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CONTEXT: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures. OBJECTIVE: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs. METHODS: We collected monthly exposure data reported to CPCS from 2012–2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling. RESULTS: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p

Topical hemostatic agents have become essential tools to aid in preventing excessive bleeding in surgical or emergency settings and to mitigate the associated risks of serious complications. In the present study, we compared the hemostatic efficacy of SURGIFLO® Hemostatic Matrix Kit with Thrombin (Surgiflo—flowable gelatin matrix plus human thrombin) to HEMOBLAST™ Bellows Hemostatic Agent (Hemoblast—a combination product consisting of collagen, chondroitin sulfate, and human thrombin). Surgiflo and Hemoblast were randomly tested in experimentally induced bleeding lesions on the spleens of four pigs. Primary endpoints included hemostatic efficacy measured by absolute time to hemostasis (TTH) within 5 min. Secondary endpoints included the number of product applications and the percent of product needed from each device to achieve hemostasis. Surgiflo demonstrated significantly higher hemostatic efficacy and lower TTH (p

Background: From 1999 to 2010, the annual number of US deaths due to opioid overdose increased about 400% as the number of opioids prescribed yearly also increased by approximately 400%. Over this period, hydrocodone combination products drove the opioid epidemic, as they became the most frequently prescribed medication in the United States. Our objective was to determine if the Drug Enforcement Administration's (DEA) 2014 policy change - which made it more difficult to prescribe hydrocodone combination products by moving them from Schedule III to Schedule II - reduced the total amount of opioid prescriptions as intended. Methods: We conducted a longitudinal analysis of the 10 most populous US states, beginning at the time each state began collecting data on opioid prescribing, and concluding at the end of 2016. The exposure was the DEA-mandated October 6, 2014 hydrocodone combination product schedule change. Results: After the DEA's schedule change for hydrocodone combination products, the total number of opioids prescribed each year per 100 people did not substantially change in California, Florida, Michigan, or New York. Although prescription rates dropped for hydrocodone combination products (CA: 43.2, 35.0; MI: 66.8, 55.6; NY: 20.8, 15.1), the reduction was commensurately counteracted by increased rates for tramadol (CA: 0.2, 9.9; MI: 0.1, 17.3; NY: 0.0, 7.6) and oxycodone (CA: 8.7, 9.7; MI: 10.3, 11.9; NY: 18.1, 18.8). Surprisingly, the other 6 states assessed had no viable mechanism in place for assessing state-wide opioid prescription totals, routinely expunged collected data, or only instituted a reporting mechanism toward the end of our study. Conclusion: Total opioid prescriptions were relatively unchanged following the 2014 DEA-mandated schedule change, however, physicians did change their prescribing habits by substituting tramadol for hydrocodone combination products. This substitution of similar medications for hydrocodone suggests alternative approaches are needed to reduce total US opioid prescription rates. Additionally, the current lack of standardized prescription reporting by states makes detailed opioid prescription analysis alarmingly difficult and insufficient to guide policy or monitor the impact of policy changes.

The US Food and Drug Administration recently granted an approved indication for the first fixed-dose combination antihypertensive (amlodipine) and nonsteroidal anti-inflammatory drug (celecoxib) for treatment of comorbid hypertension and osteoarthritis. This review summarizes available data on this combination product, to be marketed as Consensi (Kitov Pharmaceuticals, Ltd, Tel Aviv, Israel), and discusses its potential place in therapy.

Low dose mixing and its optimization process parameters are facing more challenges. Moreover, minor variation in a dose will tend to significantly have a huge impact on the products’ performance including safety and efficacy of the dosage form. Hence, the characterization in every stage of product development of a low dose compound is mandatory. For this purpose, glimepiride and metformin in the ratio of 1:500 was formulated into tablet deciphering a fixed-dose combination product. The tablet was prepared by wet granulation method and optimized by time-dependent random mixing. Confocal Raman microscopy was employed for the present work for evaluation of compatibility studies, in-process and post-compression parameters. Further, the microscopical evaluation was done for the particle scout analysis. The obtained results indicated that the powder blend was compatible and provided uniform mixing in 20 min. Microscopical evaluation has shown that glimepiride still existed in the amorphous state even after compression. Moreover, the glimepiride area in the single-layer was found to be 0.06%. With this, we propose that confocal Raman microscopy plays the promising role in the detectability of the glimepiride. Therefore, in future, the layer by layer analysing can be opted to study the entire spatial arrangement of the API and excipients, which may tend to have a better understanding of dissolution and their related parameters.

