(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects, Treatment, and Precautions

Acute infusion reactions during or within 1 to 2 hours of infusion are common with infliximab, and other TNF inhibitors, particularly with the first or second dose. Symptoms include fever, chills, pruritus, urticaria, dyspnoea, chest pain, and hypertension or hypotension. Mild reactions may respond to a reduced rate of infusion or a temporary interruption. If reactions are more severe, therapy should be stopped. Pretreatment with paracetamol, corticosteroids, and antihistamines may be considered. TNF inhibitors should only be given where facilities for resuscitation are available. Delayed reactions have occurred 3 to 12 days after infliximab treatment symptoms include myalgia, arthralgia, fever, and rash. Similar delayed reactions may also be seen when infliximab has been restarted after an extended period without treatment (see below). Other, common, adverse effects include nausea and vomiting, abdominal pain, diarrhoea, fatigue, dizziness, headache, and back pain. Antibodies to infliximab (human antichimeric antibodies) may develop, and are associated with an increased incidence of hyper sensitivity reactions. Antinuclear antibodies and anti-double-stranded-DNA antibodies have also developed with TNF inhibitor therapy. A lupus-like syndrome has occurred rarely treatment should be stopped if it develops.

Infections are common in patients treated with infliximab or other drugs that inhibit TNF, and most often affect the upper respiratory tract and the urinary tract. TNF inhibitors have also been associated rarely with the development of serious opportunistic infections, sepsis, pneumonia, and onset or reactivation of tuberculosis (see below), particularly in patients with underlying conditions predisposing them to infections in some cases death has resulted. TNF inhibitors should not be given to patients with severe infection, including active tuberculosis, abscesses, and opportunistic infections, and should be stopped if these develop. Patients should be evaluated for latent and active tuberculosis before beginning therapy if evidence of latent tuberculosis is found, the risks and benefits of treatment should be considered carefully and chemoprophylaxis should be started before giving a TNF inhibitor. They should also be used with care in those with chronic infections, a history of recurrent infections, or with underlying conditions that may predispose to infections. Patients with fistulising Crohn’s disease with suppurative fistulas should not be given infliximab until possible infection sources such as abscesses have been ruled out. Patients should be instructed to seek medical advice if symptoms suggestive of tuberculosis (such as persistent cough, weight loss, or low grade fever) occur. Patients should be monitored for signs of infection after stopping treatment: for adalimumab and infliximab, which both have long half-lives, monitoring should continue for 5 or 6 months, respectively because of its relatively shorter half-life, the elimination of etaner-cept may be quicker.

There have been rare reports of severe hepatic reactions such as acute liver failure, jaundice, hepatitis, and cholestasis with infliximab some cases have been fatal or required transplantation. Patients with signs or symptoms of hepatotoxicity should be evaluated and infliximab should be stopped in those patients with jaundice or marked elevations in liver enzyme values. Infliximab and other TNF inhibitors have also been associated with the reactivation of hepatitis B in chronic carriers, which has resulted in fatalities in some cases. Patients at risk of hepatitis B infection should be screened before starting treatment it is recommended that carriers treated with a TNF inhibitor are closely monitored during, and for several months after stopping, treatment.

Blood dyscrasias, including leucopenia, thrombocytopenia, pancytopenia, and aplastic anaemia, have been reported rarely with TNF inhibitors in some cases the outcome was fatal. They should be used with caution in patients with a history of blood dyscrasias. Rare, and sometimes fatal, cases of interstitial lung disease including pulmonary fibrosis and pneumonitis have been reported with TNF inhibitors. Infliximab and other TNF inhibitors are also associated with an increased incidence of malignancies including lymphoma (see also Carcinogenicity, below), although occurrences are rare. Some groups of patients treated with TNF inhibitors may already have an increased background risk of developing malignancies, regardless of drug treatment. Care has been advocated in patients with a history of malignancy. Anaphylactic reactions have been reported rarely with TNF inhibitors. Infliximab should be avoided in patients with a history of hyper sensitivity to the drug or other murine proteins.

TNF inhibitors have been associated in rare cases with seizures and clinical or radiological worsening of demyelinating disorders such as multiple sclerosis or optic neuritis care is required in prescribing it to patients with such disorders or symptoms suggestive of their onset.

Worsening and, in some cases, new-onset heart failure has been reported with TNF inhibitors (see Effects on the Heart, below). (NYHA class III or IV). In the UK, infliximab is contra-indicated in patients with moderate to severe heart failure however, US licensed product information advises that doses up to 5 mg/kg may be used in such patients. It should be used with caution in patients with mild heart failure (NYHA class I or II). All patients with heart failure should be closely monitored and infliximab stopped in those who develop new or worsening symptoms of heart failure. Similar recommendations are given for the TNF inhibitors adalimumab and etanercept, although UK licensed information for etanercept only advises caution in patients with heart failure.

Carcinogenicity. Malignancies, especially lymphomas, have been seen in patients treated with TNF inhibitors for rheumatoid arthritis and Crohn’s disease however, the suggestion of a causal relationship is controversial. A meta-analysis in 2006 identified 24 published reports of malignancies in 3493 study patients with rheumatoid arthritis who had received at least one dose of a TNF inhibitor (adalimumab or infliximab) along with 2 cases in 1512 control patients further, unpublished, cases were also found using FDA data to give 29 malignancies in the treatment groups and 3 in the control groups. Based on these figures, there was a 3.3-fold increase in the risk of malignancy in patients receiving TNF inhibitors when compared with controls. These results have, however, been criticised on a number of points including the difficulty in applying them to current practice because etanercept was not included in the analysis, and, in particular, the unexpectedly low rate of malignancies in the control groups. Other studies in patients with rheumatoid arthritis’ and Crohn’s disease have generally concluded that the overall risk of malignancies is not significantly increased in patients taking TNF inhibitors when compared with patients who have not taken these drugs. Some studies’ in patients with rheumatoid arthritis have, however, shown a possible increased risk of lymphoma with TNF inhibitor treatment, but caution in interpreting these results was recommended as they were based on a small number of cases in addition, the background risk of lymphoma is increased in rheumatoid arthritis regardless of treatment. The risk of malignancies with TNF inhibitors requires further study. Rare cases of hepatosplenic T-cell lymphoma have been seen in adolescents and young adults given infliximab for the treatment of Crohn’s disease. In July 2006, the manufacturer was aware of 6 cases of this type of lymphoma in 5 adolescents aged 12 to 19 years and one 31 -year-old adult 4 of the 6 cases occurred in males. The treatment duration ranged from 1 or 2 infusions to over 4 years of therapy in all cases, patients were also taking or had taken azathioprine or 6-mercaptopurine. This type of lymphoma is aggressive and 5 of the above patients died. A causal relationship was not clearly established although it could neither be excluded. Further cases have since been reported.

Delayed reactions. Ten of 37 patients with Crohn’s disease retreated with infliximab after a 2 to 4 year period without treatment had delayed hypersensitivity reactions, of which 6 were considered serious. None of the patients had had infusion-related adverse effects with their original infliximab therapy. Adverse reactions developed in 9 of the 23 patients originally treated with a discontinued liquid formulation, and in 1 of the 14 patients who previously received the marketed formulation, leading to speculation that the formulation may have been a contributing factor.

Effects on blood lipids. A 35-year-old man with psoriatic arthritis and psoriasis developed markedly elevated triglyceride levels and a mildly increased total cholesterol level after a single infusion of infliximab tests prior to therapy had shown a mild hypertriglyceridaemia for which he had received no treatment. No further doses of infliximab were given and his triglyceride levels subsequently improved.

Effects on the CNS. Aseptic meningitis developed in a patient after his fifth injection of infliximab for rheumatoid arthritis. Similar symptoms also occurred after a sixth injection. Two patients with inflammatory bowel disease developed acute motor neuropathy with multiple conduction blocks following infliximab treatment both patients improved after infliximab was stopped. Similar adverse effects were reported in 2 further patients : one was taking etanercept for rheumatoid arthritis and the other infliximab for ankylosing spondylitis. Three cases of bilateral optic neuropathy associated with infliximab therapy have also been reported. Other neuropathies have been associated with TNF inhibitor treatment, including Guillain-Barre syndrome.

