Influence of the number of daily pills and doses on adherence to antiretroviral treatment: a 7-year study.

WHAT IS KNOWN AND OBJECTIVE: Antiretroviral treatment (ART) is hampered by complicated regimens, high pill burden, drug-drug interactions, and frequent short- and long-term adverse effects, leading to decreased adherence. Over recent years, considerable effort has been directed at developing regimens that are less burdening. We undertook a 7-year retrospective study of the records of 264 HIV-infected subjects enrolled in a pharmaceutical care programme to document the progress made and to study the influence of the number of ART pills and doses on the level of treatment adherence. METHODS: Antiretroviral dispensing records were analysed for the number of pills and doses administered and the ART adherence rate estimated. RESULTS AND DISCUSSION: In 2005, the patients took a mean of 6·2 pills daily (CI 95%: 5·9-6·6), and 92·9% of them were on a twice-a-day (BID) dosage regimen. By 2012, the mean number of pills was reduced to 4·1 (CI 95%: 3·8-4·4), and only 50·9% were on a BID regimen. No statistically significant relation was observed between number of daily pills and doses and ART adherence reached by the patients in any of the analyses performed. WHAT IS NEW AND CONCLUSIONS: There has been a continuous reduction in the number of pills and doses of antiretrovirals taken by individual patients over the last 7 years due largely to the introduction of improved treatments and regimens. More daily pills or doses was not associated with worse ART adherence in our pharmaceutical care programme.

[Prevalence and factors associated with preventable adverse drug events leading to hospital admission]. / Prevalencia y factores asociados a los acontecimientos adversos prevenibles por medicamentos que causan el ingreso hospitalario.

OBJECTIVE: To determine the prevalence of adverse drug events (ADEs) leading to hospital admission, and to assess those that were potentially preventable, identifying the drug classes involved, types of medication errors and the factors associated with the preventable ADEs. METHOD: An observational study, over a six-month period on ADEs that lead or contributed to hospital admissions, carried out in 6 medical units of a university hospital. RESULTS: A total of 259 ADEs were detected of which 159 (61.4%) were assessed to be potentially preventable. The overall prevalence of admissions directly due to ADEs was of 6.7% (177) and to preventable ADEs of 4.7% (125). In addition, 82 ADEs that contributed to hospital admission were detected. Risk factors for preventable ADEs were patient age of 65-74 (OR = 1.40) or = 75 years (OR = 2.70), self-medication (OR = 15.55), prescription in primary care (OR = 2,88) and the use of narrow therapeutic index drugs (OR = 2.40). The drug classes most frequently involved in preventable ADEs were NSAID and aspirin (32.5%), diuretics (15.3%), antihypertensives (9.1%) and digoxin (7.7%). Inadequate therapy monitoring (20.7%), prescription of an inappropriate drug (15.7%) or of an excessive dosage (12.0%), lack of preventive treatment (15.7%), non-adherence (10.6%) and inappropriate self-medication (10.1%) were the most commonly identified types of error. CONCLUSIONS: A high proportion (4.7%) of hospital admissions are caused by potentially preventable ADEs. Results obtained justified the need to adopt measures directed at improving surveillance and prescription quality, and educating patients in safe drug use, focusing especially on older patients and narrow therapeutic index drugs.

[Cost-utility analysis of relapsing-remitting multiple sclerosis treatment with azathioprine or interferon beta in Spain]. / Análisis coste-utilidad del tratamiento de la esclerosis múltiple remitente-recidivante con azatioprina o interferón beta en España.

AIM: To carry out a cost-utility analysis of the treatment of relapsing-remitting multiple sclerosis (RRMS) with azathioprine (Imurel) or beta interferon (all, Avonex, Rebif and Betaferon). MATERIAL AND METHODS: Pharmacoeconomic Markov model comparing treatment options by simulating the life of a hypothetical cohort of women aged 30, from the societal perspective. The transition probabilities, utilities, resource utilisation and costs (direct and indirect) were obtained from Spanish sources and from bibliography. Univariant sensitivity analyses of the base case were performed. RESULTS: In the base case analysis, the average cost per patient (euros in 2003) of a life treatment, considering a life expectancy of 53 years, would be 620,205, 1,047,836, 1,006,014, 1,161,638 and 968,157 euros with Imurel, all interferons, Avonex, Rebif and Betaferon, respectively. Therefore, the saving with Imurel would range between 327,000 and 520,000 euros approximately. The quality-adjusted life years (QALY) obtained with Imurel or interferons would be 10.08 and 9.30, respectively, with an average gain of 0.78 QALY per patient treated with Imurel. The sensitivity analyses confirmed the robustness of the base case. The cost of one additional QALY with interferons would range between 413,000 and 1,308,000 euros approximately in the hypothetical worst scenario for Imurel. CONCLUSIONS: For a typical patient with RRMS, treatment with Imurel would be more efficient than interferons and would dominate (would be more efficacious with lower costs) beta interferon.

