Rivaroxaban (Xarelto(®)), an oral direct factor Xa inhibitor, is approved for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE. It is administered at a fixed oral dose and does not require routine coagulation monitoring. In the EINSTEIN-DVT and EINSTEIN-PE trials, in over 8,000 patients with DVT and/or PE, a single-drug approach with rivaroxaban was shown to be noninferior to standard therapy consisting of subcutaneous enoxaparin sodium overlapping with and followed by an oral dose-adjusted vitamin K antagonist (enoxaparin-VKA) with regard to the incidence of symptomatic recurrent venous thromboembolism (VTE) after 3, 6 or 12 months of treatment. Rivaroxaban was generally well tolerated in patients with DVT or PE, with no significant between-group differences in clinically relevant bleeding between the rivaroxaban and enoxaparin-VKA groups. Notably, rivaroxaban was associated with a significantly lower rate of major bleeding compared with enoxaparin-VKA when EINSTEIN-DVT and EINSTEIN-PE data were pooled. Pharmacoeconomic analyses indicated that rivaroxaban may be a cost-effective alternative to enoxaparin-VKA for the treatment of DVT or PE and prevention of recurrent VTE.

NICE Guidelines

In all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6 or 12 months.

NICE recommends rivaroxaban as a possible treatment for adults with pulmonary embolism and to prevent a further deep vein thrombosis or pulmonary embolism.

The primary efficacy outcome in EINSTEIN‑PE was symptomatic recurrent venous thromboembolism. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin K antagonist arms in the trial. The Committee concluded that rivaroxaban had acceptable clinical effectiveness compared with LMWH and a vitamin K antagonist.

EINSTEIN-PE

In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, they compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.

A total of 1173 patients (nearly 25%) in our study met our definition of extensive disease, and 608 (13%) had limited pulmonary embolism. Furthermore, nearly 25% had concomitant symptomatic deep-vein thrombosis.  64.7% of PE causes were unprovoked.

Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups.

In this study involving patients with symptomatic pulmonary embolism, oral rivaroxaban alone provided protection from recurrent venous thromboembolism that was similar to the protection provided by standard therapy, with similar bleeding rates. During a mean study duration of approximately 9 months, there was a recurrence in 2.1% of patients in the rivaroxaban group and 1.8% of those in the standard-therapy group.

The INR in the therapeutic range 62.7% of the time and exceeding 3.0 only 15.5% of the time. These results compare favorably with the findings in other contemporary studies of venous thromboembolism. Adherence to the rivaroxaban regimen was high in 94% of patients. The number of patients who were lost to follow-up was negligible.

One potential limitation to this study is that, prior to randomization into the rivaroxaban or standard therapy groups, all patients received LMWH for varying amounts of time, though almost all patients received LMWH for less than 48 hours. While the authors argue that the administration of LMWH for such a brief period should not affect results, it is possible that receiving LMWH for up to 48 hours could have some impact. The other, and perhaps more significant, limitation of this study is that it was an open trial, meaning that neither patients nor researchers were blinded as to what treatment was being administered. However, while the criteria for diagnosing recurrence of venous thromboembolism were objective diagnostic findings, the open design may have had more of an impact on secondary outcomes.

The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis—indications that are often considered to require bactericidal activity. Although bacteriostatic/bactericidal data may provide valuable information on the potential action of antibacterial agents in vitro, it is necessary to combine this information with pharmacokinetic and pharmacodynamic data to provide more meaningful prediction of efficacy in vivo.

Reference:
http://cid.oxfordjournals.org/content/38/6/864.full.pdf+html

CARBIDOPA/LEVODOPA SE

Neurologic: Dyskinesia (12.2% to 16.5% )

Asthenia

1) In clinical trials, asthenia has been reported in patients who received sustained-release carbidopa/levodopa (n=748) (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009).
2) Asthenia has been reported with immediate-release carbidopa/levodopa (Prod Info PARCOPA(R) orally disintegrating tablets, 2006).

