Drug Informatics

Drug Interactions to Warfarin

March 22, 2017 Drug Informatics, Drug Interactions, Pharmacodynamics, Pharmacokinetics No comments , , , , , , ,

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Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

Pharmacodynamic:

  • Synergism
  • Competitive antagonism
  • Alteration of vitamin K cycle and metabolism

Pharmacokinetic:

  • Enzyme induction
  • Enzyme inhibition
  • Reduced plasma protein binding

CYP450 Interactions

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CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Antibiotics and Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Botanical (Herbal) Products and Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium. Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

Make a provider and patient education for levothyroxine

February 13, 2013 Adverse Drug Reactions, Cardiology, Drug Informatics, Drug Interactions, Pharmacokinetics, Pharmacotherapy, Pharmacy Education, Therapeutics 3 comments , , , ,

Today I would like to write something about levothyroxine. My hospital uses levothyroxine often. Everyday there are lots of patients prescribed with levothyroxine. I do believe it is necessary to write below for education, which is not only for patients but also providers. The reference I use comes from U.S. FDA’s official drug information database.

Indications and Usage

Levothyroxine sodium is used for the following indications:

Hypothyroidism – As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

Pituitary TSH Suppression – In the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Contraindications

Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids. Finally, levothyroxine is contraindicated in patients with hypersensitivity to any of the inactive ingredients in levothyroxine.

Dosage and Administration

  • The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state.
  • The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue.

To acheive the two goals above, it depends on variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions (e.g., pregnancy, concomitant medications, and the specific nature of the condition being treated). As a result Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters.

Levothyroxine sodium tablets are administered as a single daily dose.

Table 1 The Indication and Dosages of Levothyroxine

Indication and UsageDosage
1HypothyroidismIndividuals who are at low risk of coronary artery diseaseStarting at 1.7 mcg/kg/day (Full dose). Adjusting dosage in 12.5-25 mcg increments until clinically euthyroid and serum TSH has normalized.
If myxedema coma, administer intravenously rather than orallyIndividuals older than 50 yrs or under 50 yrs with underlying cardiac diseaseStarting from 25-50 mcg/day, with increments of 12.5-25 mcg/day at 6-8 week intervals until clinical euthyroid and the serum TSH has normalized
Elderly individualsStarting from 12.5-25 mcg/day, with increments of 12.5-25 mcg/day at 4-6 week intervals until clinical euthyroid and the serum TSH has normalized
Individuals with severe hypothyroidismStarting from 12.5-25 mcg/day, with increments of 25 mcg/day at 2-4 week intervals until clinical euthyroid and the serum TSH has normalized
Secondary or tertiary hypothyroidismDosage as above but titrated until clinically euthyroid and serum free-T4 level is restored to the upper half of the normal range
2TSH Suppression – various types of euthyroid goiters and thyroid cancerWell-differentiated thyroid cancer> 2 mcg/kg/day (Target: TSH suppressed to <0.1 mU/L)
Contraindicated if the serum TSH is already suppressedWell-differentiated thyroid cancer (high risk)Target: TSH suppressed to <0.01 mU/L
Benign nodules and nontoxic multinodular goiter (controversial)Target: TSH suppressed to between 0.1 to either 0.5 or 1.0 mU/L

 

The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels alone may be used to monitor therapy. The frequence of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization.

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Quizartinib: Surprising, Unprecedented Activity in Relapsed AML

January 29, 2013 Chemotherapy, Drug Informatics, Hematology, Pharmacotherapy, Therapeutics No comments , , , ,

ATLANTA, Georgia — The investigational agent quizartinib (Astellas/Ambit) has shown unprecedented activity in patients with relapsed and refractory acute myeloid leukemia (AML) in a phase 2 clinical trial.

On the basis of these results, larger phase 3 clinical trials with the drug are being planned, according to Astellas/Ambit.

Patients with AML can develop many different genetic mutations, but one of the most threatening is FLT3 internal tandem duplications (ITD), which makes the leukemia even more aggressive and typically leads to resistance to standard chemotherapy. This mutation develops in 34% of AML patients and is associated with more rapid relapse and reduced overall survival, explained lead author Mark Levis, MD, PhD, associate professor of oncology, pharmacology, and medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland.