[Antisense therapy in oncology: present situation]. / Terapia antisentido en oncología: situación actual.

The purpose of antisense therapy is to control the regulation of genes contributing to cancer progression while sparing normal cell growth, which represents a novel alternative with fewer side effects when compared to conventional chemotherapy. Antisense oligonucleotides control cell proliferation by specifically blocking the expression of selected genes, and hence they are being developed as molecular drugs with potential activity for cancer treatment. Extensive clinical information and a number of clinical trials show encouraging results. This review discusses the most significant aspects of this new therapeutic alternative in oncology. Clinical trials performed thus far have demonstrated their short- to mid-term efficacy and safety; however, long-term studies are needed to definitely define their clinical effectiveness and true toxic profile.

Clinical experience with the CarboMedics valve: early results with a new bileaflet mechanical prosthesis.

Between January 1989 and August 1992, 612 CarboMedics mechanical prostheses (CarboMedics, Inc., Austin, Tex.) (295 mitral, 308 aortic, and 9 tricuspid) were implanted in 504 patients: 189 patients had isolated mitral valve replacement, 209 had isolated aortic valve replacement, and 106 had multiple valve replacement. The total follow-up was 1182 patient-years. The hospital mortality rate was 7.4% for mitral valve replacement, 5.3% for aortic valve replacement, and 13.2% for multiple valve replacement. Linearized rates for the different complications for mitral valve replacement, aortic valve replacement, and multiple valve replacement (in events per 100 patient-years) were, respectively, as follows: late mortality, 2.6 +/- 0.8, 1.5 +/- 0.5, and 3.9 +/- 1.3; thromboembolism [correction of thromboembolim], 3.7 +/- 0.9, 3.1 +/- 0.8, and 3.9 +/- 1.3; valve thrombosis, 0.5 +/- 0.3 for mitral valve replacement and 0.4 +/- 0.4 for multiple valve replacement; anticoagulant-related hemorrhage, 2.8 +/- 0.8, 1.9 +/- 0.6, and 2.6 +/- 1.1; nonstructural dysfunction, 1.6 +/- 0.6, 0.8 +/- 0.4, and 3.5 +/- 1.2; and reoperation, 1.1 +/- 0.5, 0.4 +/- 0.3, and 3.1 +/- 1.1. Actuarial estimates of freedom from the different complications for mitral valve replacement, aortic valve replacement, and multiple valve replacement (at 5 years of follow-up for mitral valve replacement and aortic valve replacement and 4.5 years for multiple valve replacement) were, respectively, as follows: overall death, 83% +/- 4%, 89% +/- 2%, and 76% +/- 4%; thromboembolism or valve thrombosis, 88% +/- 3%, 91% +/- 2%, and 86% +/- 5%; anticoagulant-related hemorrhage, 89% +/- 3%, 95% +/- 2%, and 90% +/- 5%; nonstructural dysfunction, 97% +/- 1%, 98% +/- 1%, and 91% +/- 3%; and reoperation, 96% +/- 2%, 99% +/- 1%, and 87% +/- 5%. There were no instances of prosthetic structural dysfunction. The performance of the CarboMedics valve is satisfactory at 5 years of follow-up but thromboembolic and hemorrhagic phenomena are still serious complications of mechanical prostheses.

Commissural dehiscence of Carpentier-Edwards mitral bioprostheses. Explant analysis and pathogenesis.

