AS04-adjuvanted human papillomavirus (HPV) types 16 and 18 vaccine (Cervarix®): a review of its use in the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types

The AS04-adjuvanted human papillomavirus (HPV) 16/18 vaccine (Cervarix?) is a noninfectious recombinant vaccine produced using purified virus-like particles (VLPs) that induce a strong immunogenic response eliciting high levels of anti-L1 VLP antibodies that persist at levels markedly greater than those observed with natural infection. The vaccine adjuvant (AS04) is composed of monophosphoryl-lipid A, which enhances cellular and humoral immune response, adsorbed to aluminium hydroxide. The vaccine is indicated for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types in females aged ≥10 years. The AS04-adjuvanted HPV 16/18 vaccine administered in a three-dose schedule over 6 months elicits a high immunogenic response and is highly protective against cervical intraepithelial neoplasia and infection causally related to high-risk oncogenic HPV types. In well designed clinical trials in young women aged 15-25 years who were HPV 16/18 seronegative and DNA negative to 14 HPV high-risk types, high levels of immunogenicity and protection were sustained for follow-up periods of up to 8.4 years. High and persistent immunogenicity against infection with HPV 16/18 has also been demonstrated in older and younger females (aged 10-55 years) who were seronegative for vaccine HPV types. The AS04-adjuvanted HPV 16/18 vaccine elicited a greater immunogenic response than the quadrivalent HPV vaccine in women aged 18-45 years who were seronegative and DNA negative for HPV 16/18. The AS04-adjuvanted HPV 16/18 vaccine confers cross protection against certain non-vaccine, high-risk HPV types. A rapid and strong anamnestic humoral immune response was elicited following a fourth dose of the vaccine. The AS04-adjuvanted HPV 16/18 vaccine is generally well tolerated, and pharmacoeconomic analyses have demonstrated the potential for public health benefits and cost effectiveness when vaccination programmes are run in conjunction with screening programmes. Thus, the AS04-adjuvanted HPV 16/18 vaccine prevents cervical disease associated with certain oncogenic HPV types, thereby reducing the burden of premalignant cervical lesions and, very likely, cervical cancer.     

Hyaluronic acid (Supartz®): a review of its use in osteoarthritis of the knee

Hyaluronic acid (Supartz?; molecular weight 620-1170?kDa) is a sterile, viscoelastic, non-pyogenic solution that is indicated as a medical device for the treatment of pain in patients with osteoarthritis of the knee who have failed to respond adequately to conservative nonpharmacological therapy and simple analgesics. Intra-articular injections of Supartz? were significantly more effective than control injections, according to an integrated longitudinal analysis of pooled data from five randomized, double-blind, vehicle-controlled, multicentre trials in patients with osteoarthritis of the knee. Supartz?, compared with the phosphate-buffered saline control, significantly reduced the total Lesquésne Index score in the post-injection period. Data from the individual trials demonstrated that the reduction in the total Lesquésne Index score was significantly greater than the control in two of the five studies. According to another efficacy endpoint (the mean reduction in the Western Ontario and McMaster Universities Osteoarthritis Index), which was assessed in only one of these trials, Supartz? was significantly more effective than the control in reducing the pain and stiffness subscale scores. Clinical scores of pain/inflammation and visual analogue scale (VAS) scores of pain during walking improved from baseline values for up to 6 months after treatment with Supartz? or a corticosteroid, with no significant between-group differences, in a small, randomized, open-label, multicentre trial in patients with osteoarthritis of the knee. Intra-articular injections of both Supartz? and Synvisc?, as well as a phosphate-buffered saline control, significantly reduced VAS scores of weight-bearing pain versus baseline after 26 weeks of therapy in a well designed trial; however, there were no significant differences between the three treatment groups. Neither hyaluronic acid formulation had a longer duration of clinical benefit than the saline control. Supartz? was well tolerated in patients with osteoarthritis of the knee. An integrated analysis of the five, well designed clinical trials demonstrated no significant difference between the Supartz? or control groups in the incidence of adverse events. The most common adverse events reported in Supartz? recipients were arthralgia, arthropathy/arthrosis/arthritis, back pain, nonspecific pain, injection-site reaction, headache and injection-site pain.     