Objectives This study aimed to design a fixed-dose combination dosage form which provides a sustained release profile for both the freely water-soluble metformin HCl and the poorly soluble gliclazide, two antidiabetic compounds used to treat diabetes mellitus. Methods Hot-melt co-extrusion was used as an innovative manufacturing technique for a pharmaceutical fixed-dose combination product. In this way, a matrix formulation that sustained metformin release could be developed, despite the high drug load in the formulation and the freely soluble nature of the drug. Key findings It was clear that co-extrusion was perfectly suited to produce a fixed-dose combination product with adequate properties for each of the incorporated APIs. A coat layer, containing at least 30% CAPA® 6506 as a hydrophobic polymer, was necessary to adequately sustain the release of the highly dosed freely soluble drug from the 70% metformin HCl-loaded CAPA® 6506 core of the co-extrudate. To obtain a complete gliclazide release over 24-h solubilization in Kollidon® VA, added as a second polymer to the CAPA® 6506 in the coat, was needed. Conclusions Both active pharmaceutical ingredients (APIs), which have different physicochemical characteristics, were formulated in a single dosage form, using co-extrusion.

Objectives To evaluate the effect of ritonavir (RTV) co-administration on the bioavailability of an amorphous dispersion of acetyl-11-keto-beta-boswellic acid (AKBA) and to develop a pharmaceutically acceptable AKBA–RTV combination tablet. Methods A pharmacokinetic (PK) study in rats was conducted to evaluate the influence of RTV co-administration on the oral bioavailability of an AKBA amorphous dispersion. KinetiSol was utilized to enable production of an improved RTV formulation that facilitated the development of an AKBA–RTV combination tablet. Following in-vitro characterization, the PK performance of the tablets was evaluated in male beagles. Key findings Co-administration of RTV increased oral absorption of AKBA by about fourfold over the AKBA dispersion alone and approximately 24-fold over the pure compound. The improved RTV amorphous dispersion exhibited similar purity and neutral-phase dissolution to Norvir. The AKBA–RTV combination tablets yielded a substantial increase in AKBA's bioavailability in dogs. Conclusions Oral absorption of AKBA is substantially limited by intestinal CYP3A activity and poor aqueous solubility. Consequently, AKBA's oral bioavailability is maximized by administration from a supersaturating formulation in conjunction with a CYP3A inhibitor. The AKBA–RTV combination tablet presented herein represents a breakthrough in the oral delivery of the compound facilitating future use as a drug therapy for broad spectrum cancer treatment.

A Simple, Precise, Sensitive and time efficient stability indicating reverse phase Ultra Performance Liquid Chromatography (RP-UPLC) method was developed and validated for the simultaneous determination of Acetaminophen and Tramadol impurities present in fixed dose combination product. The components were separated in gradient elution mode using 0.1% Perchloric acid in water and acetonitrile as mobile phase. The column used was Acquity HSS T3 (100 mm x 2.1 mm, 1.8 µ) at a flow rate of 0.5 mL.min−1 with 30°C temperature. Quantification was achieved with detection wavelength of 215 nm. The developed method was validated for specificity, linearity, precision, accuracy, sensitivity (LOD & LOQ) and robustness in accordance with International Conference on Harmonisation (ICH) guidelines. The method is rapid, cost effective for the quantitative determination of Acetaminophen and Tramadol impurities in Acetaminophen and Tramadol tablets dosage forms.

Background Topical treatments are usually effective in mild psoriasis. However, the complexity of their use may result in low patient adherence with treatment. Combination of a vitamin D analog and a corticosteroid into a two-compound topical formulation has increased efficacy compared with either drug administered alone. Once-daily application of such a product would likely improve adherence. The purpose of this study was to determine whether twice-daily application of a calcipotriene + betamethasone topical formulation can provide improved clinical outcomes compared with once-daily treatment with the same product. Methods A review of the literature was performed seeking clinical trials comparing once-daily versus twice-daily application of calcipotriene + betamethasone topical formulations for the treatment of psoriasis. Results We found only one relevant clinical trial. This study showed similar efficacy and safety with once-daily versus twice-daily application of a topical calcipotriene + betamethasone formulation in the treatment of psoriasis vulgaris. Conclusion Once-daily application of a topical calcipotriene + betamethasone formulation may offer increased patient convenience and potentially increased patient adherence with long-term treatment, compared with twice-daily use, without reducing the efficacy. In order to enhance adherence, patient preference regarding frequency of application of topical treatments should be considered when prescribing medications.

