWY-TT) is a quadrivalent meningococcal conjugate vaccine, comprising the polysaccharide serogroups A, C, W135 and Y, and tetanus toxoid (TT) as carrier protein. It is the first quadrivalent vaccine (administered as a single dose) to be approved in Europe for active immunization of individuals aged ≥12 months against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W135 and Y.Administration of a single dose of Nimenrix™ elicited a strong immune response against all four vaccine serogroups in healthy toddlers aged 12’23 months, children and adolescents aged 2’17 years and adults aged 18’55 years in randomized, multicentre, phase III trials. In toddlers, Nimenrix™ was noninferior to Meningitec® in terms of seroresponse rates against meningococcal serogroup C 42 days post-vaccination. In children, adolescents and adults, Nimenrix™ was noninferior to Mencevax™ in terms of vaccination response rates against all four serogroups 1 month post-vaccination. Furthermore, several phase II studies and a phase III trial showed that the immune response elicited by Nimenrix™ in all age groups persisted for 7–42 months after the primary vaccination (when evaluated by rabbit serum bactericidal activity), with the vaccine also inducing immune memory in toddlers. In addition, several randomized, multicentre, phase III, noninferiority trials showed that when coadministered with other childhood vaccines or a seasonal flu vaccine, the immunogenicity of Nimenrix™ or that of the coadministered vaccine was generally not altered.Nimenrix® was generally well tolerated in all age groups whether administered as a single vaccine or coadministered with other routine vaccines. The incidence of grade 3 local or systemic solicited adverse events during the first 4 days following vaccination and of serious adverse events over an extended follow-up period of up to 6 months was low (<4.5%).Although protective effectiveness and longer-term persistence studies are required, current evidence suggests that Nimenrix™, administered as a single dose, provides a valuable vaccination option for the prevention of meningococcal disease across a broad age group, including children as young as 12 months.

Trastuzumab: in HER2-positive metastatic gastric cancer.

Trastuzumab is a recombinant humanized IgG₁ monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor type 2 (HER2) that inhibits HER2-dependent tumour cell proliferation and survival. Proliferation of gastric cancer cells overexpressing HER2 is inhibited by trastuzumab in vitro and in vivo. HER2-positive expression (defined as immunohistochemistry 3+ or fluorescence in situ hybridization-positive) was observed in 22.1% of almost 4000 metastatic gastric cancers in patients who were screened for randomization in the open-label, multicentre, phase III ToGA trial. In patients with HER2-positive metastatic gastric cancer (n = 584), median overall survival (primary endpoint) was significantly longer for recipients of intravenous trastuzumab plus chemotherapy (comprising cisplatin and either fluorouracil or capecitabine) than in those receiving chemotherapy alone in the ToGA trial. Furthermore, the overall response rate was significantly higher and the median time to disease progression and median time of progression-free survival were also significantly longer with trastuzumab plus chemotherapy than with chemotherapy alone. In general, combination therapy with trastuzumab and chemotherapy was relatively well tolerated in patients with metastatic gastric cancer with no reports of new or unexpected adverse events.

Lopinavir/Ritonavir A Review of its Use in the Management of HIV-1 Infection

Lopinavir/ritonavir (Kaletra®) is an orally administered coformulated ritonavir-boosted protease inhibitor (PI) comprising lopinavir and low-dose ritonavir. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults, adolescents and children. Lopinavir/ritonavir is available as a tablet, soft-gel capsule and an oral solution for patients with difficulty swallowing.In well designed, randomized clinical trials, lopinavir/ritonavir, in combination with other antiretroviral therapies (ART), provided durable virological suppression and improved immunological outcomes in both ART-naive and -experienced adult patients with virological failure. Furthermore, lopinavir/ritonavir demonstrated a high barrier to the development of resistance in ART-naive patients. More limited data indicate that it is effective in reducing plasma HIV-1 RNA levels in paediatric patients. Lopinavir/ritonavir has served as a well established benchmark comparator for the noninferiority of other ritonavir-boosted PI regimens. Although generally well tolerated, lopinavir/ritonavir is associated with generally manageable adverse gastrointestinal side effects and hypertriglyceridaemia and hypercholesterolaemia, which may require coadministration of lipid-lowering agents to reduce the risk of coronary heart disease.Lopinavir/ritonavir, in combination with other ART agents, is a well established and cost-effective treatment for both ART-naive and -experienced patients with HIV-1 infection and, with successful management of adverse events, continues to have a role as an effective component of ART regimens for the control of HIV-1 infection.

Olanzapine/fluoxetine: a review of its use in patients with treatment-resistant major depressive disorder.

Olanzapine/fluoxetine (Symbyax®) is an oral, once-daily, fixed-dose combination of the atypical antipsychotic olanzapine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine. It is indicated, in adult patients, for the acute treatment of depressive episodes associated with bipolar I disorder and treatment-resistant major depressive disorder.In adult patients with treatment-resistant depression (major depressive disorder in adults who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode), olanzapine plus fluoxetine combination therapy was generally more effective than either drug as monotherapy based on an integrated analysis of clinical trials of 8–12 weeks’ duration. More limited data also indicate that longer-term treatment for 76 weeks with olanzapine plus fluoxetine was efficacious in this patient group. Combination therapy was generally well tolerated, with a tolerability profile similar to that of olanzapine monotherapy, although fluoxetine monotherapy was generally better tolerated than olanzapine plus fluoxetine. The combination of olanzapine plus fluoxetine, as a fixed-dose formulation, offers a useful treatment option in this difficult-to-treat patient group.