Rotavirus vaccine RIX4414 (Rotarix™): a pharmacoeconomic review of its use in the prevention of rotavirus gastroenteritis in developing countries

This article provides an overview of the clinical profile of rotavirus vaccine RIX4414 (Rotarix?) in the prevention of rotavirus gastroenteritis (RVGE) in developing countries, followed by a comprehensive review of pharmacoeconomic analyses with the vaccine in low- and middle-income countries. RVGE is associated with significant morbidity and mortality among children <5 years of age in developing countries. The protective efficacy of a two-dose oral series of rotavirus vaccine RIX4414 has been demonstrated in several well designed clinical trials conducted in developing countries, and the 'real-world' effectiveness of the vaccine has also been shown in naturalistic and case-control trials after the introduction of universal vaccination programmes with RIX4414 in Latin American countries. The WHO recommends universal rotavirus vaccination programmes for all countries. Numerous modelled cost-effectiveness analyses have been conducted with rotavirus vaccine RIX4414 across a wide range of low- and middle-income countries. Although data sources and assumptions varied across studies, results of the analyses consistently showed that the introduction of the vaccine as part of a national vaccination programme would be very (or highly) cost effective compared with no rotavirus vaccination programme, according to widely used cost-effectiveness thresholds for developing countries. Vaccine price was not known at the time the analyses were conducted and had to be estimated. In sensitivity analyses, rotavirus vaccine RIX4414 generally remained cost effective at the highest of a range of possible vaccine prices considered. Despite these favourable results, decisions regarding the implementation of universal vaccination programmes with RIX4414 may also be contingent on budgetary and other factors, underscoring the importance of subsidized vaccination programmes for poor countries through the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunization).     

Rotavirus vaccine RIX4414 (Rotarix™): a pharmacoeconomic review of its use in the prevention of rotavirus gastroenteritis in developed countries

The most common cause of severe diarrhoea in infants and young children is rotavirus gastroenteritis (RVGE), which is associated with significant morbidity, healthcare resource use and direct and indirect costs in industrialized nations. The monovalent rotavirus vaccine RIX4414 (Rotarix?) is administered as a two-dose oral series in infants and has demonstrated protective efficacy against RVGE in clinical trials conducted in developed countries. In addition, various naturalistic studies have demonstrated 'real-world' effectiveness after the introduction of widespread rotavirus vaccination programmes in the community setting. Numerous cost-effectiveness analyses have been conducted in developed countries in which a universal rotavirus vaccination programme using RIX4414 was compared with no universal rotavirus vaccination programme. There was a high degree of variability in base-case results across studies even when conducted in the same country, often reflecting differences in the selection of data sources or assumptions used to populate the models. In addition, results were sensitive to plausible changes in a number of key input parameters. As such, it is not possible to definitively state whether a universal rotavirus vaccination programme with RIX4414 is cost effective in developed countries, although results of some analyses in some countries suggest this is the case. In addition, international guidelines advocate universal vaccination of infants and children against rotavirus. It is also difficult to draw conclusions regarding the cost effectiveness of rotavirus vaccine RIX4414 relative to that of the pentavalent rotavirus vaccine, which is administered as a three-dose oral series. Although indirect comparisons in cost-effectiveness analyses indicate that RIX4414 provided more favourable incremental cost-effectiveness ratios when each vaccine was compared with no universal rotavirus vaccination programme, results were generally sensitive to vaccine costs. Actual tender prices of a full vaccination course for each vaccine were not known at the time of the analyses and therefore had to be estimated.     