In 2014, the US Food and Drug Administration limited the production of prescription acetaminophen-opioid combination products to 325 mg per dose unit. The goal of this mandate was to decrease the likelihood of unintentional acetaminophen hepatotoxicity. This study was designed to determine if this federal regulation has succeeded in reducing unintentional acetaminophen-induced hepatotoxicity from opioid combination products. Using data from the National Poison Data System (NPDS), we analyzed all calls to US Poison Control Centers in the years 2013 and 2015 for acetaminophen-opioid combination product exposures. We then excluded cases that were classified as intentional and those aged 12 years and younger. We used a primary endpoint of N-acetylcysteine administration; secondary endpoints included evidence of hepatotoxicity as aspartate aminotransferase elevation, opioid antagonist administration and severity of overall medical outcome. A total of 18,259 calls between the two yearlong periods met inclusion criteria. 5.16 and 5.01% of calls resulted in N-acetylcysteine administration in 2013 and 2015, respectively. 3.63 and 4.02% received naloxone in 2013 and 2015, respectively, and 0.9% in each year developed hepatotoxicity. Rates of N-acetylcysteine administration, naloxone administration, and hepatotoxicity did not differ significantly between 2013 and 2015. Severity of medical outcome was worse in 2015 as compared to 2013 with more cases being categorized as “major effect” and fewer cases being categorized as “no effect.” The Food and Drug Administration limitation on acetaminophen content per dose unit in opioid combination products did not reduce the occurrence of unintentional acetaminophen-induced hepatotoxicity or N-acetylcysteine administration as reported to NPDS.

Three separate randomized, blinded, vehicle-controlled studies were conducted to determine the effectiveness of a single treatment and consecutive monthly treatments of a combination flavored tablet product containing spinosad and milbemycin oxime (MBO) in the prevention of the establishment of heartworm infections in dogs challenged with recent field isolates of the heartworm (HW), Dirofilaria immitis. For each study, dogs were allocated randomly based on pre-treatment body weights to treated or control groups of 10 animals each. Dogs were infected once with infective HW larvae, on Day-30, using either a Michigan isolate or a Georgia (MP3) isolate of D. immitis. Treatments of beef-flavored chewable tablets were administered in two studies one time either on Day 0 or Day 15, and in one study twice (Days 0 and 30, or Days 15 and 45) or 3 times (Days 0, 30 and 60). For the combination product groups, dosages were in the range of 30-45 mg/kg (13.6-20.5mg/lb) for spinosad and 0.5-0.75 mg/kg (0.2-0.34 mg/lb) for MBO. Necropsies for heartworm counts were completed following euthanasia on Day 120 or Day 123. A single treatment with the combination product of spinosad and MBO 30 or 45 days post-inoculation with infective HW larvae was completely effective (100%) in preventing establishment of the Michigan D. immitis isolate, but efficacy against the Georgia MP3 isolate was incomplete, with geometric mean reductions in HW counts relative to vehicle treated controls of 99% reduction of the 30 day infection and a 98.9% reduction of the 45 day old infection. Against this same MP3 isolate, 3 consecutive monthly treatments provided complete prevention (100%) against establishment of D. immitis infections. The combination product of spinosad and MBO provides effective control of canine heartworms. A single treatment at 30 days post infection showed high but incomplete effectiveness against a heartworm isolate that had been shown to be partially refractory to treatment with marketed monthly heartworm preventives. Three consecutive monthly treatments provided complete control, providing support to the recommendation that heartworm prophylaxis should be maintained year round for optimal effectiveness.