Immediate-release and controlled-release carbidopa/levodopa in PD: A 5-year randomized multicenter study

Neurology September 1, 1999 53:1012

Dyskinesia

1) Summary 
a) Dyskinesias, including choreiform movements and dystonia, are the most frequent and severe adverse effects of carbidopa/levodopa (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009; Prod Info SINEMET(R) oral tablet, 2008; Prod Info PARCOPA(R) orally disintegrating tablets, 2006). Combined use with carbidopa does not lessen dyskinesias relative to levodopa alone (Nutt, 1990). Propranolol (Carpentier et al, 1996) or fluoxetine (Durif et al, 1995) may be useful in some patients.
2) Incidence: 12.2% to 16.5% (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009)
3) In randomized, controlled clinical trials, dyskinesia has been reported in 16.5% of patients who received sustained-release carbidopa/levodopa (n=491) compared with 12.2% of patients who received immediate-release carbidopa/levodopa (n=524) (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009).
4) Dyskinesias (eg, choreiform, dystonic, and other involuntary movements and nausea) are the most frequent adverse effects of carbidopa/levodopa combination therapy (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009; Prod Info SINEMET(R) oral tablet, 2008; Prod Info PARCOPA(R) orally disintegrating tablets, 2006).
5) In a study including 100 parkinsonian patients, peak dose dyskinesias were more often present in younger patients (p less than 0.0001). However, the mean latency to dyskinesia induction after levodopa initiation was no different in younger patients versus older dyskinetic patients. Also, the overall dyskinesia-free survival of younger subjects was not worse. A delay in initiating levodopa therapy of more than 3 years after disease onset, and levodopa treatment on initiation in Hoehn-Yahr stage II compared to stage I patients, did not increase the probability of developing dyskinesias over time (Blanchet et al, 1996a).
6) Severe choreiform storm was described in a 70-year-old male treated for Parkinson disease with levodopa 250 to 1250 mg daily for 1 week. The patient experienced marked difficulty in breathing and anxiety and marked choreoathetoid movements of all voluntary muscles including the diaphragm. The patient also exhibited dystonic movements of the neck and trunk. Improvement was seen with diazepam 10 mg intramuscularly and diphenhydramine 25 mg intramuscularly. The patient was rechallenged with a single 250-mg dose of levodopa and developed an identical reaction. Dosage was adjusted at 300 to 400 mg daily after 4 months with no choreiform reactions. However, the patient gradually deteriorated and died after 1 year (Hinterbuchner & Hinterbuchner, 1974).
7) Management
a) In a randomized, single-center, double-masked, placebo-controlled, 3-week crossover study (n=24), amantadine therapy (100 mg twice daily) significantly reduced the total dyskinesia score (Goetz scale) by 24% compared with placebo (p=0.004). Furthermore, the maximal dyskinesia score was significantly decreased by 17% in the amantadine group compared with placebo (p=0.02) (Pahwa et al, 2006).
b) Propranolol in doses up to 60 mg daily for 5 to 6 weeks resulted in a mean 40% improvement in dystonic reactions in 7 patients. Four patients with ballistic or choreic dyskinesias showed the greatest improvement (up to 78%), while the one patient without benefit was characterized as pure dystonia. Daily life was dramatically improved in responding patients, with fewer falls due to motor disability; withdrawal of adjunctive apomorphine; and an increase in duration of “on” time noted. No loss of parkinsonian motor control was reported subjectively or objectively; blood pressure and heart rate were not adversely effected at the low doses of propranolol used (Carpentier et al, 1996).
c) Fluoxetine 20 mg daily for 11 days improved the dystonic response to apomorphine challenge (particularly those arising in the trunk and lower limbs) by approximately 50% in 7 chronic Parkinson patients (Durif et al, 1995).
d) At least 6 different patterns of dyskinesia in Parkinson disease have been described which are thought to be directly related to levodopa therapy.(Olanow & Koller, 1998; Jankovic, 1993). A different classification scheme suggests dyskinesias can be divided as predictable or unpredictable; predictable dyskinesias can be further subdivided into 3 types (interdose, biphasic or “off-period”). Unpredictable dyskinesias (“yo-yo”, “on-off”) are random (Giron & Koller, 1996a). These dyskinesias and their recommended management include (Olanow & Koller, 1998; Jankovic, 1993; Giron & Koller, 1996a): 
Peak-dose dyskinesia (interdose dyskinesia) and respiratory dyskinesia 
reduce each levodopa dose, add dopamine agonists, add or convert to liquid levodopa, use immediate-release formulation, decrease or eliminate selegiline, add catechol-o-methyl transferase (COMT) inhibitor
Biphasic dyskinesia
increase frequency of levodopa dosing, add/increase dopamine agonist, restrict levodopa/carbidopa to several early/midday doses
Peak-dose dystonia
reduce each levodopa dose, add dopamine agonist, botulinum toxin
Early morning foot dystonia
nocturnal levodopa/carbidopa sustained-release, nocturnal dopamine agonists, early morning levodopa/carbidopa, botulinum toxin
Myoclonus
clonazepam, valproate, methysergide
Dystonic posture (“striatal”)
increase levodopa dose, anticholinergics, botulinum toxin
Akathisia
anxiolytics, propranolol, opioids