Subcutaneous recombinant interferon-β-1a (Rebif®): a review of its use in the treatment of relapsing multiple sclerosis

Subcutaneous recombinant interferon-β-1a (SC IFNβ-1a) [Rebif?] is indicated as monotherapy for the prevention of relapses and progression of physical disability in patients with relapsing multiple sclerosis (MS). This article reviews the efficacy and tolerability of SC IFNβ-1a in this indication, with further discussion of its pharmacological properties and pertinent pharmacoeconomic studies. SC IFNβ-1a efficacy and tolerability were evaluated in randomized, double-blind, multinational trials in patients with relapsing-remitting MS (RRMS). Its efficacy was demonstrated in the 2-year PRISMS trial, as SC IFNβ-1a 22 or 44 μg three times weekly (tiw) significantly reduced relapse rates, with an ≈30% relative risk reduction compared with placebo. SC IFNβ-1a was also associated with significantly delayed progression of disability, and lower disease activity according to MRI, relative to placebo. In the 24-week EVIDENCE trial, a significantly higher proportion of SC IFNβ-1a 44?μg tiw than intramuscular IFNβ-1a (Avonex?) 30 μg once weekly recipients remained relapse free. A serum-free formulation of SC IFNβ-1a 44?μg tiw was more efficacious than placebo in preventing the development of brain lesions in the 16-week IMPROVE trial. In the 96-week REGARD trial, the efficacy of SC IFNβ-1a 44?μg tiw was not significantly different to that of glatiramer acetate for clinical endpoints, although it was associated with reduced development of brain lesions compared with glatiramer acetate, according to some MRI endpoints. In the 36-month CAMMS223 trial, alemtuzumab led to significantly lower relapse rates and risk of developing sustained disability than SC IFNβ-1a 44 μg tiw, and was generally more efficacious according to other clinical and MRI endpoints. Across trials, influenza-like symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities were the most common treatment-emergent adverse events occurring with SC IFNβ-1a. In the PRISMS trial, SC IFNβ-1a 22 and 44 μg tiw recipients had more injection-site reactions than placebo recipients and, at the higher dosage, haematological disturbances and increases in ALT levels were also significantly more frequent than with placebo. Pooled data from clinical trials and postmarketing surveillance indicate that haematological and hepatic adverse events are generally asymptomatic and rarely result in treatment discontinuation. Nevertheless, some cases of serious hepatic complications have been reported. In cost-utility studies, first-line therapies for RRMS, including SC IFNβ-1a, all exceeded commonly accepted US thresholds for incremental cost per quality-adjusted life-years gained relative to symptomatic treatment. However, because of patient need and the difficulty in adequately assessing cost utility in a gradually progressive disease, these agents have been made available to many patients worldwide through special access programmes. Overall, SC IFNβ-1a has a favourable risk-benefit ratio and is a valuable first-line treatment option for patients with relapsing MS.     

Live attenuated influenza vaccine (FluMist®; Fluenz™): a review of its use in the prevention of seasonal influenza in children and adults

Live attenuated influenza vaccine (LAIV) is an intranasally administered trivalent, seasonal influenza vaccine that contains three live influenza viruses (two type A [H1N1 and H3N2 subtypes] and one type B). LAIV was effective in protecting against culture-confirmed influenza caused by antigenically matched and/or distinct viral strains in children aged ≤71 months enrolled in three phase III trials. LAIV was superior to trivalent inactivated influenza vaccine (TIV) in protecting against influenza caused by antigenically-matching viral strains in a multinational phase III trial in children aged 6-59 months. LAIV was also significantly more effective than TIV in decreasing the incidence of culture-confirmed influenza illness in two open-label studies (in children with recurrent respiratory tract illnesses aged 6-71 months and in children and adolescents with asthma aged 6-17 years). LAIV did not differ significantly from placebo in preventing febrile illnesses in adults (primary endpoint) enrolled in a phase III trial. However, LAIV significantly reduced the incidence of febrile upper respiratory tract illnesses (URTI), severe febrile illnesses, febrile URTI-related work absenteeism and healthcare provider use. In another well designed trial in adults, LAIV significantly reduced the incidence of symptomatic, laboratory-confirmed influenza compared with placebo (but not intramuscular TIV). LAIV was generally well tolerated in most age groups, with the majority of adverse events being mild to moderate in severity, and runny nose/nasal congestion being the most common. In a large phase III trial, LAIV, compared with TIV, was associated with an increased incidence of medically significant wheezing in vaccine-naive children aged <24 months and an increased incidence of hospitalization in children aged 6-11 months; LAIV is not approved for use in children <24 months. LAIV was not always associated with high rates of seroconversion/seroresponse, particularly in older children and adults, or in subjects with detectable levels of haemagglutination-inhibiting antibodies at baseline. However, LAIV did elicit mucosal (nasal) IgA antibody responses and strong cell-mediated immunity responses. Only one confirmed case of LAIV virus transmission to a placebo recipient (who did not become ill) occurred in a transmission study conducted in young children. The immunogenic response to LAIV in young healthy children was not affected by concomitant administration with other commonly administered childhood vaccines. In conclusion, intranasal LAIV seasonal influenza vaccine is effective and well tolerated in children, adolescents and adults. LAIV was more effective than TIV in children, although this advantage was not seen in adults. In the US, LAIV is indicated for the active immunization of healthy subjects aged 2-49 years against influenza disease caused by virus subtypes A and type B contained in the vaccine.     