He, J., Tang, S., Li, L., Zhang, C., Li, X., Xia, X., Xiao, X. Pharmacokinetics of a novel amoxicillin/colistin suspension after intramuscular administration in pigs. J. vet. Pharmacol. Therap. 34, 42–50. An amoxicillin (AMO) or colistin (COS) oil suspension was developed and corresponding pharmacokinetics studies were conducted in pigs after i.m. injection. The combination product is a white- to cream-colored oil suspension which is easy to be re-dispersed. Settling volume ratio, syringeability and flowability of the product is well consistent with the technical standards set by the Ministry of Agriculture of People’s Republic of China. Two studies were conducted to investigate the pharmacokinetics of the combination product in swine. First, the pharmacokinetics of the combination product was compared with those of the same products merely removing either AMO or COS. No significant change in the major pharmacokinetic parameters (Cmax, Tmax, MRT, t1/2λ, AUC and AUMC) was observed when either component was removed from the combination product, indicating that AMO and COS do not interfere with each other in their absorption and distribution in the tissue when used as a combination. Second, the pharmacokinetics of the combination product was compared with that of their respective single products. It was found that the apparent elimination half-lives (t1/2λ) of AMO and COS in combination product were 6.38 and 8.09 h, which were 2.40 and 2.38 times longer than the single products, respectively. Thus, the novel AMO/COS suspension extended significantly the half-life of both drugs to maintain a longer drug residence time in pigs when compared to their single products.

While beta-lactam antibiotics remain among the most commonly prescribed pharmaceutical products, their effectiveness is currently threatened by the development of bacterial resistance. One key resistance mechanism is the ability to destroy the antibiotic through utilization of one or more types of beta-lactamase. An effective countermeasure is to employ a combination product, consisting of both a beta-lactam antibiotic and a beta-lactamase inhibitor. Unfortunately, currently available inhibitors narrowly target only class A beta-lactamases. This review will detail our research, directed toward the development of a useful broad-spectrum beta-lactamase inhibitor. In the process, we have discovered new inhibitors capable of simultaneously inactivating class A, C, and D beta-lactamase, produced conjugate siderophore/beta-lactamase inhibitors, and explored the SAR's of tunable, cephalosporin-derived beta-lactamase inactivators. Useful synthetic methodology will be described, which simplifies the large scale production of many known inhibitors and which allows the rapid preparation of libraries of prospective inhibitors.

IN A RECENT survey of 300 patients who underwent an inpatient or outpatient surgical procedure, 65% reported experiencing moderate, severe, or extreme acute postoperative pain. Although effective postoperative pain control is the goal, it must be done safely in all patients particularly when opioids are used. A multimodal analgesic approach, where two or more drugs that act by different mechanisms are used, strives to achieve superior analgesia at the lowest effective opioid dose (‘‘opioid-sparing’’) or in some cases, avoiding opioids altogether. The hydrocodone and acetaminophen combination product (Vicodin, AbbVie Inc.; Norco, Watson Laboratories, Inc.) was developed to provide superior analgesia to either drug alone.

Advicor (lovastatin and extended-release niacin) is the first cholesterol-lowering combination product to become available for the management of hyperlipidemia. Lovastatin significantly lowers low-density lipoprotein cholesterol, whereas niacin significantly lowers triglycerides and lipoprotein (a) and markedly increases high-density lipoprotein cholesterol. These effects are ideal for managing a variety of lipid disorders, including metabolic syndrome. Lovastatin and niacin reduce coronary heart disease mortality in primary and secondary prevention patients, respectively. The extended-release niacin component uses a unique technology to minimize adverse effects (e.g., flushing and hepatotoxicity) while retaining the same lipid-altering effects as immediate-release niacin. The combination product appears to be well tolerated, with discontinuation due to adverse effects other than flushing occurring in a similar percent of patients as for lovastatin in clinical trials. Approximately 9% of patients discontinued the combination product due to flush. No confined cases of myopathy or hepatotoxicity have been reported with this product. Once-daily dosing provides ease of administration that should improve compliance and result in a greater proportion of patients meeting their low-density lipoprotein cholesterol goals. The nomenclature surrounding niacin products used to treat dyslipidemias is confusing. While only two types of niacin formulations exist (immediate-release formulations and formulations which dissolve more slowly than immediate-release formulations), government regulations allow for slowly dissolved niacin formulations to be divided into two types of niacin products; those that are available over-the-counter (OTC) and those that are available by prescription only. Over-the-counter slowly dissolved niacin preparations are not classified as OTC per se, but are considered "nutritional supplements". For this reason, they fall under the jurisdiction of the Federal Trade Commission and do not fall under the umbrella of the FDA branch that controls dyslipidemic products (Endocrine and Metabolic Division of the Center for Drug Evaluation and Research). The slowly dissolved niacin nutritional supplements have not been reviewed by the FDA for safety nor efficacy in the treatment of dyslipidemia nor are they required to meet generic drug rules (even though various brands are available). These brands are described on their labels as "sustained-release", "timed-release", and "slow-release" for example. Only two slowly absorbed niacin products have been approved by the FDA for the treatment of dyslipidemia; they are Niaspan (Kos Pharmaceuticals, Inc., Miami, FL) and Advicor (Kos Pharmaceuticals, Inc., Miami, FL). The term "extended-release" has been given to these two products to simplify the terminology and differentiate the products from immediate-release niacin. In this review, we will use "extended-release" to refer to the FDA approved slowly dissolving niacin preparation and "sustained-release" to refer to the nutritional supplements (not FDA approved).