Effects on the heart. The FDA has reported on 47 patients who developed heart failure during long-term therapy with TNF antibodies (etanercept and infliximab) for arthritic conditions or Crohn’s disease. Of these, 38 developed new-onset heart failure, 19 having documented risk factors for heart failure, and 9 had exacerbation of existing heart failure. The median time to new-onset heart failure was 3.5 months. However, studies investigating a possible association between TNF inhibitors and the development of heart failure have been equivocal and further investigation is warranted.

Preliminary investigations on the use of infliximab in the treatment of moderate to severe heart failure failed to show any clinical improvement in patients given infliximab 5 mg/kg or 10 mg/kg when compared with placebo in addition, those given the higher dose had an increased risk of death or hospitalisation due to worsening heart failure.

Effects on the lungs. Infliximab treatment has been associated with a fatal exacerbation of previously asymptomatic fibrosing alveolitis in 3 patients with chronic rheumatoid arthritis all 3 patients were also taking azathioprine and prednisolone. There was no evidence of infection or other underlying causes for the decline in respiratory function.

Effects on the skin. Patients with rheumatoid arthritis receiving TNF inhibitor therapy are more likely to develop adverse skin reactions than those who are not. Of 289 patients taking TNF inhibitors (infliximab, etanercept, adalimumab, and lenercept), 72 (25%) reported 128 dermatological events including skin infections, eczema, drug-related eruptions, and malignancies such as actinic keratosis of the 289 patients not taking TNF inhibitors, 37 (13%) reported dermatological events. In another review, cutaneous adverse effects were seen in 35 out of 150 patients receiving TNF inhibitors (adalimumab, etanercept, or infliximab) for rheumatic disorders cases included dermatitis herpetiformis and leucocytoclastic vasculitis although eczematous and skin infections were more common or infectious. Perhaps unexpectedly, psoriasis-like lesions were seen in 8 patients, 6 of whom had no history of psoriasis similar effects have also been noted in other patients with rheumatoid arthritis or Crohn’s disease.

Rare cases of serious skin reactions have been associated with TNF inhibitor treatment. Since approval in 1998, the FDA has received 15 cases of erythema multiforme, 5 cases of Stevens-Johnson syndrome, and 1 case of toxic epidermal necrolysis associated with infliximab cases for etanercept, approved in the same year, included 13 reports of erythema multiforme, and 4 reports each of Stevens-Johnson syndrome and toxic epidermal necrolysis. For adalimumab, which was marketed late in 2002, there have been 4 cases of erythema multiforme and 2 of Stevens-Johnson syndrome.

Infection. There have been spontaneous reports of onset or reactivation of tuberculosis in patients treated with infliximab, including cases of miliary tuberculosis and unusual extrapulmo-nary disease. The UK CSM noted in February 2001 that there had been 28 such reports worldwide. The US manufacturers subsequently reported (in October 2001) that other serious opportunistic infections, including histoplasmosis, listeriosis, and pneumocystosis had occurred, and had led to some deaths the number of reported cases of tuberculosis had risen to 84. Further opportunistic infections also continued to be reported FDA data up to August 2002 included reports of candidiasis, coccidioidomycosis, nocardiosis, aspergillosis, and infections due to non-tuberculous mycobacteria. Health Canada reported in October 2004 that it had received 188 and 109 reports of infections associated with infliximab and etanercept, respectively, from January 2000 to May 2004. Of these, 10 and 2 reports were of tuberculosis associated with infliximab and etanercept, respectively. The FDA also received 25 reports of tuberculosis associated with etanercept between November 1998 and March 2002. Although the majority of patients also had a history of treatment with im-munosuppressants including corticosteroids, the inhibition of TNF may affect normal immune responses and predispose patients to opportunistic infections.

Guidelines have been issued by the British Thoracic Society to quantify the risks of reactivation of tuberculosis with TNF inhibitors and to advise on the treatment of such infection in patients being assessed for TNF inhibitor therapy.

Interactions

Live vaccines should not be given with infliximab or other drugs that inhibit TNF as the effect of such drugs on vaccine efficacy or the risk of infection transmission is unknown. The use of TNF inhibitors with the interleukin-1 receptor antagonist anakinra may increase the risk of serious infections and neutropenia such combinations are not recommended. A similar interaction has been seen with TNF inhibitors and the co-stimulation blocker abatacept.

Abatacept. Use of the TNF inhibitor etanercept with abatacept has resulted in an increase in the incidence of serious adverse effects including serious infections in addition, there was no increase in clinical benefit. Combinations of abatacept with TNF inhibitors are not recommended by UK licensed product information.

Anakinra. The incidence of serious infections, injection site reactions, and neutropenia is increased when anakinra is given with the TNF inhibitor etanercept. In addition, the combination did not provide any further clinical benefit when compared to etanercept alone. Similar findings may be expected if anakinra is given with other TNF inhibitors.

Pharmacokinetics

Infliximab shows linear pharmacokinetics. It is distributed primarily in the vascular compartment and, after single doses, has a terminal elimination half-life of 8 to 9.5 days. After repeated doses, infliximab has been detected in serum for at least 8 weeks.

Uses and Administration

Infliximab is a chimeric monoclonal antibody to tumour necrosis factor a (TNF), a pro-inflammatory mediator. Elevated levels of TNF have been found in the affected tissues and fluids of patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and Crohn’s disease and ulcerative colitis. Elevated TNF levels are also found in psoriatic plaques. Infliximab is given by intravenous infusion over a usual period of not less than 2 hours shorter infusion times have been used in some patients with rheumatoid arthritis (see below for further details).

Infliximab is used with methotrexate in the management of moderate to severe, active rheumatoid arthritis to reduce the signs and symptoms of the disease, delay structural damage, and improve physical function in the UK it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs) although, in severe progressive cases, it may be used in patients not previously treated with methotrexate or other DMARDs in the USA it may be used for treating early rheumatoid arthritis. Infliximab is given in a dose of 3 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks thereafter. For the first 3 doses infliximab should be infiised for at least 2 hours however, UK licensed product information suggests that subsequent infusion times may be reduced to a minimum period of 1 hour in those who tolerate the initial infusions. A clinical response is usually achieved within 12 weeks of starting treatment.

Patients with an inadequate response during this period or who later relapse may benefit by increasing the dose: in the UK, a maximum dose of 7.5 mg/kg every 8 weeks (with increases made in steps of 1.5 mg/kg) is recommended whereas, in the USA, a maximum dose of 10 mg/kg is allowed. Alternatively, a dose of 3 mg/kg may be given as often as every 4 weeks in such patients. Continuing therapy in those who show no response within the first 12 weeks of treatment or after dose adjustment should be carefully reconsidered: in the UK NICE recommends that infliximab be withdrawn if there is no adequate response within 6 months of starting treatment. Patients with moderate to severe, active Crohn’s disease unresponsive to conventional treatment may be given a single infliximab dose of 5 mg/kg. This may be followed by a maintenance regimen of additional infusions of 5 mg/kg at 2 and 6 weeks after the initial infusion and then every 8 weeks, or the drug may be read-ministered when signs and symptoms of the disease recur (but see below). UK licensed product information does not recommend further doses in patients who are unresponsive after the first 2 doses in the USA, a patient is not considered to be unresponsive until 3 doses have been given. A similar regimen is used in patients with fistulising Crohn’s disease although therapy should not be considered ineffective until after the third dose of infliximab. US product information suggests that doses of up to 10 mg/kg may be used in patients who relapse after an initial response. Infliximab is also used in the treatment of moderate to severe, active ulcerative colitis in patients unresponsive to conventional therapy the recommended dose is 5 mg/kg given as a regimen similar to that used for Crohn’s disease (see above). Therapy should not be considered ineffective until after the third dose of infliximab.

In the treatment of ankylosing spondylitis, UK licensed product information recommends that infliximab should only be used in patients with severe disease who have had an inadequate response to conventional treatment however, in the USA it may be used in early treatment, to reduce the signs and symptoms. The initial dose is 5 mg/kg, repeated at 2 and 6 weeks and then every 6 to 8 weeks if there is no response after 2 doses no further treatment should be given.