OnabotulinumtoxinA (BOTOX®): a review of its use in the prophylaxis of headaches in adults with chronic migraine

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of intramuscularly injected onabotulinumtoxinA (onaBoNTA; BOTOX?) for headache prophylaxis in adults with chronic migraine, with a focus on UK labelling for the drug. The pharmacological actions of onaBoNTA include a direct antinociceptive (analgesic) effect; while not fully understood, the mechanism of action underlying its headache prophylaxis effect in chronic migraine is presumed to involve inhibition of peripheral and central sensitization in trigeminovascular neurones. Pooled findings from two large phase III studies of virtually identical design (PREEMPT [Phase III REsearch Evaluating Migraine Prophylaxis Therapy] 1 and 2) showed that treatment with up to five cycles of onaBoNTA (155-195 units/cycle) at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life (HR-QOL) in patients with chronic migraine, approximately two-thirds of whom were overusing acute headache medications at baseline. During the double-blind phase of both trials, significantly more patients treated with onaBoNTA (two cycles) than placebo experienced clinically meaningful improvements in the monthly frequencies of headache days, moderate to severe headache days and migraine days, and in the cumulative hours of headache on headache days/month. OnaBoNTA therapy also resulted in statistically significant and clinically meaningful improvements in functioning and HR-QOL compared with placebo. Notably, improvements in headache symptoms, functioning and HR-QOL favouring onaBoNTA over placebo were seen regardless of whether or not patients were medication overusers and irrespective of whether or not they were naive to (oral) prophylactic therapy. Further improvements relative to baseline in headache symptoms, functioning and HR-QOL were observed during the open-label extension phase of both trials (all patients received three cycles of onaBoNTA). Treatment with up to five cycles of onaBoNTA was generally well tolerated in the PREEMPT trials. Treatment-related adverse events reported by onaBoNTA recipients (e.g. neck pain, facial paresis and eyelid ptosis) were consistent with the well established tolerability profile of the neurotoxin when injected into head and neck muscles; no new safety events were observed. Debate surrounding the PREEMPT studies has centred on the small treatment effect of onaBoNTA relative to placebo, the possibility that blinding was inadequate and the relevance of the evaluated population. Nonetheless, the totality of the data showed that onaBoNTA therapy produced clinically meaningful improvements in headache symptoms, functioning and HR-QOL; on the basis of these trials, it has become the first (and so far only) headache prophylactic therapy to be specifically approved for chronic migraine in the UK and US. Overall, onaBoNTA offers a beneficial, acceptably tolerated and potentially convenient option for the management of this highly disabling condition, for example in patients who are refractory to oral medications used for prophylaxis.     

Octocog alfa, antihaemophilic factor (recombinant), plasma/albumin free method (Advate®): a review of its use in the management of patients with haemophilia A