“Quizartinib is the first and only single-agent drug that has produced a clinical benefit in AML patients with this deadly mutation who have failed previous therapy,” he said. “It caught us by surprise how well it worked.”

Dr. Levis presented results from a large phase 2 study of patients with relapsed or refractory AML here at the American Society of Hematology (ASH) 54th Annual Meeting. Many patients achieved a complete response to quizartinib, and one third were stabilized with quizartinib for long enough to undergo potentially life-saving hematopoietic stem cell transplantation (HSCT).

“The number of patients bridged to a transplant was very significant,” Dr. Levis said in a statement. “We plan on using these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible for patients who previously had no hope for a cure,” he added.

“I am desperate to get this drug in the clinic…. I treat mainly a refractory patient population, and this is the drug that I want to use in them,” he explained.

Patients with a FLT3 mutation present a “major management problem,” said ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada. “You can put them in remission, but then they relapse…and the disease progresses so quickly that they don’t get a chance for transplant and for cure,” he said.

“This study is important because it shows that quizartinib can stabilize these patients for long enough to do a transplant. It shows that this is possible in about a third of patients,” Dr. Keating reported. It is another example of a new drug offering fresh hope for a hard-to-heal patient population, he said at a premeeting press briefing.

Mutation Is Like a Power Switch

“The FTL3 mutation is essentially a power switch that leukemia cells use to spread more aggressively and helps them to grow back immediately after chemotherapy,” Dr. Levis explained. “The only way to treat this type of mutation is to find a way to turn the switch off — a feat that has eluded researchers for far too long.”

Quizartinib appears to do just that. It was designed to “turn off” the mutated FLT3 enzyme, which forces the immature cancer cells to die immediately or to undergo maturation and then die. This eliminates enough cancer cells to stabilize the patient for long enough to offer them another treatment, including transplantation.

The phase 2 study of quizartinib was conducted in AML patients who had relapsed, did not respond to second-line therapy, or had relapsed after HSCT. The patients were divided into 2 groups: 133 were older than 60 years, and 137 were 18 to 60 years.

Dr. Levis presented data from the younger cohort. Of the 137 patients, 99 had the FLT3 mutation and 38 did not.

Oral quizartinib was used alone at a starting dose of 135 mg/day for men and 90 mg/day for women, and was given continuously in 28-day cycles. The difference in the dose between the sexes relates to an adverse cardiac effect of the drug; quizartinib can cause a prolongation of the QT interval on electrocardiogram, and women are more sensitive to this effect than men, Dr. Levis explained.

The drug elicited responses in patients with and without the mutation, but the responses were better in those with the mutation. The primary end point was a composite complete remission rate (CR), which included complete remission with no active disease, complete remission with incomplete platelet recovery (so no active disease but an incomplete platelet count), and complete remission with incomplete hematologic recovery (no active disease but abnormal red and white blood cells counts).

For the 99 patients who had the FLT3 mutation, the composite CR was 44% (4% with CR, 0% with incomplete platelet recovery, and 40% with incomplete hematologic recovery). The median duration of response was 11.3 weeks and median overall survival was 23.1 weeks.

For the 38 patients without the mutation, the composite CR was 34% (3% with CR, 3% with incomplete platelet recovery, and 29% with incomplete hematologic recovery). The median duration of response was 5.0 weeks and median overall survival 25.6 weeks.

Of the 137 patients 18 to 60 years of age, 47 (34%) underwent HSCT after responding to quizartinib. Some of these patients have survived more than 2 years without any disease recurrence, Dr. Levis said.

Adverse events included nausea (reported by 38% of patients), anemia (29%), QT prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). Adverse events led to discontinuation of treatment in 10% of patients.

Quizartinib was “extremely well tolerated,” Dr. Levis noted. The main adverse events are the QT prolongation and myelosuppression, but these are “manageable,” he said.
“We are still playing around with the dose,” he explained. A future trial will look at using lower doses of the drug, and a randomized trial of 30 mg vs 60 mg is planned.