Ganciclovir ophthalmic gel 0.15%: in acute herpetic keratitis (dendritic ulcers).

Dendritic epithelial keratitis is most commonly caused by infections of herpes simplex virus (HSV) type 1 (HSV-1), and less frequently by HSV type 2 (HSV-2). Ganciclovir, a guanosine nucleoside analogue, is a well established broad-spectrum antiviral agent that inhibits replication of viral DNA and is active against both HSV-1 and -2 and several other viruses. Ganciclovir ophthalmic gel 0.15% is a five-times-daily topical preparation that is indicated for the treatment of acute herpetic keratitis (dendritic ulcers).A randomized, open-label, phase III trial in immunocompetent patients with acute herpetic keratitis showed that ganciclovir ophthalmic gel 0.15% applied five times daily provided effective clinical resolution of dendritic ulcers following 7 days of treatment (primary endpoint). Moreover, a retrospective analysis of noninferiority showed that ganciclovir ophthalmic gel 0.15% was no less effective than aciclovir (acyclovir) ointment 3%.A pooled analysis of three randomized, single-masked, phase II multinational trials also showed high rates of dendritic ulcer healing at day 7 for eyes treated with ganciclovir ophthalmic gel 0.15% and aciclovir ointment 3%. Furthermore, in the individual phase II trials, most patients showed evidence of healed dendritic and geographic ulcers at day 14 in either treatment arm. Median healing times with either treatment ranged from 6 to 10 days.Ganciclovir ophthalmic gel 0.15% was generally well tolerated and was associated with a significantly lower incidence of visual disturbances than aciclovir ointment 3% in the phase III trial.

Ulipristal acetate: a review of its use in emergency contraception.

Ulipristal acetate (ellaOne®; ella®) is the first of a new class of selective progesterone receptor modulators, and is indicated for emergency contraception within 120 hours after unprotected sexual intercourse or contraceptive failure. The principal effect of ulipristal acetate is to inhibit or delay ovulation. This effect may result from the drugs ability to delay the onset of luteinizing hormone (LH) surge or postpone LH peak if LH surge has started, or possibly by a direct inhibitory effect on follicular rupture, when administered in the follicular phase (including just before ovulation).In clinical trials, a single oral dose of ulipristal acetate 30 mg was effective in preventing pregnancies in women requesting emergency contraception after unprotected sexual intercourse and provided sustained efficacy throughout the 120-hour postcoital period in which it is indicated. When compared with levo-norgestrel in well designed noninferiority trials, it was no less effective in preventing pregnancies when administered within 72 hours of unprotected intercourse, but was more effective when administered later (within 72–120 hours). Results of a meta-analysis suggest that ulipristal acetate may be more effective than levo-norgestrel from day 1 and throughout the entire 5-day period following unprotected sexual intercourse.Ulipristal acetate is generally well tolerated, with a similar tolerability profile to that of levonorgestrel. In general, the onset of menses is delayed by 2–3 days following treatment. Although, ulipristal acetate is more expensive than levonorgestrel, it may represent a cost-effective alternative to levonorgestrel for women requesting emergency contraception within 120 hours of unprotected intercourse. Thus, ulipristal acetate provides effective, sustained and well tolerated emergency contraception when taken within 120 hours of unprotected sexualintercourse, thereby offering an extended treatment window compared with levonorgestrel, which should be administered within 72 hours.

Corifollitropin alfa: a review of its use in controlled ovarian stimulation for assisted reproduction.

Corifollitropin alfa (Elonva®) is a fusion product of human follicle-stimulating hormone (FSH) and the C-terminal peptide of the β-subunit of human chorionic gonadotropin (hCG) produced by recombinant DNA technology. It has the same pharmacologic activity as FSH and recombinant FSH (rFSH; follitropin alfa; follitropin beta), but with a slower absorption and a longer half-life. Corifollitropin alfa is indicated as a multifollicular stimulant for women undergoing controlled ovarian stimulation using gonadotropin-releasing hormone (GnRH) antagonist-assisted reproduction protocols.In two large, randomized, double-blind, phase III trials, a single subcutaneous injection of corifollitropin alfa was no less effective as a multifollicular stimulant than seven once-daily injections of rFSH when used as part of a GnRH antagonist-assisted controlled ovarian stimulation cycle. With regard to primary endpoints, the mean number of retrieved oocytes per started cycle demonstrated that the two treatments were equivalent, and the ongoing pregnancy rate in recipients of corifollitropin alfa was noninferior to that in recipients of rFSH. The median duration of stimulation with FSH was 9 days in both treatment arms of both trials, which means that, on average, recipients of corifollitropin alfa required only 2 further days of stimulation with rFSH prior to triggering oocyte maturation with the administration of hCG. Fertilization rates were high, ranging from 66% to 68%, in recipients of corifollitropin alfa or rFSH in both trials.When used as part of a GnRH antagonist-assisted reproduction protocol, corifollitropin alfa was generally well tolerated, with a tolerability profile similar to that of rFSH. In large, pooled analyses of clinical trials, the incidence of ovarian hyperstimulation syndrome in both the corifollitropin alfa and rFSH treatment arms was consistent with that expected in the relatively young patient population. Furthermore, there were no clinically relevant differences in pregnancy complications and the incidence of infant adverse events between treatment arms.In conclusion, a single subcutaneous injection of corifollitropin alfa provides sustained multifollicular stimulation for up to a week in women undergoing controlled ovarian stimulation. Compared with seven once-daily injections of rFSH, a single injection of corifollitropin alfa achieves equivalent efficacy, and provides a well tolerated and more convenient treatment option to induce multiple follicular growth prior to assisted reproduction.