Octocog alfa, antihaemophilic factor, plasma/albumin free method (Advate?) is a recombinant, human, full-length coagulation factor VIII that does not contain human- or animal-derived plasma proteins. It is indicated for the control and prevention of bleeding episodes, for perioperative management and for routine prophylaxis in children and adults with haemophilia A. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of Advate? in these patients. In previously treated paediatric and adult patients with moderately severe or severe haemophilia A, Advate? administered prophylactically, on demand or during surgery was effective for the prevention and treatment of bleeding episodes in three pivotal, uncontrolled clinical trials. The haemostatic efficacy of Advate? in these trials was rated as 'excellent' or 'good' in most bleeding episodes, with the majority of episodes being managed with one infusion. These findings were supported by pooled analyses of clinical trials and routine clinical practice studies, including the Post-Authorization Safety Study. Additionally, in a comparative study, routine prophylaxis with Advate? administered in a standard regimen or in a pharmacokinetic-tailored regimen was effective for the prevention of bleeding episodes in patients with moderately severe or severe haemophilia A, with no significant difference between the two regimens in terms of efficacy. Moreover, any routine prophylaxis with Advate? was found to be more effective in preventing bleeding episodes than on-demand therapy with Advate?. Advate? was generally well tolerated in clinical trials and postmarketing studies, with the most common treatment-emergent adverse events being pyrexia and headache. Serious adverse events with Advate? therapy are development of high-titre factor VIII inhibitors (usually in previously untreated patients) and hypersensitivity reactions. As expected, the incidence of factor VIII inhibitors (any titre) appeared to be lower in previously treated patients (≤ 1.8%) than in previously untreated patients (≤ 20%). There are no head-to-head comparative trials of Advate? and other factor VIII concentrates. Nevertheless, current evidence indicates that Advate? is an effective option for the management of paediatric and adult patients with haemophilia A.     

Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine, adsorbed (Boostrix®): a review of its properties and use as a single-dose booster immunization

Reduced-antigen, combined diphtheria, tetanus and three-component acellular pertussis vaccine (Tdap; Boostrix?) is indicated for booster vaccination against diphtheria, tetanus and pertussis in individuals from age four years onwards in Europe and from age 10 years onwards in the US. Compared with infant formulations used for primary vaccination, Tdap contains reduced quantities (10-50%) of all toxoids and antigens, which are adsorbed to either ≤0.39?mg/dose (US licensed formulation) or 0.5?mg/dose (rest-of-world formulation) of aluminium adjuvant. The reduced antigen content is designed to avoid the increasing reactogenicity historically seen with the fourth and fifth doses of infant vaccine. This article reviews the immunogenicity, protective efficacy and reactogenicity of Tdap booster administered to children, adolescents and adults, including those aged ≥65 years. In clinical trials, a single booster dose of Tdap induced seroprotective levels of antibodies to diphtheria and tetanus toxoids in virtually all children and adolescents, and in a high proportion of adults and elderly individuals at approximately 1 month post-vaccination irrespective of their vaccination history. In all age groups, seropositivity rates for antibodies against pertussis antigens were ≥90% (including in unvaccinated adolescents), and booster response rates were high. Tdap was safely co-administered with other common vaccines without significantly affecting the immune responses. The immunogenicity and reactogenicity profiles of booster doses of Tdap were generally similar to those of infant diphtheria-tetanus-whole-cell pertussis vaccine and infant diphtheria-tetanus-acellular pertussis vaccine in children aged 4-6 years, and infant diphtheria-tetanus vaccine in older children. In adolescents and adults, the immunogenicity and reactogenicity of Tdap were generally similar to those of reduced-antigen diphtheria-tetanus vaccine, reduced-antigen diphtheria-tetanus-five-component acellular pertussis vaccine and reduced-antigen acellular pertussis vaccine. Therefore, Tdap is suitable as a booster in place of these vaccines, including tetanus toxoid vaccine in the management of tetanus-prone wounds in adults. The quantity of aluminium adjuvant in Tdap did not markedly affect the immunogenicity or reactogenicity of the vaccine. Seropositivity rates for antibodies against pertussis toxin had begun to decline by 5 years after a booster dose of Tdap in adolescents/adults, and a subsequent booster dose 10 years later was generally as immunogenic as the initial booster and was well tolerated. Tdap was safe and well tolerated in all age groups. Local injection-site reactions were the most common adverse events. Most adverse events were of mild or moderate intensity and transient; there were few serious vaccination-related adverse events. Thus, Tdap is highly immunogenic, with low reactogenicity, in all age groups and appears suitable for targeted and/or repeat Tdap boosters in children, adolescents, adults and elderly individuals as part of immunization strategies that may prove beneficial in further limiting the burden of pertussis.     