Dystonia

1) Incidence: 0.8% to 1.8% (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009)
2) In randomized, controlled clinical trials, dystonia has been reported in 1.8% of patients who received sustained-release carbidopa/levodopa (n=491) compared with 0.8% of patients who received immediate-release carbidopa/levodopa (n=524) (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009).

Probenecid & Abx

• Probenecid inhibits excretion of weak organic acids in the proximal and distal convoluted tubules, altering the pharmacokinetics of many drugs. It also inhibits glucuronidation of some drugs. Probenecid inhibits renal tubular excretion of many β-lactam antibacterial agents (e.g., cephalosporins and penicillins), an interaction that has been exploited clinically to maintain serum levels of the antibacterial agent, thereby reducing the frequency of administration. Probenecid does not alter serum levels of ceftriaxone or ceftazidime. Probenecid does not alter the pharmacokinetics of digoxin or theophylline.

• According to the 2008 update of the Canadian guidelines on sexually transmitted infections, the combination of oral probenecid and cefoxitin, as a single dose in combination with doxycycline for 14 days, is used as an alternative to ceftriaxone for outpatient treatment regimen for pelvic inflammatory disease [www.phac-aspc.gc.ca/std-mts/sti_2006/pdf/404_Pelvic_Inflammatory_Disease.pdf].
• According to the 2005 Anti-infective guidelines for community-acquired infections, the combination of cefazolin with oral probenecid (given 30 minutes prior to cefazolin) is used as an alternative treatment regimen for severe non-facial uncomplicated cellulitis [Clin Infect Dis 2002;34(11):1440-8].
• According to the 2009 Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents, oral probenecid is administered in combination with cidofovir (administered iv) for the prevention of cidofovir-related nephrotoxicity. Cidofovir is used for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS in whom other drugs are inappropriate [www.cdc.gov/mmwr/pdf/rr/rr5804.pdf].

Bisphosphonate

steonecrosis of the jaw has been reported in patients receiving bisphosphonate therapy. Although the majority of patients affected receive either pamidronate or zoledronic acid for the management of metastatic cancer to the bone, there have been reports of osteonecrosis in patients receiving oral bisphosphonate therapy for the treatment of osteoporosis, including risedronate.[30737] Most of the reported cases have appeared after dental tooth extraction; however, some cases have appeared spontaneously. It is not possible to determine if the reported events are related to bisphosphonates, concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), a patient’s underlying disease state, or other comorbid risk factors (e.g., anemia, infection, preexisting oral disease). Typical signs and symptoms of osteonecrosis of the jaw include pain, swelling, infection, or poor healing of the gums, loosening of the teeth, numbness or a feeling of heaviness in the jaw, and drainage of exposed bone. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The treating physician and dentist should use their best clinical judgment to guide the management plan of each patient based on individual benefit and risk assessments. Based on a review of the available literature, treatments that have been used include local debridement, bone resection or other surgery, antimicrobials, antiseptic mouthwash, and hyperbaric oxygen.[33138] While a consensus on the best treatment strategies does not exist, the American Academy of Oral Medicine recommends prevention. Preventive measure include evaluation by a dentist prior to intravenous bisphosphonate initiation and within 3 months of oral bisphosphonate initiation, correction of dental complications prior to drug initiation, and continued regular follow-up with a dentist. For the treatment of osteonecrosis, recommendations include superficial debridement, bone resection when indicated, systemic antimicrobial for infections with culture-directed therapy or penicillin, amoxicillin, or clindamycin empirically, or use of chlorhexidine mouthwash 3—4 times daily. Discontinuation of the bisphosphonate once osteonecrosis occurs is controversial as the half-life of bisphosphonates within the bone is estimated to be years