When a new drug therapy is introduced, it is important to consider the economic impact of the treatment. This is particularly relevant for a chronic disease such as asthma. Despite an increased understanding of the physiology of asthma, this condition remains an important cause of morbidity and mortality in many countries and places a large financial burden on healthcare systems.

Asthma is a common chronic disease that places a large financial burden on healthcare systems and society. It is therefore important to consider the economic impact of new asthma therapies. Three economic analyses were performed using clinical data from multicentre comparative trials of a salmeterol/fluticasone propionate combination product (50/100, 50/250 and 50/500μg twice daily) with fluticasone propionate alone (100, 250 and 500μg twice daily, respectively) in patients with asthma. Successfully treated weeks, symptom-free days and episode-free days were the parameters used to assess treatment effectiveness. The analyses were conducted from the perspective of the Swedish healthcare system and considered direct healthcare and drug costs. Cost-effectiveness and incremental cost-effectiveness ratioswere determined, and extensive sensitivity analyses were performed. This paper summarises the methods used to evaluate the study objectives.

Background The use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV). Methodology/Principal Findings Biodegradable poly(lactide-co-glycolide) nanoparticles loaded with efavirenz (NP-EFV) or saquinavir (NP-SQV) were individually prepared by emulsion or nanoprecipitation techniques. Nanoparticles had reproducible size (d ∼200 nm) and zeta potential (-25 mV). The drug loading of the nanoparticles was approximately 7% (w/w). NP-EFV and NP-SQV were nontoxic to TZM-bl cells and ectocervical explants. Both NP-EFV and NP-SQV exhibited potent protection against HIV-1 BaL infection in vitro. The HIV inhibitory effect of nanoparticle formulated ARVs showed up to a 50-fold reduction in the 50% inhibitory concentration (IC50) compared to free drug. To quantify the activity arising from delivery of drug combinations, we calculated combination indices (CI) according to the median-effect principle. NP-EFV combined with free TFV demonstrated strong synergistic effects (CI50 = 0.07) at a 1∶50 ratio of IC50 values and additive effects (CI50 = 1.05) at a 1∶1 ratio of IC50 values. TFV combined with NP-SQV at a 1∶1 ratio of IC50 values also showed strong synergy (CI50 = 0.07). Conclusions ARVs with different physicochemical properties can be encapsulated individually into nanoparticles to potently inhibit HIV. Our findings demonstrate for the first time that combining TFV with either NP-EFV or NP-SQV results in pronounced combination drug effects, and emphasize the potential of nanoparticles for the realization of unique drug-drug activities.

To determine whether patients given prescriptions for acetaminophen-containing narcotic analgesics receive appropriate discharge instructions to reduce their intake of or stop taking other acetaminophen-containing products, we evaluated discharge instructions given by an urban, tertiary-care emergency department from September 1 to September 18, 2001 to find patients discharged while taking narcotic-analgesic compounds containing acetaminophen. We evaluated these discharge instructions to determine whether they included instructions to reduce or discontinue the use of acetaminophen compounds. Among the 1,505 discharge instructions evaluated, we found that 108 patients were discharged with a narcotic-analgesic combination product containing acetaminophen. Of these 108 patients, none of those given a prescription for such an acetaminophen-containing product was instructed to reduce or discontinue the use of other acetaminophen products. Emergency physicians, during the specified study period, did not explain to their patients the need to reduce the use of other acetaminophen-containing products when prescribing acetaminophen-containing medications. Further inquiry into this potentially dangerous activity is warranted.