Infliximab is also used in the treatment of active and progressive psoriatic arthritis in the UK, its use is limited to patients who have had an inadequate response to standard DMARD but, as before, US licensed product information allows earlier use. In the USA, it may be given with or without methotrexate however, UK product information only recommends use without methotrexate in those patients who are intolerant of or have contra-indications to such treatment. It is given in a single dose of 5 mg/kg, repeated at 2 and 6 weeks and then every 8 weeks thereafter. Guidance issued by NICE in the UK recommends that treatment with infliximab is stopped after 12 weeks in those who show an inadequate response. Infliximab is used in the treatment of moderate to severe plaque psoriasis. Its use is usually limited to patients in whom other treatments are not suitable. Infliximab is given in a dose of 5 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks thereafter. Treatment should be stopped after 14 weeks (4 doses) in patients who show no response.

If the signs and symptoms of rheumatoid arthritis or Crohn’s disease recur infliximab may be readminis-tered if within 16 weeks of the last infusion. Readministration after a drug-free interval of more than 16 weeks may be associated with an increased risk of delayed hypersensitivity (see Delayed Reactions, above) and consequently is not recommended. Recommendations regarding the readministration of infliximab for other indications (other than those detailed above) have not been established. Limited data from readministration with a single dose of infliximab in psoriasis after an interval of 20 weeks suggest reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared with the initial regimen. For details of infliximab use in children, see below.

Administration in children. Infliximab is licensed for use in moderate to severe, active Crohn’s disease in children aged 6 years and over who have not responded to conventional therapy, or who have contraindication for or are intolerant of such treatments doses are the same as those used in adults (see above). UK licensed product information suggests that the dosage interval may be adjusted to maintain any benefits however, further treatment is unlikely to be of use in patients not responding within the first 10 weeks.

Although unlicensed for such use in the UK, infliximab has also been used in children with fistulising Crohn’s disease the BNFC recommends that those aged 6 to 18 years may be treated with the same dosage regimen that is used for this indication in adults (see above).

Asthma. TNF inhibitors such as infliximab have been investigated in the treatment of refractory asthma. There is some evidence that only a minority of patients will respond to such therapy, and that the benefits and risks must therefore be carefully assessed.

Inflammatory bowel disease. Infliximab is used in adults for the treatment of Crohn’s disease and ulcerative colitis (see Inflammatory Bowel Disease) it has also been used in children in the treatment of inflammatory bowel disease, particularly Crohn’s disease.

In the treatment of Crohn’s disease, guidance issued in the UK by NICE recommends that infliximab is used in patients with severe disease when treatment with immunomodulators and corticosteroids has failed or is not tolerated, and when surgery is inappropriate.

In the treatment of ulcerative colitis, guidance issued by NICE recommends against the use of infliximab in subacute manifestations of moderately to severely active disease (defined as that which would normally be managed in an outpatient setting, and does not require hospitalisation or the consideration of urgent surgical intervention). The use of infliximab in acute manifestations of moderately to severely active ulcerative colitis is under review by NICE.

Leprosy. Infliximab has been used in the treatment of recurrent type 2 (erythema nodosum leprosum) lepra reactions (see Leprosy). However, 2 cases of rapidly progressive leprosy developing in patients given infliximab for rheumatoid arthritis have also been described reversal (type 1) reactions occurred in both when infliximab was stopped.

Psoriasis. Infliximab is used in the treatment of moderate to severe plaque psoriasis. In the UK, NICE recommends that it be reserved for severe cases, unresponsive to standard therapies (including ciclosporin, methotrexate, and PUVA) or where such therapies cannot be used.

Rheumatoid arthritis. TNF inhibitors play an increasingly important role in the management of rheumatoid arthritis they tend to be reserved for patients who are unresponsive to more conventional disease-modifying drugs, although some favour use earlier in management.

Some references to the use of infliximab in rheumatoid arthritis and juvenile idiopathic arthritis.

Sarcoidosis. For a mention of possible benefit from infliximab in sarcoidosis.

Spondyloarthropathies. References to the use of infliximab in the treatment of ankylosing spondylitis and psoriatic arthritis. In the UK, NICE considers that TNF inhibitors should be reserved for severe active psoriatic arthritis unresponsive to at least 2 standard disease-modifying drugs etanercept or adalimumab are preferred to infliximab.

Uveitis. Infliximab has been tried with some success in the treatment of uveitis including that associated with Behcet’s syndrome. Uveitis can also develop as a complication of other inflammatory disorders such as rheumatoid arthritis treatment with infliximab may improve ocular symptoms in addition to its effect on the primary disorder. References.

Vasculitic syndromes. For a preliminary report on the use of infliximab in Takayasu’s arteritis. Infliximab has also been investigated in the management of Kawasaki disease in patients who are unresponsive to standard treatment.

Proprietary Preparations

Argentina: Remicade † Revellexl

Australia:: Remicade

Belgium: Remicade

Brazil: Remicade

Canada: Remicade

Chile: Remicade

Czech Republic: Remicade

Denmark: Remicade

Finland: Remicade

France: Remicade

Germany: Remicade

Greece: Remicade

Hong Kong: Remicade

Hungary: Remicade

Indonesia: Remicade

Ireland: Remicade

Israel: Remicade

Italy: Remicade

Japan: Remicade

Malaysia: Remicade

Mexico: Remicade

The Netherlands: Remicade

Norway: Remicade

New Zealand: Remicade

Philippines: Remicade

Poland: Remicade

Portugal: Remicade

Russia: Remicade

South Africa: Revellex

Singapore: Remicade

Spain: Remicade

Sweden: Remicade

Switzerland: Remicade

Thailand: Remicade

Turkey: Remicade

UK: Remicade

USA: Remicade

Venezuela: Remicade

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects and Precautions

As for Infliximab.

Injection site reactions including erythema, itching, pain, and swelling are the most common adverse reactions with adalimumab however, most reactions are mild and do not result in drug withdrawal. Other common reactions include headache, rashes, back pain, hypertension, paraesthesias, increased alkaline phosphate levels, and cough. Autoantibodies to adalimumab have been detected.

Interactions

As for Infliximab.

Methotrexate is reported to reduce the clearance of adalimumab by up to 44% but licensed product information for the latter states that dosage adjustment for either drug does not appear to be necessary.

Pharmacokinetics

Adalimumab is reported to have linear pharmacokinetics at usual dosages. After subcutaneous injection peak concentrations are reached in about 3 to 8 days and bio-availability is estimated to be 64%. The mean terminal half-life is about 2 weeks.

Uses and Administration

Adalimumab is a recombinant human monoclonal tumour necrosis factor (TNF) antibody that binds specifically to TNF-a and blocks its interaction with endogenous cell-surface TNF receptors. It also modulates biological responses that are induced or regulated by TNF. Elevated levels of TNF have been found in the affected tissues and fluids of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and Crohn’s disease. Adalimumab is used in the treatment of moderate to severe, active rheumatoid arthritis and active and progressive psoriatic arthritis to delay structural damage and improve physical function. In the UK, it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs), although in severe progressive rheumatoid arthritis it may be used in patients not previously treated with methotrexate in the USA, it may be used to reduce the signs and symptoms of early disease. Adalimumab is also used in the treatment of active ankylosing spondylitis: UK licensed product information recommends that it should only be used in patients with severe disease who have had an inadequate response to conventional treatment however, in the USA it may be used to reduce signs and symptoms in early disease. For all the above indications, it is given by subcutaneous injection in a dose of 40 mg every other week. In the treatment of rheumatoid arthritis, UK licensed product information recommends that adalimumab should be given with methotrexate, although monotherapy may be used where treatment with methotrexate would be inappropriate. When used as monotherapy in rheumatoid arthritis, some patients may benefit from increasing the dose to 40 mg every week. Clinical response is usually achieved within 12 weeks of treatment.

Adalimumab is also used in the treatment of moderate to severe, active Crohn’s disease unresponsive to conventional treatment it may also be used in patients who have relapsed while taking infliximab. Patients may be given an initial dose of 160 mg on day 1 (given as four 40-mg injections in one day or two 40-mg injections daily for 2 consecutive days), followed by 80 mg two weeks later (day 15). After a further two weeks (day 29), a maintenance dose of 40 mg every other week may be started. Alternatively, UK licensed product information advises that patients at risk of adverse effects may be given 80 mg initially, followed by 40 mg 2 weeks later thereafter, usual maintenance doses may be given. A clinical response is usually seen within 12 weeks of starting treatment those patients who relapse while on adalimumab may benefit from increasing the maintenance dose to 40 mg every week. In the treatment of moderate to severe chronic plaque psoriasis in patients unresponsive to, or intolerant of, conventional systemic therapy including phototherapy, the recommended initial dose of adalimumab is 80 mg subcutaneously this may be followed by a maintenance dose of 40 mg subcutaneously on alternate weeks, starting 1 week after the initial dose. A clinical response is usually seen within 16 weeks of starting treatment.