Manufacturing factors have seldom been implicated as a direct cause of structural deterioration of valvular bioprostheses; this phenomenon has generally been considered to be of a host-dependent origin. We analyzed the clinical and pathologic data from 12 Carpentier-Edwards mitral bioprostheses removed from 12 patients because of severe dysfunction and showing detachment of the porcine aortic wall from the stent in one commissure or more. These 12 prostheses were part of a group of 92 such valves that were explanted and displayed structural deterioration. They belong to a population of 405 Carpentier-Edwards bioprostheses implanted in the mitral position in our institution between May 1978 and November 1988. The patients included three men and nine women with a mean age of 54 +/- 13 years. One patient had a history of chronic renal failure, and two had systemic hypertension. Prosthesis sizes were 29, 31, and 33 mm (n = 4 for each size). The models of the valves were 6625 (n = 8) and 6650 (n = 4). Mean duration of implantation of the prostheses was 99 +/- 27 months (52 to 136 months) and did not differ depending on the model. There was no significant clustering of commissural detachments depending on valve size, year of implantation, or gender of the patient. No similar phenomenon was observed among 76 explanted aortic Carpentier-Edwards bioprostheses with structural deterioration from a population of 441 valves implanted during the same time frame. Native porcine aortic roots (n = 5) and aortic Carpentier-Edwards bioprostheses explanted because of structural deterioration (n = 4) were used as controls for comparison. Macroscopic examination showed single commissural dehiscence in 10 patients and double in two. Radiology disclosed no or mild mineralization in eight valves and no calcium in the area of aortic wall dehiscence, except for heavily calcified valves. Light microscopy evidenced a significant thinning of the aortic wall at the paracommissural level of mitral bioprostheses (351 +/- 68 microns) compared with either aortic bioprostheses (526 +/- 59 microns; p < 0.01) or control native porcine aortic roots (419 +/- 50 microns; p < 0.01). No difference was found in terms of aortic wall thickness between detached (322 +/- 42 microns) and intact (366 +/- 74 microns) commissures in mitral bioprostheses.(ABSTRACT TRUNCATED AT 400 WORDS)

Left main coronary artery patch angioplasty: midterm experience and follow-up with spiral computed tomography.

BACKGROUND: Patch angioplasty is an alternative surgical technique in cases of left main coronary artery stenosis. We report our experience with this technique, with particular mention of the use of spiral computed tomography for the follow-up of our patients. METHODS: In this retrospective study we analyzed the results obtained in all 7 patients (3 women and 4 men) who were operated on with this technique in our institution between July 1992 and August 1994. Five consenting patients also underwent graft patency assessment with spiral computed tomographic imaging. RESULTS: The operation was uneventful in all patients and there were no hospital deaths. Two patients required reoperation (1 of them dying at reoperation), 1 because of restenosis of the graft and 1 because of the presence of a new stenosis in the proximal anterior descending coronary artery. The remaining 5 patients were asymptomatic after 51 +/- 2 months. Spiral computed tomographic images were artifacted and of poor quality. CONCLUSIONS: Patch angioplasty of the left main coronary artery can be a valuable therapeutic method in selected cases. Conventional spiral computed tomography is not an optimal noninvasive method for the assessment of graft patency.

Effect of physical protection on the mesothelial integrity of the pericardium.

BACKGROUND: Mesothelial integrity is essential for the prevention of pericardial adhesions. This study was performed to determine the effect of physical protection of the pericardium on mesothelial integrity. METHODS: A pericardial biopsy specimen was obtained at the time of pericardiotomy (0 minutes) in 10 patients undergoing a cardiac operation for the first time. The left free edge of the pericardiotomy was plicated inward to protect the mesothelium. Biopsy specimens were obtained from the protected and unprotected pericardium at 45 and 90 minutes after the start of extracorporeal circulation. Mesothelial integrity and the local inflammatory response were then assessed and graded histologically. RESULTS: The mesothelium was found to be present in the protected specimens at 0, 45, and 90 minutes, but it was found to be denuded in the unprotected specimens (p = 0.003 at 45 minutes; p = 0.004 at 90 minutes). Local inflammation was totally established in both the protected and unprotected specimens at 45 minutes. CONCLUSIONS: Physical agents appear to be the main factor that is damaging to the pericardial mesothelium, and this is an important concept to be taken into consideration when designing a method to prevent pericardial adhesions.

Poor clinical performance of the Wessex porcine heart valve bioprosthesis at nine years' follow up.