The findings from this phase 2 trial of quizartinib in patients with relapsed and refractory AML are “especially encouraging,” said Jorge Cortes, MD, deputy chair in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston, in a statement. “In the patients with the FLT3-ITD mutation, quizartinib represents the most active single agent we have observed with any class of investigational drugs in this challenging patient population,” he added.

The study was funded by Astellas/Ambit, the developers of quizartinib. Dr. Levis reports consultancy for Ambit Biosciences. Several of his coauthors are company employees. Dr. Keating reports serving on the data safety monitoring board for Clavis, Novartis, and Pfizer.

American Society of Hematology (ASH) 54th Annual Meeting: Abstract 673. Presented December 10, 2012.

Management of Gout (Medications)

October 25, 2012 Adverse Drug Reactions, Drug Informatics, Pharmacotherapy No comments , , , ,

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying health problems. However, aspirin should not be used because it can alter uric acid levels and potentially prolong and intensify an acute attack.

Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used but used cautiously), and patients in the intensive care unit who are predisposed to gastritis. In patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

NSAIDs are prescribed at full dosage for 2-5 days to control the acute attack, and the dose is reduced to approximately one half to one fourth of that amount once the acute attack is controlled. Taper the dose down over approximately 2 weeks. But the consistent low-dose of NSAIDs used for 6-24 months may help to prevent the occurring of acute gout attack during the chronic lowering uric acid treatment.

Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.

Colchicine

Although colchicine was once the treatment of choice for acute gout, it is now a second-line approach because of its narrow therapeutic window and risk of toxicity.

Colchicine therapy must be initiated within 24 hours of onset of the acute attack to be effective. Dosing recommendation for colchicine in acute gout therapy have been modified in recent years because of an increased awareness of its toxicities. The most recent recommendations have been trending toward lowered daily and cumulative doses. The favored regimen is low-dose colchicine 1.8 mg total over 1 hour (1.2 mg PO initially then 0.6 mg q1hr, total not to exceed 1.8 mg over 1 hour-period).

Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min. Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

For prophylaxis the dose of colchicine is 0.6 mg bid or lower. In patients with renal insufficiency, this dose may need to be decreased to daily or overy-other-day administration. Even in prophylactic dose, colchicines can cause marrow toxicity and neuromyopathy in the setting of renal insufficiency. Long-term use of colchicine can lead to a muscle weakness associated with elevated levels of creatine kinase due to a drug-induced neuromyopathy, particularly in patients with renal insufficiency.

Corticosteroids

Corticosteroids can be given to patients with gout who cannot use NSAIDs or coclchicine, but adrenocorticotropic hormone (ACTH) would be preferred. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via ACTH.

ACTH 40 IU can be given to induce corticosteroid production by the patient’s own adrenal glands. Such a regimen dose not depend on the patient to properly taper prednisone. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.

Intra-articular, long-acting (depot) corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids.

Allopurinol

Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid. It is the most effective urate-lowering agent. However, alcohol can interfere with effectiveness of allopurinol.

Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, and/or pruritic maculopapular rash. Less frequently, patients taking allopurinol can develop allopurinol hypersensitivity, which carries a mortality rate of 20-30%. Features of allopurinol hypersensitivity include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat allopurinol hypersensitivity.

Allopurinol hypersensitivity is more likely to occur in patients with renal insufficiency, patients who are taking a diuretic, and patients begun on 300 mg of allopurinol. Although allopurinol hypersensitivity is more common (although still rare) in patients with renal insufficiency, this effect dose not appear to be dose-related. Thus, a slow and careful titration of allopurinol dosing sufficient to achieve uric acid levels of less than 6 mg/dL is also recommended in these patients.

Allopurinol is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. The underlying mechanism is thought to be a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4%, the rate of organ failure and death is high. Treatment is with intravenous N-acetyl cysteine and steroids. Allopurinol should be discontinued in patients who develop a rash.

In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved.

While adjusting the dosage of allopurinol in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

Update from Medscape Reference at http://emedicine.medscape.com/article/329958-medication#6 on Sep 6th 2013.

Pegloticase

Pegloticase is a pegylated uric acid–specific enzyme that is a polyethylene glycol conjugate of recombinant uricase. It achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin, thereby lowering serum uric acid levels. Pegloticase is indicated for gout in adults refractory to conventional therapy (ie, when serum uric acid levels have not normalized and either signs and symptoms are inadequately controlled with xanthine oxidase inhibitors or uricosurics at maximum appropriate doses or xanthine oxidase inhibitors are contraindicated).

