Month: July 2012

Clinical Report-Drug Interaction Between Fluoxetin and Mirtazapine

July 23, 2012 Adverse Drug Reactions, Drug Interactions, Entertainment 55 comments , , ,

Clinical Case Report

 

Fluoxetin and Mirtazapine.

Date: July 8 2012

Place: Outpatient Pharmacy, 416 Hospital

Abstract and Introduction:

On the afternoon, July 8 2012 one male patient came to the outpatient pharmacy to take his drug. The phyisican prescribed fluoxetin accompanied by mirtazapine. I checked these two drugs in drug interaction checker and drug interactions were found between fluoxetine and mirtazapine – Potential for dangerous interaction ( may causes serotonin syndrome, although serotonin is rare but is life-threatening). I suggested the patient take these two drugs carefully. I told the man if he have the symptoms or signs of serotonin syndrome he should withdraw both drug immediately and back to hospital for further care if necessary.

Detail:

The Neurology Clinics prescribled fluoxetine accompanied by mirtazapine  to a middle-age man. The dosage and frequency for fluoxetine is 20mg po Qd meanwhile that for mirtazapine is 30mg po Qd.

I checked these two drugs in drug interaction checker and a drug interaction was found between fluoxetine and mirtazapine – Fluoxetine and mirtazapine both increase serotonin levels, potential for dangerous interaction ( may causes serotonin syndrome, although serotonin is rare but life-threatening).

So due to this drug interaction, when I was dispensing these two to him, I asked him whether he was also taking or had recently taken any other psychotropic medications such as antidepressants, MAOIs, SSRIs or some drugs such as analgesics and so on, which also increase serotonin levels and may cause serotonin syndrome if they are coadministered. He told me negative. So I told him that he could take these two medications in combination, but should take with caution due to the drug interaction between fluoxetine and mirtazapine. And the most important is that I taught him how to identify serotonin syndrome. Simply that the general symptoms and signs of serotonin syndrome are clonus, agitation or diaphoresis, tremor and hyperreflexia or hypertonia, temperature above 100.4°F (38° C) and I said if he have any symptoms or signs of serotonin syndrome both drugs should be withdrawed immediately and he should go back to hospital for further care if necessary, I told him.

Finally the patient told me he knew what he should and took both drugs home.

Discussion:

Serotonin is a neurotransmitter that is synthesized from the amino acid L-tryptophan. Synthesis is necessary in the central and peripheral nervous system because serotonin cannot cross the blood-brain barrier. Once synthesized, serotonin is either stored in neuronal vesicles or metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Serotonin binds 1 of 7 postsynaptic 5-hydroxytryptophan (5-HT) receptors. The hyperstimulation of the 5-HT receptors in the brain and/or spinal cord is the cause of serotonin syndrome. So what is serotonin syndrome? Serotonin syndrome, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Serotonin syndrome is a potentially life-threatening set of symptoms caused by serotonin toxicity, and usually involves a combination of psychotropic medications that increase serotonergic transmission. That means specific drug interactions can be the reason for serotonin syndrome. Serotonin syndrome can ensue after the addition of a second serotonergic drug to an existing drug regimen or with administration of a serotonergic drug before allowing an inadequate washout period after discontinuation of another serotonergic drug. Potential mechanisms and corresponding agents of serotonin syndrome include:

  1. Increasing production of serotonin by providing increased amount of precursors – L-tryptophan-containing substances;
  2. Prevention of metabolism of stored serotonin – Monoamine oxidase inhibitors (MAOIs);
  3. Increased release of stored serotonin – Amphetamine, cocaine, fenfluramine, methylenedioxymethamphetamine (MDMA or ecstasy), or meperidine;
  4. Prevention of reuptake of serotonin released into the synapse – SSRIs, tricyclic antidepressants (TCAs), MDMA, dextromethorphan, meperidine, or St John’s Wort;
  5. Direct stimulation of serotonin receptors – Buspirone, lysergic acid, diethylamide (LSD);
  6. Unknown mechanism – Lithium.

I summarize the drugs which are implicated in serotonin syndrome. They are in  Table 1.