For the uses of adalimumab in children, and recommended doses, see below.

Administration in children. In the USA, adalimumab is licensed in the treatment of moderate to severe, active juvenile id-iopathic arthritis in children aged 4 years and above: it may be used alone or with methotrexate. The dose is calculated according to weight and is given subcutaneously: those weighing 15 kg to less than 30 kg should be given 20 mg every other week, while heavier children may receive 40 mg every other week.

Inflammatory bowel disease. Adalimumab is used in the management of Crohn’s disease, including in patients who are intolerant of, or relapse on, infliximab treatment. It has also been tried in the treatment of ulcerative colitis.

Psoriasis. Adalimumab is used in the treatment of plaque psoriasis.

Rheumatoid arthritis. References to the use of adalimumab in rheumatoid arthritis.

Spondyloarthropathies. References to the use of adalimumab in ankylosing spondylitis and psoriatic arthritis (see Spondyloarthropathies).

Uveitis. Adalimumab has been tried with some success in the treatment of idiopathic uveitis. Uveitis can also develop as a complication of other inflammatory disorders such as rheumatoid arthritis treatment with adalimumab may improve ocular symptoms in addition to its effect on the primary disorder.

Proprietary Preparations

Argentina: Humira

Australia: Humira

Belgium: Humira

Brazil: Humira

Canada: Humira

Chile: Humira

Czech Republic: Humira

Denmark: Humira

Finland: Humira

France: Humira

Germany: Humira

Greece: Humira

Hong Kong: Humira

Hungary: Humira

Ireland: Humira

Israel: Humira

Italy: Humira

Malaysia: Humira

Mexico: Humira

The Netherlands: Humira Trudexa

Norway: Humira

New Zealand: Humira

Poland: Humira

Portugal: Humira

Singapore: Humira

Spain: Humira

Sweden: Humira

Switzerland: Humira

UK: Humira

USA: Humira

Venezuela: Humira

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects and Precautions

Acute infusion reactions occurring within 1 hour of starting an infusion are common with abatacept use. The most frequently reported infusion events are dizziness, headache, and hypertension hypotension and dyspnoea occur less commonly. Other acute events include nausea, flushing, pruritus, rash, and wheezing. Most events are usually mild to moderate although stopping treatment may be necessary in a few patients. Other common adverse effects include headache, na-sopharyngitis, nausea, dyspepsia, diarrhoea, dizziness, back pain, fatigue, cough, and abnormal liver function values. Antibodies to abatacept may develop and ana-phylaxis or anaphylactic reactions have been reported rarely. Uncommon adverse reactions include paraes-thesia, thrombocytopenia, and leucopenia. Infections are frequent in patients treated with abatacept and most often affect the respiratory and urinary tracts. More serious infections such as pneumonia, sepsis, cellulitis, bronchitis, diverticulitis, and acute pyelonephritis have also been rarely associated with abatacept treatment. Treatment should be stopped in patients who develop a serious infection. Abatacept should not be given to patients with severe and uncontrolled infections such as sepsis and opportunistic infections. It should be used with caution in patients with a history of recurrent infections, with underlying conditions that may predispose to infections, or with chronic, latent, or localised infections. Patients should be screened for latent tuberculosis before starting treatment those testing positive should be treated with standard chemoprophylaxis before beginning abatacept.

Some disease-modifying antirheumatic drugs have been associated with hepatitis B reactivation licensed product information for abatacept recommends screening for viral hepatitis before starting treatment. Adverse effects of abatacept are more frequent in patients with chronic obstructive pulmonary disease and may include a worsening of their respiratory symptoms.

Carcinogenicity. The role of abatacept in the onset of malignancies such as lymphoma in humans is not known.

In placebo-controlled studies the overall frequency of malignancies in patients treated with abatacept compared to those that received placebo was similar (1.4% and 1.1 %, respectively). However, there were more cases of lung cancer and lymphomas in those given abatacept. In animal studies in mice, increases in lymphomas and mammary tumours have been noted, although these increases have not been seen in some studies with other mammals.

Interactions

Live vaccines should not be given with abatacept, or within 3 months of stopping it, as its effect on vaccine efficacy or the risk of infection transmission is unknown. The use of TNF inhibitors with abatacept may increase the risk of serious infections such combinations are not recommended. Use with anakinra or rituximab is also not recommended because of insufficient evidence to assess safety.

Pharmacokinetics

Abatacept is reported to have linear pharmacokinetics at usual dosages. After repeated intravenous doses, its mean terminal half-life is about 13 days. Studies in animals suggest that abatacept is distributed into breast milk.

Uses and Administration

Abatacept, a fusion protein, is a co-stimulation blocker. It prevents the activation of T-cells activated T-cells have been found in the synovium of patients with rheumatoid arthritis. It is used in the treatment of moderate to severe active rheumatoid arthritis to delay structural damage and improve physical function. In the UK, it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs), including at least one TNF inhibitor in the USA, it may be used to reduce the signs and symptoms of early disease.

Abatacept is given by intravenous infusion over a period of 30 minutes in the following doses, based on body-weight:

• 500 mg for patients weighing less than 60 kg

• 750 mg for those weighing 60 to 100 kg

• 1 g for those over 100 kg.

The dose is repeated at 2 and 4 weeks, then every 4 weeks thereafter. If a response to treatment is not seen within 6 months, the benefits of continuing abatacept may need to be considered. In the UK, abatacept is licensed for use with methotrexate however, in the USA it may be given alone or with other DMARDs (but see Interactions, above).

For the use of abatacept in children, and recommended doses, see below.

Abatacept is also being studied for other auto-immune diseases such as inflammatory bowel disease, psoriatic arthritis, and SLE.

Administration in children. In the USA, abatacept is licensed in the treatment of moderate to severe, active juvenile idiopathic arthritis in children aged 6 years and above it may be used alone or with methotrexate. The dose is calculated according to body-weight and is given as an intravenous infusion over 30 minutes those weighing less than 75 kg should be given 10 mg/kg initially, while heavier children may receive the appropriate adult dose (see above). Doses should be repeated at 2 and 4 weeks, and then every 4 weeks thereafter.

Rheumatoid arthritis. References to the use of abatacept in rheumatoid arthritis.

Proprietary Preparations

Argentina: Orencia

Czech Republic: Orencia

France: Orencia

Portugal: Orencia

United Kingdom: Orencia

USA: Orencia

It is now accepted practice to have pharmacists and nurses manage disease states by following accepted and approved clinical guidelines. Until January 1994, the Mayo Clinic used 7- to 10-day anti-biotic regimens for acute female cystitis. The medical director for practice guidelines, Dr. Angstman and his committee, redesigned the antibiotic order sheet to include check-off boxes, allowing the physicians to make ordering the smaller supply the easiest option. This promoted the goal of increasing the number of three-day regimens prescribed for TMP-SMX [Septra, Bactrim], nitrofurantoin, or ciprofloxacin. The results were that “the shorter regimen has proven efficacious in treating cystitis, with fewer antibiotic-related side effects than when utilizing the 7- to 10-day regimens.

Columbia Medical Plan (CMP) designed a drug-use evaluation (DUE) for fluoroquinolones used for the treatment of acute female cystitis when TMP-SMX [Septra, Bactrim] or nitrofurantoin would have been appropriate. Of patients prescribed a fluoroquinolone for acute female cystitis, 95% had no contraindications to either nitrofurantoin or TMP/SMX. One finding was that the length (42% >7 days) and the dosage (43% = 500 mg BID) of ciprofloxacin therapy contributed to high prescription costs. After an educational intervention program is conducted for providers to adopt an AFC guideline, data will be reviewed again.