OBJECTIVE: To assess the long term performance of the Wessex porcine bioprostheses implanted in a consecutive series of patients. DESIGN: A retrospective case series. PATIENTS: Between January 1985 and July 1991, 184 Wessex bioprostheses (78 mitral, 102 aortic, and 4 tricuspid) were implanted in 150 patients. The patients were 55% (83/150) male and 45% (67/150) female; mean age was 60 (SD 10) years. RESULTS: Hospital mortality was 9.3% (14/150). Total follow up was 696 patient-years (mean 4.7 years per patient). Linearised rates (events per 100 patient-years (SEM) for postoperative complications for patients with isolated mitral valve replacement, isolated aortic valve replacement, and multiple valve replacement were, respectively: late mortality: 4.7 (1.6), 3.3 (0.9), and 4.9 (1.9); thromboembolism: 5.8 (1.8), 3.0 (0.9), and 2.8 (1.4); valve thrombosis: 1.0 (0.7), 0.3 (0.3), and 0.7 (0.7); structural failure: 5.8 (1.7), 1.9 (0.7), and 7.1 (2.2). Actuarial freedom from complications at nine years (70% confidence interval) was: late mortality: 61 (9)%, 57 (13)%, and 59 (12)%; thromboembolism and valve thrombosis: 71 (9)%, 79 (6)%, and 81 (8)%; structural failure: 33 (14)%, 50 (16)%, and 12 (14)%; all valve related morbidity/mortality: 31 (10)%, 21 (11)%, and 7 (9)%. Stent fractures appeared in 11 of 17 explanted prostheses; actuarial freedom from stent fracture at nine years was 66 (12)%. CONCLUSIONS: The Wessex bioprosthesis is associated with high thrombogenicity, early structural dysfunction, and a high valve related morbidity/mortality which justifies very close follow up of patients fitted with them.

Clinical experience with the Carpentier-Edwards supra-annular porcine bioprosthesis implanted in the aortic position.

BACKGROUND AND AIMS OF THE STUDY: Between 1st January 1988 and 30th June 1996, a total of 165 patients (115 males, 50 females; mean age 66.8 years) underwent isolated aortic valve replacement with Carpentier-Edwards supra-annular porcine bioprostheses in our unit. Our clinical experience with this device is reported. METHODS: In this retrospective study, mortality and complications observed in these patients were analyzed. Complications appearing with a non-biased time-course were expressed by means of linearized rates. Actuarial analysis was performed using the Kaplan-Meier method. RESULTS: Cumulative follow up was 551.2 patient-years, with a mean follow up of 3.5 years per patient. The hospital mortality rate was 6.7%. Linearized rates (events per 100 patient-years) and actuarial probabilities of freedom from the different complications at 8.5 years follow up, respectively, were: late mortality, 4.5 and 58.6%; valve-related mortality, 1.1 and 82.6%; thromboembolism, 1.3 and 92.7%; prosthetic endocarditis, 0.5 and 97.4%; non-structural dysfunction, 0.5 and 94.7%; structural deterioration, 0.5 and 91.6%; reoperation, 0.5 and 94.2%. Actuarial freedom from any valve-related mortality or morbidity at 8.5 years was estimated at 66.3%. CONCLUSIONS: The Carpentier-Edwards supra-annular bioprosthesis, when implanted in the aortic position, presents a low rate of valve-related complications at this length of follow up. However, the limited life expectancy of our patients undergoing aortic valve replacement with bioprostheses (usually elderly subjects) may overshadow the potential good performance of this device.

Age-dependent dystrophic calcification of the aortic valve leaflets in normal subjects.

The aortic valves of 43 subjects (14 females and 29 males, mean age 48.9 +/- 22.2 years, range 3-88 years), dying from accidental causes and without any previous record of cardiovascular disease, were studied. The whole aortic root was removed and morphological features recorded. Calcium content was determined by atomic absorption spectrophotometry. Calcium content sustained a positive significant correlation (p < 0.001) with age. Comparison of regression lines from subjects of different age groups disclosed a significantly greater slope in the regression line of persons older than 50 years than in those of the younger population (p < 0.05). The increase with age of calcium content displayed no significant differences between male and female nor between any of the three aortic cusps. The presence of Lambl's excrescences on the aortic leaflets became more frequent with age and was associated with a higher calcium content.

Total aortic arch replacement by a cryopreserved aortic homograft.