Categories

Drugs

Amphetamines and their derivativesEcstasy Dextroamphetamine, Methamphetamine and Sibutramine
AnalgesicsCyclobenzaprine, Fentanyl, Meperidine, Tramadol
Antidepressants/Mood stabilizersBuspirone, Lithium
Monoamine Oxidase InhibitorsPhenelzine
SSRIsFluoxetine
Serotonin-Norepinephrine Reuptake InhibitorsVenlafaxine
Serotonin 2A Receptor BlockersTrazodone
St. John’s Wort
Tricyclic Antidepressants
AntiemeticsMetoclopramide, Ondansetron
Antimigraine Drugscarbamazepine, ergot alkaloids, triptans, and valproic acid

Table 1 Drugs that are potential to serotonin syndrome.

Other drugs if used in combination that may cause serotonin syndrome include cocaine, dextromethorphan, linezolid, l-tryptophan, and 5-hydroxytryptophan. (more…)

Fidaxomicin Beats Vancomycin for C difficile in Cancer

July 21, 2012 Hematology, Infectious Diseases, Pharmacoeconomics, Therapeutics No comments , , ,

I have read a similar article before. It was about Fidaxomicin and CDAD too. But today this newer one describes more exactly. This article compares fidaxomicin to vancomycin in aspects of cure rate in terms of initial clinical cure, recurrence, and sustained response. According to this article fidaxomicin appears to be better than vancomycin in treating Clostridium difficile-associated diarrhea (CDAD). However, vancomycin also can treat CDAD effiaciously, according to the data shown in these studies.

According to the North American study, clinical cure rate of fidaxomicin was 87.7% and that of vancomycin was 86.8%. From this point both fidaxomicin and vancomycin are able to treat CDAD satisfactorily. However, differ between the two drugs does exist. The incidence of recurrence with vancomycin over fidaxomicin were 26.9% vs 12.7%. And the sustained response rates of fidaxomicin over vancomycin were 76.6% vs 63.4%. Thus from these two aspects fidaxomicin appears to be better than vancomycin.

I want to emphasize that we should compare these two drugs in the specific group population – the cancer survivors. According to the studies, those with cancers treated with fidaxomicin had significantly higher clinical cure and sustained clinical cure rates and significantly lower rates of recurrence than patients treated with vancomycin.

One more thing is that the price of these two drug is not considered in this article. I check the price of fidaxomicin and vancomycin. The dosage of fidaxomicin is 200 mg po Bid, that of vancomycin is 125 mg po Qid. The cheapest vancomycin capsule’s unit price is $27.78 (per 125 mg/capsule, Vancocin-VIROPHARMA INCO), and that of fidaxomicin tablet is $135 (per 200 mg/tablet). So a 10-day course we need $2700 for fidaxomicin vs $1111.2 for vancomycin. From this perspective I think we should use vancomycin to treat CDAD first, fidaxomicin should be the alternative. However considering the lower recurrence rate and higher sustained response rate, the fidaxomicin regimen’s cost may be less than vancomycin’s.

References

  1. Becky McCall. Fidaxomicin Beats Vancomycin for C difficile in Cancer. Medscape News. 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). 2012 Apr 3. Poster 2289 and abstract O670.
  2. Jason W. Lancaster, PharmD, BCPS. Economic Impact of Fidaxomicin on CDI Treatment in United States. The American Journal of Pharmacy Benefits. 2012 May; 4: 114-117.

April 4, 2012 (London, United Kingdom) — Fidaxomicin (Dificid, Optimer Pharmaceuticals) treatment was superior to vancomycin for initial cure, recurrence, and sustained response, according to a subanalysis of patients with cancer and Clostridium difficile–associated diarrhea (CDAD).

In addition, concomitant antibiotics had less effect on clinical cure rate with fidaxomicin than with vancomycin, according to data from a phase 3 clinical trial conducted in Europe and North America. Both studies were presented here at the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Oliver A. Cornely, MD, oncologist/hematologist and infectious diseases physician from the University Hospital Cologne in Germany, led the European/North American phase 3 study (OPT-80-004). He presented the results of a subanalysis of data from both studies.

The European/North American multicenter, randomized, controlled, double-blind, noninferiority study was published in February (Lancet Infect Dis. 2012;12:281-289). An earlier phase 3 study of fidaxomicin conducted in the United States and Canada was published last year (N Engl J Med. 2011;364:422-431).

The subanalysis of cancer patients with CDAD was presented here at ECCMID for the first time.