Group Health Cooperative of Puget Sound developed a clinical practice guideline for presumed cystitis in women 18–55 years of age. Their goal was to decrease morbidity and costs by standardizing the use of effective, well-tolerated, inexpensive treatments and decrease laboratory utilization. When a patient complaint is dysuria or urgency, nurses are utilized in clinics and by telephone to start antibiotic therapy. Subsequent to guideline implementation, a significant decrease in the proportion of patients who receive urinalysis, have a urine culture or an initial office visit has resulted. In addition, there has been an increase in the proportion of patients prescribed the guideline-recommended antimicrobial regimen (first choice TMP-SMX, but if the patient had a sulfa allergy, then trimethoprim, nitrofurantoin or ciprofloxacin) without any increase in associated adverse outcomes. From a telephone questionnaire, 85% stated that if they developed another urinary tract infection, they would rather speak to a nurse over the telephone and receive a prescription than have an office visit.

Most recently, the Department of Defense piloted these guidelines at a medical treatment facility. Patients were given the choice of choosing a treatment by telephone or a clinic visit. If they chose the telephone treatment, a nurse would review the inclusion and exclusion criteria and if the patient met the criteria she was prescribed a three-day course of antibiotic (algorithm). Carefully selected patients with symptoms of acute dysuria or urgency may be safely managed without a doctor’s visit or laboratory test. The algorithm applies only to patients who do not have an exclusion as noted in the guideline, and includes the option of a visit based on patient preference.

The guideline antibiotics were TMP-SMX, TMP or nitrofurantoin. To prevent bacterial resistance, a fluoroquinolone was not a guideline recommendation. After the first three months of guideline implementation, 50% of the 300 respondents elected a telephone treatment rather than a visit. The length of antibiotic duration changed from 75% of patients being on the 7- to 10-day regimen to 75% of patients being on the three-day regimen. The use of fluoroquinolones decreased from 20% to less than 1%. Patient satisfaction with the nurse protocol treatment was high and no increase in recurrence rates of urinary tract infections was observed. Future plans include expanding the information about this service through newsletters, and providing information on urinary tract infection (UTI) prevention. Guidelines are currently being implemented to standardize treatment medications and duration in addition to increasing patient satisfaction while decreasing costs.

The mainstay of UTI prevention is to keep the urine dilute by drinking fluids and urinating often. Since the mid-1800s, cranberry juice has been associated with antibiotic properties. Using Klebsiella pneumoniae as an indicator, cranberry juice diluted at least as much as 1:32 showed anti-bacterial activity. A randomized, double-blind, placebo-controlled study reported bacteriuria and pyuria reduction when patients drank 300 mL of cranberry juice daily. Bacteria in the GI could metabolize the benzoic and quinic acids from 300 mL of cranberry juice (equivalent to 100 g of cranberries) to about one gram of excreted hippuric acid, in the urine. Hippuric acid may be bacteriostatic for E coli in concentrations of 1–2 mg/mL. Cranberries and blueberries also contain proanthocyanidins and a high-molecular weight compound that may inhibit 80% of E. coli adherence to uroepithelial cells. The fructose content may interfere with mannose-sensitive adhesions on type 1 fimbriated E. coli to uroepithelium. The most widely accepted “dose” is three ounces of 33% pure cranberry juice daily to prevent an infection and 12–32 ounces per day for treatment. Drinking more than 3–4 liters causes diarrhea or GI upset. Other citrus juices and drinking at least 8-ounce glasses of water a day to encourage urination are also useful to prevent bacterial adherence. Coffee, soda, and other caffeinated beverages may irritate the bladder lining and are not recommended.

Pharmacists need to explain what is being treated, what an antibiotic does and why the duration of treatment may be shorter than patients are accustiomed to when taking them for other infections. In addition, written patient information is important to help guide patients in recognizing, managing and preventing acute female cystitis.

Algorithm for Acute Dysuria in Women

A. Age Range

There is no clear answer in the scientific literature regarding the appropriate age range appropriate for this guideline. Although most studies of cystitis have been performed with women age 18–35 years, the guideline development team concluded that the guideline recommendations may be safely applied to women age 18–55 years, and to selected women of other ages (i.e., 14–18 years, or over 55 years). However:
• For women 14–18 years, an occurrence of dysuria may be used as an opportunity to screen for sexually transmitted disease and initiate contraceptive counseling.
• After the age of 55, a woman’s risk of complications from urinary tract infections increases with age. Use caution in treating women >55 years based on symptoms alone, without a visit or urinalysis. Treatment based on symptoms alone is contraindicated in elderly or frail women.

B. Exclusion

C. Options to Counter Recurrent RTIs

*Regular use of N-9 spermicide-coated condoms has been linked to an increased risk of urinary tract infection: 1–2x week, OR=3.34; >=2x week, OR=5.65
**Same doses (3 days) as listed for treatment above
***Single-dose therapy of trimethoprim sulfa 1 SS, trimethoprim 100 mg, or nitrofurantoin 50–100 mg (nitrofurantoin for a maximum of 1 year)

The goals of treatment are to eradicate the bacteria, relieve symptoms, avert irreversible damage, and prevent recurrence. Antibiotics serve this purpose by quickly eliminating the organism(s) and shortening the length of symptom discomfort. Since the choice of antibiotic treatment is empiric, based on predictable eradication for a defined group of bacteria, other factors become appropriate to consider. TABLE 5 lists additional considerations for antibiotic selection.

In the past, the treatment of acute female cystitis with an antibiotic for 7–14 days was the standard of care. Although highly efficacious, the associated adverse events, poor compliance, and unnecessary costs necessitated a reevaluation. To prevent complications and costs associated with longer treatments, single-dose therapies were studied. However, the Infectious Diseases Society of America (IDSA) has stated that single-dose therapy is generally less effective than the same antimicrobial used for 7–14 days, Yet most antimicrobials given for three days are as effective as the same antimicrobial given for 7–14 days.The shorter, three-day regimens have proven efficacious by providing high urine concentrations in excess of the minimal inhibitory concentration (MIC) for the expected pathogens while maintaining the normal bowel and vaginal flora. These regimens were associated with fewer side effects, fewer adverse reactions, enhanced compliance, less antimicrobial pressure and selection of resistant strains, and were cost-effective.

Numerous evaluations of the standard three-day regimen of trimethoprim-sulfamethoxazole (TMP-SMX) have shown that it is as effective and less expensive than three-day regimens of nitrofurantoin, quinolones, or beta-lactams,cefadroxil,cephalothin,or amoxicillin for the treatment of uncomplicated cystitis in women. Fosfomycin as a single-dose therapy was significantly less effective than ofloxacin or TMP-SMX [Septra, Bactrim] as single-dose therapies. The increased efficacy of TMP-SMX is likely related to its antimicrobial effect against E. coli in the rectum, urethra, and vagina. TMP-SMX [Septra, Bactrim] produces few allergic reactions, eradicates most Gram-negative rods, sterilizes the vaginal introitus, and is inexpensive. The cure rate is 90%–95% when used for three days. TMP and TMP-SMX resistance is 5%–15% and varies regionally. Resistance has increased from 9% in 1992 to 18% in 1996.

When needed, alternatives to TMP-SMX [Septra, Bactrim] include the quinolones, nitrofurantoin, or fosfomycin. These antibiotics will also sterilize the urine and provide symptom relief in 24 hours or less. Quinolone overuse may pose a risk for the selection and spread of resistant E. coli,as has occurred with previous antibiotic overuse against S. aureus and P. aeruginosa. IDSA recommendations are to limit the use of broad-spectrum fluoroquinolones as initial empirical therapy for uncomplicated cystitis, except when there is >10%–20% resistance among uropathogens, the patient has had recent antibiotic treatment, or the patient cannot tolerate sulfonamides or TMP. Nitrofurantoin’s advantages include no increase in resistance over the 5-year period studied (1992–1996), fewer allergic reactions and the fecal flora is not altered. Nitrofurantoin, fluoroquinolone and fosfomycin may become more useful if and when E. coli resistance to TMP-SMX and TMP increases to clinically significant levels.Currently, 80% of uropathogens are susceptible to fosfomycin; however, fosfomycin is less effective for S. saprophyticus than is TMP-SMX [Septra, Bactrim]. If the patient has no signs or symptoms after finishing the antibiotic, the assumption is made that the infection is eradicated.

Phenazopyridine (Pyridium) is not an antibiotic but is used as a bladder analgesic to alleviate the symptoms of dysuria and urgency within one to two hours. It should not be utilized more than one to three days, as it may mask an ineffective antibiotic.