The case is presented of a 60-year-old man with previous surgery on the transverse aorta and a pseudoaneurysm of the aortic arch and hemoptysis. The patient was operated upon with cardiopulmonary bypass and cerebral perfusion. The aortic arch was resected preserving a cuff of the aorta containing the three supra-aortic trunks. A bronchial fistula was closed with a pediculated flap of the native arch. A long segment of cryopreserved human aorta (ascending, arch and upper descending thoracic aorta) was inserted in the orthotopic position. The aortic cuff with the supra-aortic vessels was re-inserted onto the allograft. The patient is asymptomatic 2 months after the operation. Aortic homografts are a good alternative in cases with suspected infection or contamination, like this one. Other conditions, such as infected aneurysms, infected grafts, aorto-esophageal fistula and aorto-gastrointestinal fistula, are potentially good candidates for homografting. We believe that this case is the first report of a complete substitution of the aortic arch with a human cryopreserved homograft.

Arrhythmia prophylaxis after coronary artery surgery. A randomised controlled trial of intravenous magnesium chloride.

One hundred and thirty patients undergoing elective myocardial revascularisation were randomised to receive an intravenous infusion containing either 50 mmol magnesium chloride or placebo during the first 48 h following surgery. Magnesium was given to 66 patients and a placebo infusion to 64 patients. Postoperative serum magnesium concentrations fell in the placebo group (from 0.83 +/- 0.06 to 0.79 +/- 0.11 mmol/l) but were elevated in the magnesium group (from 0.82 +/- 0.05 to 1.2 +/- 0.25 mmol/l). In total, 35 patients (26.9%) had a supraventricular arrhythmia, of which 11 were in the magnesium group (16.7%) and 24 (37.5%) in the placebo group (P = 0.013). Three patients in the magnesium group had an episode of ventricular fibrillation and three patients in the placebo group had frequent ventricular ectopics. There was one death in the magnesium group associated with a perioperative myocardial infarction. This study shows that intravenous magnesium supplements reduce the incidence of supraventricular arrhythmias following coronary artery surgery.

Long-term clinical performance of Sorin tilting-disc mechanical prostheses in the mitral and aortic position.

OBJECTIVE: Analyzing the long term performance of sorin tilting-disc mechanical prostheses. EXPERIMENTAL DESIGN: Retrospective patient-oriented study. The total follow-up was 460.2 patient-years. Follow-up data was obtained from the patients themselves or from their relatives. SETTING: Department of Cardiovascular Surgery in a general community hospital. PATIENTS: Seventy four patients undergoing valve replacement with Sorin tilting-disc mechanical prostheses between May, 1982 and July 1991. INTERVENTIONS: Thirty one of those patients underwent isolated mitral valve replacement (MVR) and 43 isolated aortic valve replacement (AVR). MEASURES: The incidence of the different complications is expressed as linearized rates. Actuarial analysis was performed with the Kaplan-Meier method. RESULTS: Linearized rates for MVR and AVR for the different complications (events per 100 patient-years) were, respectively: Late mortality: 4.5 +/- 1.6 and 1.8 +/- 0.8; Thromboembolism: 3.4 +/- 1.4 and 1.1 +/- 0.6; Anticoagulant-related hemorrhage: 2.8 +/- 1.3 and 0.3 +/- 0.3; Prosthetic endocarditis: 1.1 +/- 0.8 and 0.7 +/- 0.5; Non-structural dysfunction: 0.5 +/- 0.5 and 1.1 +/- 0.6; Reoperation: 1.1 +/- 0.8 and 0.3 +/- 0.3. Actuarial probabilities of freedom from the different complications were, respectively, at 13 years follow-up for MVR and 12 years follow-up for AVR, the following: Late mortality: 45.7 +/- 12.4% and 70.3 +/- 7.9%; Thromboembolism: 74.6 +/- 10.8% and 90.7 +/- 5.1%; Anticoagulant-related hemorrhage: 79.4 +/- 11.6% and 97.3 +/- 2.7%; Prosthetic endocarditis: 92.7 +/- 4.9% and 91.2 +/- 6.4%; Non-structural dysfunction: 95.6 +/- 4.3% and 88.2 +/- 6.6%; Reoperation: 83.6 +/- 11.8% and 97.3 +/- 2.7%. All valve-related mortality and morbidity: 42.2 +/- 11.0% and 56.7 +/- 8.6%. There was no instances of prosthetic structural failure. CONCLUSIONS: The Sorin mechanical prosthesis presents a good durability and its performance in the long term is comparable to other tilting-disc devices of the same generation.