Fidaxomicin is a novel macrocyclic antibiotic with a narrow spectrum of activity against Gram-positive bacteria and minimal activity against normal gut flora. “Fidaxomicin is not absorbed, which makes it like a magic bullet because it stays where it is needed in extremely high concentrations,” Dr. Cornely told Medscape Medical News.

Further to the North American study, results of the second phase 3 trial in 509 patients from Europe and North America also demonstrated that clinical cure for fidaxomicin was noninferior to vancomycin in the modified intent-to-treat population (87.7% vs 86.8%).

Dr. Cornely emphasized the recurrence rates with fidaxomicin. “This is the first point at which we see a difference in the 2 antibiotics, and it is a large difference,” he said. “We see double the incidence of recurrence with vancomycin over fidaxomicin [26.9% vs 12.7%; difference, 14.2%; 95% confidence interval [CI], –21.4% to –6.8%; P < .001]. It cuts the recurrence rate in half. A high recurrence rate is expected with vancomycin in a very sick population, but this is still an extreme.”

These findings were also reflected in the sustained response rates, which showed fidaxomicin was superior to vancomycin (76.6% vs 63.4%; difference, 13.2%; 95% CI, 5.2% to 20.9%; P = .001).

Cancer Patients a Special Population

The subanalysis in cancer patients was drawn from data derived from the 2 phase 3 trials. “Patients with cancer are a population of special interest because of their lower response rates, and they are very prone to recurrent disease,” Dr. Cornely told Medscape Medical News. (more…)

Nine agents in one Rx. and twenty drug interactions found (Not finished)

July 20, 2012 Anticoagulant Therapy, Cardiology, Drug Interactions 2 comments , , , ,

This afternoon I met a perscription that consist of nine different agents, which have twenty drug interactions. Many of them are cardiovascular drugs. They are  Beta-Blockers, Electrolytes, Statins, ARBs, Inotropic Agents, Thiazide, Calcium Channel Blockers, and Benzodiazepines. I list them and their dosage below.

  1. Alprazolam 0.4 mg po Qd
  2. Metoprolol 12.5 mg po Bid
  3. Potassium Chloride 1 g po Bid
  4. Simvastatin 20 mg po Qn
  5. Irbesartan 0.15 g po Qd
  6. Irbesartan/Hydrochlorothiazide 1 tablet po Qd
  7. Digoxin 0.125 mg po Qd
  8. Amlodipine 5 mg po Qd
  9. Warfarin 2.5 mg po Qd

I check these nine drug in Multi-Dug Interaction Chechker and find there are twenty drug interactions between these nine drugs. They are:

Serious – Use alternative

Amlodipine + Simvastatin. Amlodipine increases levels of simvastatin by Other (See comment). Possible serious or life-threatening interaction. Monitor closely. Use alternatives if available. Comment: Benefits of combination therapy should be carefully weighed against the  potential risks of combination. Potential for increased risk of myopathy/rhabdomyolysis. Limit simvastatin dose to no more than 20 mg/day when used concurrently.

Significant – Monitor Closely

Hydrochlorothiazide + Digoxin. Hydrochlorothiazide increases effects of digoxin by pharmacodynamic synergism. Significant interaction possible, monitor closely. Hypokalemia increases digoxin effects.

Potassium Chloride + Hydrochlorothiazide. Potassium chloride increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Potential for dangerous interaction. Use with caution and monitor closely.

Simvastatin + Warfarin. Simvastatin, warfarin. Either increases effects of the other by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Significant – Monitor Closely. Competition by each drug for CYP3A4-mediated metabolism may result in increased INR and increased risk of rhabdomyolysis.

Simvastatin + Digoxin. Simvastatin will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin will increase the level or effect of hydrochlorothiazide by basic (cationic) drug competition for renal tubular clearance. Significant – Monitor Closely.

Metoprolol + Irbesartan. Metoprolol, irbesartan. Mechanism: pharmacodynamic synergism. Significant – Monitor Closely. Risk of fetal compromise if given during pregnancy.

Alprazolam + Digoxin. Alprazolam increases levels of digoxin by unknown mechanism. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol increases effects of digoxin by pharmacodynamic synergism. Significant – Monitor Closely. Enhanced bradycardia.

Metoprolol + Amlodipine. Metoprolol and amlodipine both increase anti-hypertensive channel blocking. Significant – Monitor Closely.