1

Assessment

A preliminary diagnosis of acute female cystitis (AFC) is made by assessing patient risk factors, signs and symptoms. A combination of the classic words, “I have this pain when I urinate (dysuria), urgency, burning or frequency that just started,” describes the symptoms of acute cystitis. The urgent need to urinate may allow only a few drops of urine to pass before the burning sensation occurs and the need to urinate begins again. The urine may be cloudy, bloody, or foul-smelling. Infrequently there may be a mild fever or pain in the lower back or groin area.

Dysuria

Dysuria is associated with bacterial cystitis, STDs (sexually transmitted diseases), or vaginitis. A differentiation needs to be made between location, risk factors and cause of the dysuria before treatment can be initiated. Internal dysuria is associated with urinary tract infections or STDs, while external dysuria is associated with vaginitis. Pyuria and hematuria are absent in vaginitis. Patients with vaginitis usually complain of vaginal discharge, odor, itching or burning around the vaginolabial area. Cervical cultures for N. gonorrhoeae and C. trachomatis are indicated, if the diagnosis is in question.See TABLE 4 for clinical differentiation of major causes of dysuria.

Urine Culture / Testing

Urine culture and susceptibility testing add little to the choice of an empiric antibiotic for treatment, because of the limited spectrum and number of acute female cystitis pathogens. Susceptibility is usually predictable, but regional variations in resistance patterns do occur. Many patients, therefore, may receive an abbreviated laboratory work-up using dipstick tests to screen for the presence of bacteria or pyuria. When combined, the two tests have a sensitivity of 70%–100% and a specificity of 60%–90%.

The leukocyte esterase (LE) dipstick test is used to screen for pyuria (presence of pus in the urine when voided). LE, an enzyme found in neutrophil granules, reacts with an impregnated reagent pad to produce a blue color within 2–5 minutes. A positive test indicates the presence of white blood cells (WBC). When compared to standard methods of defining UTIs (isolating >=10 CFU/mL of pathogenic bacteria) or significant pyuria (>=10 WBC/mm urine) the sensitivity is 75%–96% and the specificity is 94%–98%. Pyuria indicates inflammation and not necessarily an infection. This is an efficient, cost-effective method for determining the presence of pyuria when routine microscopy is unavailable, impractical or for an outpatient evaluation.Vitamin C and phenazopyridine may cause false-negative or unreadable results.

The nitrate test is also widely available, for use at home or in the office. The nitrate test is qualitative in that it is used as a surrogate to detect Gram-negative bacteria, since only Gram-negative bacteria are able to produce nitrate. An aromatic amine-impregnated pad produces an azo color within 60 seconds if urinary nitrites are present. Urinary nitrites are produced by the action of Gram-negative bacteria (Enterobacteriaceae) metabolism on dietary nitrates through nitrate reductase. False-negatives can result from recent antibiotic therapy, low urinary pH (as occurs with high doses of ascorbic acid), lack of dietary nitrates, or when diuresis has created insufficient urinary nitrate levels. False-negatives also occur when Pseudomonas sp. or Gram-positive bacteria such as Staphylococcus sp., or Enterococcus sp., which lack nitrate reductase, are unable to produce nitrite. Sensitivity of the test ranges between 35%–85%, and the specificity ranges between 92%–100%.

In summary, the diagnosis may be based on objective data, subjective signs and symptoms, or both. Women with classic signs and symptoms are often empirically treated with antibiotics. Cultures need to be performed when the diagnosis is unclear; or there are other risk factors, including a history of recurrent infections; or more than the classic signs or symptoms are involved, including symptoms such as fever, lower back or flank pain, or signs associated with vaginitis.

Acute bacterial cystitis affects 8–10 million Americans a year, according to the American Foundation for Urological Diseases — and most of these patients are women. The National Institute of Diabetes and Digestive and Kidney Diseases notes that acute cystitis prompts about 9.6 million doctor visits annually; $4.5 billion is spent on 11 million antibiotic prescriptions. Occurring in otherwise healthy young women with no congenital, neurological or structural abnormalities, acute, symptomatic, uncomplicated urinary tract infection (UTI) or acute female cystitis (AFC) is the most common infection next to the common cold. Twenty-five to 40% of females will experience an acute UTI in their lives, and up to 6% of women will have one or more urinary tract infections in a given year. A urinary tract infection is painful, costly and can interfere with work, sex, and the patient’s quality of life. If promptly treated, the period of discomfort can be shortened and the potential for serious damage and recurrence is reduced.

Risk Factors

Female Gender: The largest risk factor for acquiring and developing an acute UTI is female gender. The short female urethra provides access to the bladder, and the vagina provides a favorable environment for bacterial colonization and growth.

Poor Hygiene: Poor personal hygiene following urination and defecation can expose the vagina and urethra to bacteria from the perianal area. Tampons and sanitary pads may provide a favorable environment for bacteria if they are not changed frequently.

Irritants: Sanitary pads and tampons may contain deodorants or perfumes that irritate the skin, allowing bacteria to enter. Taking tub baths with moisturizing lotions or soaps may alter the flora of the vaginal area, allowing colonization and growth.

Prior Infection: The risk of acquiring an acute infection is more than 3-fold higher among women with a previous infection compared to women with no history of urinary tract infection.

Sexual Activity: Once referred to as “honeymoon-cystitis” many women acquired their first infection after their first sexual experience. The relative risk of a UTI among unmarried women increased from 1.0 for women who had not been sexually active during the previous week to 2.6 for women who had engaged in sexual intercourse 3 times a week, to 9.0 for women who had had intercourse seven times during the previous week. New sex partners and intercourse methods introduce bacteria into the vagina and urethral area. If bacteria are not removed by voiding, they will colonize in this area, posing a risk for infection.

Barrier Methods: Barrier methods of birth control can also increase the risk of acquiring a urinary tract infection. Condoms increase the risk of vaginal tears, allowing bacteria to invade and adhere. Contraceptive sponges, foams, creams, gels, and condoms use nonoxynol-9 (N-9) as an active agent. Lactobacilli, the normal flora of the vagina, provide protection from external bacteria overgrowth, and are eradicated by N-9. The removal of lactobacilli by N-9 or an antibiotic alters the vaginal pHand natural flora, allowing Escherichia coli and Staphylococcus saprophyticus to proliferate, colonize and adhere to the vaginal mucosa. The odds that a woman exposed to condoms coated with N-9 would get a urinary tract infection were three times higher than for sexually active women who did not use coated condoms.The incidence of a UTI was 26.6 per 1,000 patient-months for diaphragm-users, and the relative risk for urinary tract infection development was 2.5 for diaphragm users. Those using a diaphragm and spermicide combination were at risk from the spermicide and from bacterial contamination associated with diaphragm usage. Bacteria are introduced into the vagina on the fingers during insertion, and as the diaphragm is pushed in from the outer to inner vaginal areas. Diaphragms that are worn >24 hours or improperly fitted can harbor bacteria or irritate tissue. A cervical cap, however, may not be associated with an increased UTI risk; less spermicide is used inside the enclosed cap, causing less alteration of the vaginal flora.

Other products that alter the normal flora or irritate the bladder will increase the risk of acquiring a urinary tract infection. Recent antibiotic usage or frequent douching alters the vaginal flora. Consuming large amounts of nonbuffered vitamin C, caffeine, alcohol or carbonated beverages, or acidic or spicy foods can cause irritation and disrupt the bladder’s protection against bacterial adherence. Risk factors for acute female cystitis are summarized in TABLE 1.

Risk factors do not cause an infection. Infection occurs when the following three things combine: an alteration that weakens the host’s resistance or defense, pathogen virulence factors, and a sufficient quantity of the pathogen. For example, bacteria originating in the GI tract must invade, adhere, colonize and multiply within the vagina, urethra, or bladder to be uropathogenic. When the superficial mucosal lining of the bladder or urethra is inflamed, an infection can occur.

The term acute female cystitis describes the onset, the gender and the anatomic location of the infection, but it does not describe the cause. E. coli, a Gram-negative, aerobic bacillus, is responsible for more than 80% of all AFC infections.S. saprophyticus, a Gram-positive cocci, is more often isolated from women using spermicide-coated condoms (74%) and diaphragms than is E. coli. Other enterobacteriaciae are occasionally isolated from uncomplicated UTIs (TABLE 2). Vaginitis and urethritis caused by sexually transmitted pathogens such as herpes simplex, Chlamydia trachomatis, or Neisseria gonorrhoeae may mimic cystitis.