Live attenuated influenza vaccine (Fluenz™): a guide to its use in the prevention of seasonal influenza in children in the EU

Live attenuated influenza vaccine (LAIV).[Fluenz?] has a convenient intranasal route of administration. In the EU, it is indicated for the prevention of influenza disease caused by the influenza virus strains contained in the vaccine in children and adolescents aged 2 years to <18 years. The vaccine elicits a high immunogenic response, is protective against seasonal influenza infection and is associated with the development of herd immunity. LAIV is generally well tolerated, with the safety of the vaccine in the approved pediatric population generally considered to be similar to that of placebo based on clinical trials and extensive experience involving more than 39 million vaccine doses.     

Inhaled human insulin (Exubera®): its pharmacologic profile,efficacy and safety in the treatment of adults with diabetes mellitus

Exubera^® (EXU, insulin human [rDNA origin]) is the first inhaled insulin approved for the treatment of diabetes in adults. Its pharmacokinetic properties make it suitable as therapy for postprandial glycemia. Clinical trials have demonstrated equal efficacy with short-acting subcutaneous regular and analog insulin in both Type 1 and 2 diabetes, and have also shown that it has value as adjunctive therapy in Type 2 patients inadequately controlled on maximal doses of oral hypoglycemic agents. EXU is well tolerated and associated with a high level of patient satisfaction. Hypoglycemia is the most common adverse event but its incidence does not exceed that expected for the degree of glycemic improvement. Minor reductions in some measures of pulmonary function have been observed in EXU-treated patients but safety studies of up to 2 years duration reveal that they occur early, do not progress and resolve quickly after treatment cessation. Longer-term postregistration pulmonary function studies that include assessment of insulin antibodies and the associated risk of allergic/immune disorders are in progress. EXU overcomes problems associated with the invasive nature of subcutaneous injection without loss of efficacy. Depending on cost and confirmation of safety, it could be a valuable part of future treatment strategies for both Type 1 and 2 diabetes.     

Spotlight on Tdap₅ vaccine (Covaxis®) as a single-booster immunization for the prevention of tetanus, diphtheria, and pertussis: in children (aged ≥4 years), adolescents, and adults

Covaxis? (also licensed as Triaxis? or Adacel? in individual countries) is a Tdap? (i.e. combined tetanus toxoid, reduced diphtheria toxoid, five component acellular pertussis [namely detoxified pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3]) vaccine for the prevention of diphtheria, tetanus, and pertussis. It is approved for use in Europe as a single intramuscular booster dose in children (aged ≥4 years), adolescents, and adults, and in the US it is approved for use in individuals aged 11-64 years. In large, randomized, controlled clinical trials conducted in the UK and North America, a single intramuscular booster dose of Covaxis? induced robust immune responses for all of its component antigens when given to children (aged ≥4 years), adolescents, and adults. In addition, Covaxis? vaccine was safe and generally well tolerated in terms of solicited and unsolicited local injection-site and systemic adverse events, most of which were of mild intensity and resolved without sequelae. Furthermore, the immunogenicity of each individual component and the reactogenicity of Covaxis? vaccine in children, adolescents, and adults was generally similar to that of comparator vaccines. Despite being a vaccine-preventable disease and having >90% primary vaccination coverage worldwide, pertussis remains uncontrolled, particularly amongst adolescents and adults. Given the changing epidemiology of pertussis and the requirement to reduce infection in adolescents and adults (including healthcare workers) and thereby prevent transmission of the disease from these individuals to very young infants, the new 'cocoon strategy' recommended in current vaccination guidelines has become a key strategy in the management of morbidity and mortality associated with pertussis. This strategy focuses on the immunization of healthcare workers, and the parents and family members of infants who are too young to have undergone primary immunization, so as to prevent the transmission of pertussis to these young at-risk infants. The implementation of the 'cocoon strategy' may finally give countries the ability to control pertussis infections in these at-risk infants and ultimately provide the desired herd immunity against pertussis. In line with this strategy, a booster dose of Covaxis? vaccine provides a valuable option to reduce pertussis morbidity and mortality, and to maintain seroprotection against diphtheria and tetanus in children (aged ≥4 years), adolescents, and adults.