Irbesartan + Potassium Chloride. Irbesartan and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Potassium Chloride. Metoprolol and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Potassium Chloride + Digoxin. Potassium chloride and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Metoprolol. Irbesartan and metoprolol both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Digoxin. Irbesartan and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Hydrochlorothiazide. Irbesartan increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol and digoxin both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Hydrochlorothiazide. Metoprolol increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Irbesartan + Irbesartan/Hydrochlorothiazide (Not listed in the multi-drug interaction checker. I add this interaction by myself). Both Irbesartan and Irbesartan/Hydrochlorothiazide increase the level or effects of each other. The combination use of these two drugs is repeated administration and may enhance adverse effects of Irbesartan. I think this combination use should be avoid absolutely.

I alysis these twenty drug interactions. These twenty drug interactions include ten refered to  potassium disorder, three refered to pharmacodynamic synergism, one refered to myopathy/rhabdomyolysis, one hepatic/instestinal enzyme, one MDR1 (P-gp), one renal tubular excretion, one unknown, one anti-hypertension channel, and one repeated administration.

I think the next thing to do is to modify this pharmacotherapy regimen as there are many drug interactions in this regimen.

Maternal Antidepressant Use May Promote Pregnancy-Induced Hypertension

July 19, 2012 Adverse Drug Reactions, Pregnancy Medicine 2 comments , , , , ,

Today I read an article that disscusses the adverse effects of the antidepresants use during pregnancy. It says that when using antidepressant during pregnancy will causes hyperstension. The article is below.

One thing I want to emphase is that according to the authors of this study in the article, 4% to 14% of pregnant women are receiving antidepressants. Indeed, depression is one of the most commmon chronic illnesses among pregnant women. But should we use antidepressants during pregnancy? I check one of  antidepresants – Paroxetine – one of the SSRIs on medscape. Paroxetine belongs to Pregnancy Category: D and has Teratogenic Effects: Paroxetine increases the risk of congenital malformations, particularly cardiovascular malformations.

As above I think pregnancy should be one of the contraindications of this SSRI due to the teratogenic effects. Maybe all SSRIs have the effect of teratogenicity during pregnancy, but 4% to 14% of pregnant women are receiving antidepressants, maybe also the SSRIs such as Paroxetine. So anyone can tell me in U.S. do the pregnant women receive SSRIs to treat depression?

Clinical Context

Depression is one of the most common chronic illnesses among pregnant women, with a prevalence of approximately 20%. According to the authors of the current study, 4% to 14% of pregnant women receive antidepressants, and these medications are not without adverse effects. The use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy is most associated with a modest increase in the risk for congenital abnormalities, including heart defects.

Less data suggest serious adverse events of antidepressants on the pregnancy itself. However, antidepressants generally increase levels of circulating serotonin, which can, in turn, raise blood pressure. Some previous research has suggested that antidepressants can increase the risk for pregnancy-induced hypertension and preeclampsia during pregnancy. The current study by De Vera and Bérard uses a large patient database to further investigate the association between pregnancy-induced hypertension and antidepressants.

Study Synopsis and Perspective

Women who use antidepressants while pregnant have an increased risk of developing pregnancy-induced hypertension, new research shows.

The increased risk is beyond the risk that could be attributed to their depression or anxiety disorders, Mary A. De Vera, PhD, from the University of Montreal, and Anick Bérard, PhD, from Sainte Justine Research Center, Montreal, Quebec, Canada, write.

“Antidepressants are used widely during pregnancy, up to 14% of pregnant women use them,” Dr. Bérard told Medscape Medical News. “Our study adds one more piece to the puzzle with regard to the risk of using antidepressants during pregnancy.”

The study is published online March 22 in the British Journal of Clinical Pharmacology.

Do Not Stop Meds

SSRIs are the main antidepressants in use today, and serotonin is a vasoconstrictor and also directly affects diastolic blood pressure, although the mechanism of action for this is not very well understood, Dr. Bérard noted.

In this study, the researchers analyzed data from the Quebec Pregnancy Registry and compared 1216 women who had been diagnosed with pregnancy-induced hypertension, with or without preeclampsia, who had no history of hypertension before they became pregnant, with 12,160 matched control individuals.

They found that among the participants with pregnancy-induced hypertension, 45 (3.7%) had used antidepressants during pregnancy, compared with 300 (2.5%) of the women in the control group (odds ratio [OR], 1.52; 95% confidence interval [CI] 1.10 – 2.09).