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The largest intrinsic defense mechanism against bacterial inflammation and adherence to the bladder or urethral lining is urine. Invading bacteria stimulate micturition. Voiding washes out bacteria from the bladder and urethra. Urine dilutes bacterial concentrations, preventing adherence. Bacterial growth is impeded by low pH of urine (urine pH can range from 4.5–8.0). The pH can also be lowered by taking medications or foods such as vitamin C, cranberries, prunes, and plums. The high urea and organic acid concentrations and the extremes of high and low osmolality deter and inhibit bacterial colonization.

The bladder also has its own defense mechanisms. The uroepithelial cells are coated with a urinary mucus called glycosaminoglycan, or uromucoid. This thin, hydrophilic and negatively charged surface layer of mucopolysaccharide attracts water molecules to form a barrier between the bladder and urine, preventing bacterial adherence.

The ascending limb of the loop of Henle produces Tamm-Horsfall mucoprotein. This protein contains mannose residues that compete with the bladder for attachment of E. coli with Type 1 fimbriae. (Fimbriae are bacterial surface adhesions responsible for attachment to an epithelial surface receptor.) Type 1 fimbriae are mannose-sensitive and are also attracted to the mannose residues in Tamm-Horsfall and glycosaminoglycan, preventing their attachment to the uroepithelium. E. coli bound to the Tamm-Horsfall protein are then excreted.

Polymorphonuclear leukocytes (PMNs) and secretory immunoglobulin (Ig) A have receptors for type 1 fimbriae. Bacteria attach, bind, and then are excreted during micturition. PMN phagocytosis is stimulated by inflammation from bacterial adhesions to the bladder mucosa.

Treatment is usually recommended because if the infection progresses and spreads to the kidneys it is then classified as a complicated infection. Signs and symptoms of a complicated infection include nausea, vomiting, flank pain, fever and chills. Treatment may require hospitalization and longer, more expensive antibiotic treatment.

Orlistat (Xenical, Roche Laboratories) was approved by the Food and Drug Administration in 1999. It differs from the agents previously discussed as its mechanism of action does not exert effects in the central nervous system. Orlistat exerts its activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. It is a reversible lipase inhibitor that decreases the absorption of dietary fats by approximately 30%. These unabsorbed triglycerides are eliminated, resulting in caloric deficit leading to weight loss.

The mechanism of action of orlistat allows it to be considered as a potential weight loss agent for patients on therapies contraindicated with sibutramine or other amphetamine-like anorexiants. Of particular concern are those patients for who are taking serotonergic agents. Orlistat offers the advantage of increasing weight loss without precipitating the serotonin syndrome as would sibutramine. Research is underway to determine if orlistat might be an alternative to sibutramine in obese patients on atypical antipsychotic agents.

The effect of orlistat on obese hypertensive patients was studied in a 1-year, prospective, randomized, double-blind, placebo-controlled multicenter trial. The study examined patients taking orlistat and adhering to a reduced calorie diet with no more than 30% of the calories from fat with patients on placebo with the same dietary restrictions. The researchers monitored the patients for weight loss, decline in body mass index (BMI), diastolic blood pressure, and plasma lipids. The orlistat group demonstrated a greater weight loss and decline in BMI than the placebo group. The treatment group also demonstrated a greater reduction in diastolic blood pressure with significant reductions in plasma cholesterol. The results demonstrated that orlistat causes weight loss and reduces cardiovascular risk.

As the site of action of orlistat is the gastrointestinal tract, there is little systemic absorption and exposure to orlistat. Plasma levels after a single dose were near the limits of detection (<5ng/mL). Metabolism of orlistat likely occurs within the gastrointestinal tract. Orlistat undergoes fecal and biliary excretion. About 97% of orlistat is excreted in the feces, with 83% as unchanged orlistat. Renal elimation of orlistat is less than 2%. The therapeutic dose of orlistat is 120mg three times daily.

Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis. Hypersensitivity to orlistat is also a contraindication to its use. Orlistat does exhibit a potential for misuse by patients with anorexia nervosa or bulimia. Precautions to be taken with administration of orlistat are related to its mechanism of action. Patients who do not adhere to a reduced fat diet may experience an increase in gastrointestinal adverse drug reactions if orlistat is taken with a high fat diet. Dietary fat should be distributed over three meals. If one meal is particularly high in fat, there may be gastrointestinal side effects. To ensure adequate nutrition, patients taking orlistat should be advised to take a multiple vitamin that includes fat-soluble vitamins once daily at a time when orlistat is not taken, such as bedtime. As some patients develop increased levels of urinary oxalate following treatment, orlistat should be employed with caution in patients with a history of hyperoxaluria or nephrolithiasis. Patients with diabetes mellitus may experience enhanced metabolic control which may warrant the reduction in dose of oral medications for diabetes mellitus (sulfonylureas, metformin, thiazolidinediones) and insulin.

Orlistat may cause up to one-third reduction in cyclosporine absorption. Changes in cyclosporine absorption occur with changes in dietary fat intake. Caution is to be employed in the concomitant use of cyclosporine and orlistat. As vitamin K is fat-soluble and its absorption may be decreased with concomitant orlistat use, patients on warfarin therapy and orlistat should be monitored for changes in coagulation monitoring parameters. As was previously mentioned, orlistat may potentially reduce the absorption of fat-soluble vitamins (vitamins A, D, E, and K) and beta-carotene. Co-administration of orlistat with pravastatin demonstrated an increase in pravastatin levels.

Adverse drug reactions associated with orlistat are primarily gastrointestinal due to its activity in the gastrointestinal tract and minimal systemic exposure. Gastrointestinal effects include abdominal pain, diarrhea, fecal urgency, oily spotting, flatus with discharge, fecal incontinence, increased defecation, nausea, vomiting, and rectal pain. Although other adverse drug reactions may occur with orlistat, intolerance of the gastrointestinal effects was the most common reason cited for discontinuation of therapy. Central nervous system adverse drug reactions are headache, dizziness, and anxiety. Respiratory effects are upper and lower respiratory tract infections, influenza and ear, nose and throat symptoms. Musculoskeletal effects of back pain, arthritis, myalgia, and joint disorder have been reported. Female reproductive effects were menstrual irregularity and vaginitis. Miscellaneous adverse drug reactions included urinary tract infection, fatigue, otitis, pedal edema, and sleep disorder.

Summary

In light of the behavior modification, caloric restriction, and medications that are employed to help reduce weight, an important aspect of managing overweight and obesity is prevention. Scientists have predicted an increase in obesity worldwide, along with an increase in the health risks associated with the condition. Of parti cular concern are industrializing nations, whose abilities to handle existing health problems in their own population is limited. An increase in obesity-related disabilities will weaken the currently overwhelmed health care systems. Programs aimed at prevention may be more effective against obesity than weight loss programs.

After review of the pharmacologic agents for weight loss, several key points are evident. First, appropriate use of prescription agents in overweight patients with risk factors or obese patients is as an adjunct to behavior modification and dietary changes. Second, adherence to diet and exercise programs as well as compliance to medication regimens is critical to the patient’s achievement of weight loss goals. Finally, health care professionals (pharmacists, physicians, and nurses), motivational support groups, and family members all play important supportive roles for the patient to achieve not only weight loss, but to improve overall health.

Sibutramine (Meridia, Knoll Pharmaceuticals), approved by the Food and Drug Administration in 1997, is a newer agent that differs in mechanism of action from the anorexiant agents. The mechanism of action of sibutramine involves inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin to stimulate the satiety center in the brain. Sibutramine does, however, share the recommendations for use with the previously discussed anorexiants. Patients taking sibutramine should be those with body mass index (BMI)>30kg/m and concurrently adhering to a reduced calorie diet and exercise program. Patients with risk factors and a BMI>27kg/m, are also potential candidates for sibutramine therapy.