Mitral valve replacement with small-sized tilting-disc mechanical prostheses may lead to moderate stenosis.

BACKGROUND: Analyzing the hemodynamics of small-sized tilting-disc mechanical prostheses implanted in the mitral position. EXPERIMENTAL DESIGN: this is a retrospective study. The mean follow-up of patients was 114+/-27 months (range 68-152 months). SETTING: departments of Cardiovascular Surgery and Cardiology in a general community hospital Patients: this study includes 9 survivors of 17 patients undergoing mitral valve replacement with this type of device between May, 1982 and July, 1991. INTERVENTIONS: all subjects underwent mitral valve replacement with size 25 mm Sorin tilting-disc mechanical prostheses. MEASURES: all patients underwent transthoracic echocardiography. Five consenting patients also underwent transoesophageal echocardiography. The following parameters were measured: peak gradient, mean gradient, peak velocity, mean velocity, pressure half-time and Doppler area. RESULTS: The ejection fraction was 50% or more in all patients. The following mean results were obtained: peak gradient: 17.4+/-2.5 mmHg; mean gradient: 8.2+/-0.6 mmHg; peak velocity: 2.1+/-0.1 m/sec; mean velocity: 1.43+/-0.06 m/sec; pressure half-time: 135.9+/-29.7 msec; Doppler area: 1.7+/-0.3 cm2. CONCLUSIONS: Valve replacement with Sorin 25 mm tilting-disc mechanical prostheses appears to originate a moderate degree of mitral stenosis and, therefore, we do not recommend their use if at all possible.

Peri-incisional and preoperative administration of cefmetazole for the prophylaxis of wound infection after appendicectomy.

The tissue and blood levels of Cefmetazole are compared after preoperative administration of a single dose of 30 mg/K body weight of the antibiotic administered intravenously (15 patients) and peri-incisionally (30 patients) to patients scheduled for emergency appendicectomy. Local and general tolerance to the antibiotic was good by both routes. No local or general complications arose in any of the patients. As expected, the tissue concentrations achieved with peri-incisional infiltration were significantly higher than those obtained by the intravenous route. With the blood levels, exactly the opposite happens at the start of the operation whereas at the end, there were no significant differences between the two routes employed. The prophylactic administration by peri-incisional infiltration is an easy and safe method which provides high tissue concentrations simultaneously with adequate blood levels and should be considered as useful in the preoperative administration of antibiotics for prophylaxis.

Pharmacogenetic analysis of SNPs in genes involved in the pharmacokinetics and response to lopinavir/ritonavir therapy.

Despite the known benefits and the experienced use of lopinavir/ritonavir (LPV/r) in the management of HIV infection, important interindividual variability in the pharmacokinetics (PKs) and the response to treatment with standard doses of this drug has been observed. Host genetic factors have been recently suggested as being responsible for part of this variability as they may affect the expression and functional activity of many proteins involved in the kinetic behavior, the immune recovery or the adverse effects related to LPV/r. Here, we present a genetic association study in 106 HIV-infected individuals collected over a period of 5 years with the aim of identifying and confirming single nucleotide polymorphisms (SNPs) with a significant influence on the PK parameters of LPV/r, the immunovirological response or toxicity derived from treatment with the studied drug. Genotyping was performed by MALDI-TOF and KASPar; LPV/r plasma concentrations were quantified using high-performance liquid chromatography with an ultraviolet detection system and the PK parameters were estimated using Bayesian algorithms. Genetic association analysis was performed with SPSS. The most significant associations were found between SNPs in the dopamine receptor D3 gene and the PK of LPV/r. Additionally, other suggestive relationships were established between genetic factors and the response during treatment with this drug. Thereby, identifying HIV-infected individuals who are at increased risk of achieve non-optimal LPV/r plasma concentrations with the emergence of toxicity, drug resistance or absence of clinical response could be helpful as a tool to optimize the LPV/r-based antiretroviral therapy.

[Biosimilars: assessment of efficacy, safety and cost]. / Biosimilares: balance de eficacia, seguridad y coste.

A biosimilar medicinal product is a successor to a biological medicinal product for which patent protection no longer applies. Manufactured by recombinant DNA technology (insertion of gene into the host cell to produce the protein). Comparable with the selected comparator, reference product, in terms of quality, safety and efficacy. The biosimilar product is usually approved for the same indications as the comparator reference product given that they share the same mode of actions.