• cefazolin
  • better gram positive coverage
  • useful for cellulitis
• cefuroxime
  • more respiratory
  • more gram negative coverage

Amiodarone and Simvastatin:

• amiodarone is known to inhibit CYP3A4 and 2D6
• 200mg amiodarone for 6 wk and simva 80mgx 4 wk has been associated with weakenss and muscle pain
• simvastatin dose should not exceed 20mg daily
• alternative: selective statin that is not a CYP 3A4, such as pravstatin and rosuvastatin
• atorva: 2.24
• simva: 0.21-0.65
• amiodarone: terminal elimination half-life ranges from 26—107 days with a mean of around 53 days

Heparin Recommendation in STEMI:

Amiodarone

• Amiodarone is both an antiarrhythmic and a potent vasodilator.
• amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. Delayed repolarization is a result of inhibition of potassium ion fluxes that normally occur during phase 2 and 3 of the action potential.[24497] This results in prolongation of the effective refractory period in all cardiac tissue (e.g., atria, ventricles, AV node, and His-Purkinje system).
• By definition, class III agents act only on the repolarization phase of the action potential and therefore should leave conduction unchanged. However, amiodarone possesses actions similar to both class II and class IV antiarrhythmics: Amiodarone is a weak sodium channel blocker (class I effect). The result of this cellular action is a slowing of the upstroke velocity of phase 0 which reduces the rate of membrane depolarization and impulse conduction. Amiodarone also depresses automaticity of both the SA and AV nodes directly (class II effect),[24497] and slows conduction in the His-Purkinje system, and in the accessory pathway of patients with Wolff-Parkinson-White syndrome.
  Amiodarone also noncompetitively inhibits alpha- and beta-receptors, and possesses both vagolytic and calcium-channel blocking properties. The drug relaxes both smooth and cardiac muscle, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload.
• The 2006 ACC/AHA/ESC practice guidelines for inpatient pharmacological cardioversion of atrial fibrillation recommend a dose of 1.2—1.8 g/day PO, divided, until a total of 10 g has been administered, followed by a maintenance dose of 200—400 mg/day (Class IIa recommendation). For outpatient therapy, 600—800 mg/day PO in divided doses is recommended until a total of 10 g has been administered, followed by a maintenance dose of 200—400 mg/day (Class IIa recommendation).

Digoxin:
(How does it affect HR? MOA?)

• • : Digoxin inhibits the Na-K-ATPase membrane pump. Na-K-ATPase regulates intracellular sodium and potassium. Inhibition of this enzyme leads to an increase in intracellular sodium concentration (i.e., decreased outward transport) and ultimately to an increase in intracellular calcium as sodium-calcium exchange is stimulated by high intracellular sodium concentrations. It is believed that increased intracellular concentrations of calcium allow for greater activation of contractile proteins (e.g., actin, myosin).
  • Digoxin directly increases the force and velocity of myocardial contraction in both healthy and failing hearts.
  • Digoxin also possesses direct vasoconstrictive properties and reflex CNS-mediated peripheral vasoconstriction. Although this increases vascular resistance, in patients with failing hearts, increased myocardial contractility predominates and total peripheral resistance drops. In patients with congestive heart failure, an increased cardiac output will decrease sympathetic tone, thereby reducing the heart rate and causing diuresis in edematous patients and improving coronary blood flow
  • shortens the action potential duration, and decreases the maximal diastolic potential. The increase in vagal activity mediated by cardiac glycosides decreases conduction velocity through the atrioventricular (AV) node, prolonging its effective refractory period. In atrial flutter or fibrillation, digoxin decreases the number of atrial depolarizations that reach the ventricle, thereby slowing ventricular rate