The development of combination products (CPs) is a challenging field that faces complex product jurisdiction and development issues. Despite these issues, companies are driven by the potential therapeutic success of combining two components into a single product. The driving force behind this new enthusiasm is the local delivery of drugs or biologics to a specific tissue, thereby minimizing the exposure of the whole body to potential toxic compounds as well as maintaining drug/biologic levels at a specific site within a tissue to obtain a desired therapeutic response. As a recent example, Cordis, a subsidiary of Johnson & Johnson, successfully commercialized the CYPHER™ Sirolimus-Eluting Coronary Stent, bringing cardiologists a promising new therapy for the prevention of restenosis. The CYPHER Sirolimus- Eluting Coronary Stent consists of a device that brings a drug component to the coronary tissue to maintain vessel patency by minimizing the occurrence of restenosis following stent implantation. The device component provides mechanical prevention of restenosis, whereas the drug component delivers a pharmacologic/biologic locally to assist in the vessel’s recovery from any injury caused by the stent implantation. Cordis developed this product with both speed and regulatory finesse. The dramatic clinical trial results indicate the CYPHER Sirolimus-Eluting Coronary Stent is a very promising new therapy.1

PurposeTo compare the safety and efficacy of the fixed combination product with nonfixed combination use of the same active ingredients in separate bottles (bimatoprost oncedaily [qd], and timolol ...

Lotrisone® a topical agent intended for the treatment of cutaneous fungal and yeast infections, is a combination of the broad spectrum antifungal/anticandidal agent clotrimazole and the antiinflammatory corticosteroid betamethasone dipropionate. While the individual ingredients in the formulation have been safely marketed for many years, dermal safety testing of the combination product was considered necessary. The potential of the product to check contact irritation or sensitization reactions or photocontact irritation or sensitization reactions was determined using modifications of standard methodologies. The new combination formulation did not elicit any contact photo-irritant, contact photosensitization, or contact sensitive reactions and was not considered to be any more irritative than controls. Results from predictive tests—where possible-were in agreement with those from clinical experiences.

Cost reduction resulting from decreasing the number of theophylline products on a hospital formulary is reported. A special review subcommittee of the pharmacy and therapeutics (P&T) committee of a 1049-bed hospital was appointed to study tee literature on theophylline preparations. Bids were requested on all theophylline preparations. Bids were requested on all theophylline products. The subcommittee recommended one liquid preparation, one combination product, two sustained-release products, and two rapid-release solid oral theophylline products for inclusion in the formulary. The P&T committee approved the action, and all other oral and rectal theophylline products were deleted. In 1978 (before the product reduction), the hospital purchased 357,551 doses of theophylline at a cost of $27,926.10. In 1979, this cost was reduced to $11.624.39 for 309.069 doses, a savings of over $16,000. Substantial cost savings can be achieved by reducing the number of therapeutically equivalent products and by using teh bid system.

SUMMARY Beta adrenoceptor blocking drugs and diuretics are frequently given together to control hypertension and increasingly the two agents are being combined in a single preparation. Possible interactions between the two agents are therefore of interest. In this study the addition of chlorthalidone has been shown not to influence the plasma levels or beta-blocking action of a sustained release form of metoprolol. In addition, when the combination product containing sustained release metoprolol and chlorthalidone is given over 21 days, the plasma levels of each drug are similar to those reported for each drug when given alone.

A double-blind trial of a combination tablet containing orphenadrine and paracetamol, ‘Norgesic', was carried out to assess the value of this product compared with paracetamol alone. All three symptomatic parameters which were measured: pain, spasm and impaired activity, showed a significantly quicker recovery when the combination product was used. Further studies are necessary to evaluate the combination product against orphenadrine citrate alone.

To obtain a direct clinical evaluation of a new sulpha-trimethoprim combination product (Kelfiprim®) from general practitioners or specialist practitioners, an extensive post-marketing survey has been organized in Brazil involving 1,177 doctors and 5,885 patients. These experienced different infections susceptible to oral antimicrobial chemotherapy with a sulpha-trimethoprim combination. The results indicated that the product was very effective (91.2% cure rate) and well tolerated (4% incidence of side-effects). Side-effects were usually mild and transient. No life-threatening adverse reactions were observed. The results obtained support those already published in clinical trials involving 1,119 patients.