Fixed combination therapy

Fixed combination therapy. A combination of two or more treatments combined in one pharmaceutical formulation so that they are delivered together. 

A fixed combination of ICS plus long-acting P2-agonist, such as fluticasone/salmeterol or budes-onide/formoterol, is available and may simplify therapy. However, new insights in treating patients with these combinations on an as needed regimen in combination with a daily low dose maintenance therapy, is still debated. 

Lopinavir is available in the United States only as a fixed-dose combination with ritonavir (Kaletra). In this regimen, a low dose of ritonavir is used to inhibit the rapid inactivation of lopinavir by CYP3A4. Side effects, which are generally mild, include diarrhea, nausea, asthenia, and headache. Pancreatitis occurs rarely. Ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6. In addition to the drugs contraindicated for all protease inhibitors, fiecainide, propafenone, pimozide, and rifampin should not be given with lopinavir-ritonavir combination therapy. 

To decrease the likelihood of irritation, application should be limited to a low concentration (2.5%) once daily for the first week of therapy and increased in frequency and strength if the preparation is well tolerated. Fixed-combination formulations of 5% benzoyl peroxide with 3% erythromycin base (Benzamycin) or 1% clindamycin (BenzaClin) appear to be more effective than individual agents alone. 

Suggestive case histories raised at an early phase the notion of a possible correlation of oral contraceptives with endometrial cancer. Among cases of endometrial cancer there seemed to be an excess of users of oral contraceptives, particularly of the early high-dose estrogen type. With the virtual demise of these early products, the situation seems to have reversed a 1983 study from the Centers for Disease Control (CDC) in Atlanta showed that women who had used fixed combinations for oral contraception at some time in their lives had a relative risk of endometrial cancer of only 0.5 compared with never-users (112). The protective effect occurred only in women who had used oral contraception for at least 12 months, and lasted for at least 10 years after withdrawal. The WHO adopted the same view in 1988 in the light of multinational data (113). As in the case of hormonal replacement therapy, the protective effect seems to be due to the progestogen component. 

Clindamycin has in vitro activity against Propionibacterium acnes this has been postulated as the mechanism of its beneficial effect in acne therapy. Approximately 10% of an applied dose is absorbed, and rare cases of bloody diarrhea and pseudomembranous colitis have been reported following topical application. The hydroalcoholic vehicle may cause drying and irritation of the skin, with complaints of burning and stinging. The water-based gel and lotion formulations are well tolerated and less likely to cause irritation. Allergic contact dermatitis is uncommon. Clindamycin is also available in a fixed-combination topical gel with benzoyl peroxide (BenzaClin). 

In 2001, tenofovir disoproxil fumarate 61, a prodrug of tenofovir was approved for treatment of HIV, subsequently being preregistered in the USA for treatment of hepatitis B. Emtricitabine 62, a reverse transcriptase inhibitor, was approved in 2003 for HIV. What is of import is that these compounds are now part of fixed dose combination therapies for treatment of HIV, either two drug (tenofovir disoproxil fumarate/emtricitabine) or three drug Atripla (tenofovir disoproxil fumarate/emtricitabine/efavirenz) formulations. Thus, even 50 + years after Bergmann s discovery of bioactive arabinose nucleosides, small molecules synthesised as result of his discoveries are still in clinical use and others are in clinical trials for treatment of viral diseases. 

Bamebey HS, Orengo-Nania S, Flowers BE, et al.The safety and efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution.Am J Ophthalmol 2005 140 1-7. Bartlett JD, Olivier M, Richardson T, et al. Central nervous system and plasma lipid profiles associated with carteolol and timolol in postmenopausal black women.) Glaucoma 19S>9 8 388-395. Becker B. Use of mettiazolamide (Neptazane) in the therapy of glaucoma comparison with acetazolamide (Diamox). Am ) Ophthalmol 1960 49 1307-1311. 

Use of Topical CAIs in Clinical Practice. Although, as monotherapy, this class of medication can lower lOP by -20%, topical CAIs are generally used as adjunctive therapy either as an additional separate administration or, more commonly, in a fixed combination with timolol maleate (Cosopt). It is important to explain to patients that this medication can be uncomfortable on the eye and that they may experience a bitter metalUc taste associated with its use. This side effect is far more common with dorzolamide than brinzolamide. 

Abacavir plus lamivudine plus zidovudine, wliich is coimnercially available as a fixed combination in a single tablet, has inferior rates of viral suppression and should only be used when an NNRTI or a Pl-based regimen cannot or should not be used as first line of therapy. 

Combined therapy of NSAIDs plus low-efficacy opioid, either as a fixed-dose formulation, which is convenient for acute pain or separately to find the optimum dose of each, which may be preferable for chronic pain though less convenient. 

A variable-dose plasma concentration-controlled approach to combination antiretroviral therapy (zidovudine, lamivudine, and indinavir) has been compared with conventional fixed-dose therapy in 40 patients in a randomized, 52-week, open trial (6). Significantly more concentration-controlled recipients achieved the desired concentrations for aU three drugs there was a good response in 15 of 16 concentration-controlled recipients compared with nine of 17 conventional regimen recipients. However, there was no difference in the occurrence... 

PBS listing on medical grounds, economic factors including cost-effectiveness are taken into account, as required by the National Health Act, 1953. Fixed combination products are seldom considered suitable for inclusion in the PBS. Notable exceptions to this norm are oral contraceptives and combination hormone replacement therapies. Any new listing which has the potential to cost the PBS more than 10 million in the first full year of reimbursement must be approved by the Federal Cabinet. Otherwise, applications are approved by the Health Minister. 

The manufacturer does not recommend use of the fixed combination as initial therapy of primary hypercholesterolemia or mixed dyslipidemia. It is specifically Indicated in patients receiving lovastatin alone plus diet who require an additional reduction in triglyceride levels or increase in HDL cholesterol levels it is also Indicated In those treated with niacin alone who require additional decreases in LDL cholesterol. 

Atovaquone (mepron) has potent activity against Plasmodium species and the opportunistic pathogens Pneumocystis jirovici arul Toxoplasma gondii it is FDA approved for treatment of P. jirovici pneumonia in patients intolerant of trimethoprim-sulfamethoxazole. In patients with uncomplicated P. falciparum malaria, combination therapy with proguanil and atovaquone evoked high cure rates with few relapses and minimal toxicity. A fixed combination of atovaquone with proguanil (maiarone) is available in the U.S.for malaria prophylaxis and treatment. 

The greater amount of dopamine that is formed in the brain after orally administered levodopa/carbidopa presumably provides symptomatic relief of parkinsonian symptoms, such as rigidity and bradykinesia. Parkinsonian patients not previously treated with levodopa usually are started on a combination therapy with Sinemet, which is available in a fixed ratio of 1 part carbidopa and 10 parts levodopa. Once formed from levodopa, metabolism of dopamine then proceeds relatively rapidly to the principal excretion products 3,4-dihydroxyphenylacetic acid and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid) (Fig. 25.2). 

Free combination therapy (or drug). A therapy consisting in combining two or more individual treatments but without physically incorporating them into one formulation so that, unlike a fixed combination, each constituent treatment could still, in principle, be given alone. 

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