Wirth and Krause conducted a randomized, double-blind, parallel-group, placebo-controlled trial, to study long term weight loss with sibutramine from April 1997 to September 1998 in Germany. A total of 1,102 obese adults with BMI 30-40kg/m entered a four week period of open label 15mg sibutramine daily. The patients with weight loss of 2% or 2 kilograms (1,001 patients), were then moved into the 44 week randomized treatment period. The patients were divided into three groups: 1) 405 patients received continuous sibutramine therapy 15mg/day weeks 1-48; 2) 395 patients received intermittent sibutramine therapy at 15mg/ day weeks 1-12, 19-30, and 37-48 with placebo during all other weeks; or, 3) 201 patients on placebo for weeks 5-48. Mean weight loss in the continuous therapy group during the 44-week random period was 3.8 kg, compared 3.3 kg mean weight loss in the intermittent therapy group. The difference between the mean weight loss between the continuous and intermittent therapy groups was not found by the researchers to be statistically significant. The patients receiving placebo for weeks 5-48 demonstrated a mean weight gain of 0.2kg. The researchers also found that waist circumference and triglyceride levels were reduced, and high-density lipoprotein levels were elevated as a result of sibutramine therapy. The incidence of adverse effects to sibutramine was lower in the intermittent therapy group than in the continuous therapy group. The researchers concluded that continuous and intermittent therapy of sibutramine were equivalent with respect to therapeutic response.

Obesity is Undertreated in the U.S. Today

An article in the November 2002 issue of JAMA reported on the growing epidemic of obesity in the U.S., and reported a troubling trend. Despite the growing awareness in the medical community of the dangers of obesity over the course of the past decade, only 42% of obese adults who visited a primary care physician in 1996 were counseled about weight loss. (While this study relied exclusively on self-reported data from patients, several other studies have come to similar conclusions.) It has been shown that patients who are counseled on weight loss and urged to shed pounds by a physician are much more likely to attempt to do so than those who receive no such advice. One reason for the undertreatment of obesity could be that the most appropriate interventions in most cases – lifestyle modifications (i.e., diet and exercise) and in some cases pharmacotherapy – generally result in a mere 5%-10% weight loss maintained over a maximum period of one to two years. Additionally, 95% of patients who undergo weight reduction regain lost weight within seven years. Nevertheless, it is still extremely important for obese patients to be given the information they need to understand the serious medical risks of overweight and obesity, as well as the methods available to treat it. Even minor weight losses of 5%-10% can improve glycemic control, blood pressure, and lipid profiles.

Following oral administration, sibutramine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentration occurring within 3-4 hours. Bioavailability is about 77% of a single dose of the agent. Plasma protein binding of sibutramine is 94%-97%. Sibutramine undergoes hepatic metabolism by the cytochrome P-450 (3A₄) isoenzyme. Elimination of sibutramine is 85% combined urinary and fecal elimination, with the majority of elimination being renal (77%). Contraindications to sibutramine are numerous. Obviously, concurrent use of other centrally acting appetite suppressants is to be avoided. Use of sibutramine is to be avoided in the following cardiovascular conditions: moderate to severe hypertension, history of coronary artery disease, congestive heart failure (CHF), arrhythmias or stroke. Other contraindications include anorexia nervosa, co-administration or within 14 days of MAO inhibitor use, severe hepatic dysfunction, glaucoma (particularly narrow angle glaucoma), and history of drug abuse. As a component of sibutramine mechanism of action is the inhibition of serotonin reuptake, concomitant administration of selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, nefazodone, citalopram) should be avoided due to the risk of development of serotonin syndrome (increased blood pressure, flushing, tachycardia).

Precautions of sibutramine use are renal or hepatic impairment, concomitant cardiovascular disease, history of seizures, gallstones, and glaucoma. Sibutramine is a pregnancy category C drug.

Adverse drug reactions of sibutramine that affect the cardiovascular system are tachycardia, vasodilation, hypertension, and palpitations. The central nervous system side effects include headache, nervousness, anxiety, depression, emotional lability, insomnia, agitation. Gastrointestinal system effects are dry mouth, anorexia, constipation, dyspepsia, diarrhea, and flatulence. Dysmenorrhea, urinary tract infection, vaginitis, and menorrhagia are side effects of the genitourinary system. Respiratory system effects. Dermatologic effects of rash, sweating, acne and pruritus may occur. Miscellaneous effects are back, neck or chest pain, allergic reactions, edema, arthralgia, fever, and leg cramps.

Drug interactions associated with sibutramine involve primarily agents that affect the neurotransmitter serotonin. Concurrent use with monoamine oxidase inhibitors may precipitate hypertensive crisis. The serotonin syndrome may be precipitated through concomitant use of sibutramine with serotonin receptor agonists, selective serotonin reuptake inhibitors, tricyclic antidepressants, bupropion, and meperidine. (For a summary of these agents see Table 3). Additive anorectic effects occur when sibutramine is combined with other centrally acting appetite suppressants. Augmentation of the cardiovascular adverse drug reactions associated with sibutramine (tachycardia, increased blood pressure) may occur with concurrent administration of systemic sympathomimetic agents (pseudoephedrine, ephedra). Dosing of sibutramine should be initiated at 10 mg daily. After four weeks of therapy and inadequate weight loss, the dose may be increased to 15 mg daily. For patients who have difficulty tolerating a 10 mg daily dose of sibutramine, a dosage regimen of 5 mg daily may be considered. Monitoring of cardiovascular status should play a pivotal role in decisions regarding dosage adjustment.

The anorexiants constitute the mainstay of pharmacologic therapy for obesity. Other terms for these agents include the anorectics or anorexigenics. Appetite suppression is produced by direct stimulant effect on the satiety center of the hypothalamic and limbic regions. Agents within this category demonstrate various neurotransmitter activity. Diethylpropion and phentermine have activity on adrenergic activity, while mazindol demonstrates activity along both adrenergic and dopaminergic pathways. Patients report a decrease in appetite as well as an increase in energy.

The pharmacokinetic profiles of these agents are similar as well. The effects of the agents last approximately 4-6 hours, with an average half-life of 6 hours. The exception is mazindol, with effects lasting between 8 and 15 hours. Elimination of the anorexiants is primarily renal for both unchanged drug and metabolites.

The anorexiants are associated with abuse, as they are chemically and pharmacologically related to amphetamines. The dependence associated with these agents may be psychological and/or physiological, and is usually associated with long-term therapy or abuse. Chronic intoxication is associated with severe dermatoses, marked insomnia, irritability, hyperactivity, personality changes and psychosis. Gradual dosage reduction is warranted to avoid symptoms of withdrawal (mental depression, extreme fatigue, sleep EEG changes).

The effects of tolerance to the anorexiants may occur within a few weeks of initiation of therapy. If the patient continues to lose weight and does not develop side effects or dependence, therapy may be continued past 12 weeks. If the patient does not continue to lose weight, then the dosage should not be increased. The agent should be discontinued. Total length of therapy with the anorexiant agents should not exceed six months.

Phenmetrazine and phendimetrazine tartrate contain tartrazine dye, which is associated with allergic-type reactions. Reactions generally manifest as respiratory symptoms similar to bronchial asthma, such as wheezing. Sensitivity to tartrazine occurs frequently in patients who are allergic to aspirin. Tartrazine sensitivity is uncommon as its incidence in the general population is low.

Contraindications to the anorexiants include advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, glaucoma, history of drug abuse and MAO (monoamine oxidase) inhibitor use within fourteen days.

Adverse drug reactions associated with the anorexiants affect primarily the cardiovascular and central nervous systems. Common cardiovascular adverse reactions include palpitations, tachycardia, arrhythmias, hypertension, fainting and precordial pain. Side effects in the central nervous system include nervousness, restlessness, dizziness, insomnia, tremor and headache. Other systems are affected by these medications as well. With respect to the gastrointestinal system, patients report dry mouth, unpleasant taste, nausea, vomiting, diarrhea and constipation. In the genitourinary tract, dysuria, polyuria, urinary frequency and impotence are reported. Other miscellaneous adverse drug reactions include mydriasis, blurred vision, hair loss, muscle pain, excessive perspiration, flushing and fever.

At toxic levels, signs and symptoms may include restlessness, tremor, hyperreflexia, rapid respiration, hyperpyrexia, hallucinations, panic states, convulsions, arrhythmias, circulatory collapse, hypertension, hypotension, coma, and death. Overdose is managed with sedation using chlorpromazine. Intravenous phentolamine or nitroglycerin may help mediate cardiovascular effects. The patient’s urine may be acidified to enhance elimination of the offending agent.