The dosage is 8 mg IV every 2 weeks. Complications include anaphylaxis, infusion reactions, flare of gout attacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia, muscle spasms, pyrexia, back pain, diarrhea, and rash.[134, 135] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a contraindication.[135]

Systemic Therapy for Bone Metastases

August 24, 2012 Adverse Drug Reactions, Drug Informatics, Hematology, Pharmacology, Therapeutics No comments , , ,

zoledronic acid

Accelerated bone loss in patients with cancer is a frequent problem that may result from [1]invasion of the cancer to bone, [2]paraneoplastic tumor proteins, and/or [3]hormonal therapies utilized for cancer treatment.

  • Invasion of the cancer to bone;
  • Paraneoplastic tumor proteins;
  • Hormonal therapies utilized for cancer treatmen.

Invasion of cancer to bone is common complication in patients. The proportion of cancer invading to bone is 20% to 25% in kidney cancers, 65% to 75% in breast and prostate cancers, and almost all patients (70% to 95%) with multiple myeloma.

Mechanism of Bone Metastases

  1. Metabolically active tumor cells invade and populate bone and secrete growth factors that affect bone resorption and formation by stimulation of osteoclasts, cells that destroy bone by attacking the mineralized bone matrix.
  2. On the other hand osteoclasts also secrete growth factors that induce tumor cells in the bone to grow, spread, and stimulate the activity of osteoblasts, cells responsible for the formation of bone. However, osteoblastic activity creates new bone formation away from the sites of osteolytic bone resorption. So weakened areas are not strengthened by osteoblastic activity.
  3. Also, osteoblasts release receptor activator of nuclear factor κB ligand (RANKL), a key mediator of osteoclast formation, function, and survival, which is one of the mechanisms of metastatic bone disease.

Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both ostelytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy.

  • Pathological fractures;
  • Hypercalcemia;
  • Spinal cord compression;
  • The need for surgical intervention and radiation therapy.

Untreated patients with bone metastases are at risk for multiple SREs within a single year, ranging from 1.5 events for prostate cancer to 4.0 for breast cancer.

Treatment Agents

Now two types of agents are used to treat bone metastases – bisphosphonates and denosumab.

Bisphosphonates

Bisphosphonates are unique drugs with an affinity for bone mineral matrix with the ability to inhibit bone resorption. Bisphosphonates decrease bone resorption and increase mineralization by entering osteoclasts and inhibiting farnesyl diphosphate synthase, a key enzyme in the biosynthetic mevalonate pathway.

Bisphosphonates may also affect bone resorption through the inhibition of osteoclast precursor maturation, induction of apoptosis in mature osteoclasts, inhibition of tumor cell adhesion to bone, and inhibition of inflammatory cytokine production.

Nitrogencontaining bisphosphonates (N-BPs) have the greatest antiresorptive activity. Based on in vitro studies, zoledronic acid is the most potent aminobisphosphonate and is the only intravenous bisphosphonate found to be effective in all types of metastatic bone lesions.

Bisphosphonates also have a potential antitumor effect. Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.

However data from the FDA and the United Kingdom showed the issue of potential risk of esophageal cancer with oral bisphosphonate use was raised. The FDA recently announced plans to continue review of the conflicting studies.

Safety and efficacy data of intravenous bisphosphonates in the metastatic setting are predominantly limited to 24 months of treatment. The most frequently reported side effects from intravenous bisphosphonates are fever and myalgias, which may occur in up to 55% of patients, typically within 12 hours of the initial infusion. Antiinflammatory agents may easily provide relief. Diarrhea and gastric irritation may develop with the oral bisphosphonates ibandronate and clodronate, which are not approved in the management of bone metastases in the United States. Electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia, are rarely reported with intravenous bisphosphonates. Other condition such as  vitamin D deficiency, hypoparathyroidism, hypomagnesemia, or use of medication such as interferon, aminoglycosides, or loop diuretics may provoke these abnormalities. (more…)