Antidepressant use during pregnancy was associated with a 53% increased risk for pregnancy-induced hypertension (OR, 1.53; 95% CI, 1.01 – 2.33). Use of SSRIs was associated with a 60% increased risk (OR, 1.60; 95% CI, 1.00 – 2.55); of the SSRIs, paroxetine was associated with the greatest risk for pregnancy-induced hypertension (OR, 1.81; 95% CI, 1.02 – 3.23).

“It is very important for physicians and women to discuss the risks and benefits of antidepressants before prescribing,” said Dr. Bérard.

“Close monitoring needs to be done, because there could be benefits, and there can also be risks. The message isn’t as simple as telling pregnant women to stop taking antidepressants.

“The decision has to be made one woman at a time. Anyone affected by this study should not stop taking their prescribed medication but seek a consultation with their doctor if they are concerned,” she said.

“Important” Limitations

Linda Chaudron, MD, associate chair for clinical services in the Department of Psychiatry at the University of Rochester Medical Center in New York, said the study adds to recent studies that have explored the hypothesis of an association between antidepressant use and pregnancy-induced hypertension. (more…)

Top docs provide free online advice for rare leukemia

July 14, 2012 Hematology, Pharmacy Education No comments , ,

July 11, 2012 — Seven hematologists from leading cancer centers have volunteered to provide free medical advice to patients with myeloproliferative neoplasms (MPNs), a rare form of leukemia, and to their healthcare providers.

The physicians have signed on with the online MPNforum Magazine, which is published monthly by an MPN patient collective. They offer help to patients and caregivers on MPN Clinic, an online roundtable hosted by the publication.

The term MPN covers a rare set of disorders occurring in about 5 people per million, according to a press release from the publication, which operates on a shoestring budget. This rarity means that community-based clinicians may never see a case and if one comes along, help is needed.

The initial volunteers for the project are Richard Silver, MD (Weill-Cornell in New York City), Srdan Verstovsek, MD (M.D. Anderson in Houston, Texas), Ruben Mesa, MD (Mayo Clinic in Scottsdale, Arizona), Claire Harrison, DM (Guy’s and St. Thomas’ in London, United Kingdom), Jason Gotlib, MD (Stanford Medical Center in Palo Alto, California), Ross Levine, MD (Sloan-Kettering in New York City), and Attilio Orazi, MD (Weill-Cornell).

“It’s amazing that we have this group of doctors,” said Zhenya Senyak, the founder and editor of MPNforum, about the eminence of the participating experts. “They are really concerned about getting this information out,” he told Medscape Medical News in an interview. Senyak, who lives in Asheville, North Carolina, is a writer who has myelofibrosis.

I’ve never waited more than a day for a response.

The service is free. Patients, caregivers, and healthcare providers can email questions to MPNclinic@gmail.com, which are then forwarded to all members of the panel. One of the experts responds, and circulates that response among the other panel members for review and comment. The final response is then forwarded to the individual who submitted the question. “I’ve never waited more than a day for a response,” said Senyak. The volunteer experts have even responded while on vacation, he said, adding that the answers are highly detailed and “powerful.”

All the questions, answers, and comments will eventually be published in the monthly MPN Clinic section of MPNforum Magazine. The entries will be archived in a searchable, publicly available online database.

The first MPN Clinic report will be published on September 15. However, Senyak said that responses to 27 questions have already been received and forwarded to patients in the United States and England. He is delighted by the volunteer experts’ helpfulness. “They have nothing to gain. It is purely altruistic of them,” he said.

MPNforum is financed by small donations, which, to date, amount to about $2000.

More About MPNs

MPNs are caused by one or more mutations, usually acquired after middle age. However, increasing numbers of younger adults and children are being diagnosed with the disorder, according to an MPNforum press statement. In MPNs, an overproduction of blood cells disrupts normal hematopoiesis. The various MPNs are differentiated by what is overproduced, such as erythrocytes in polycythemia vera or platelets in essential thrombocythemia.

If treated properly, many patients can live a normal life span with minimal suffering, according to the organization; however, some forms, such as myelofibrosis, can be debilitating and even fatal.

Myelofibrosis is associated with the dysregulation of 2 enzymes — janus-associated kinase (JAK)1 and 2 — which are involved in regulating blood and immunologic functioning. As the disease progresses, bone marrow is replaced with scar tissue, leading to anemia and thrombocytopenia. However, the scarred bone marrow tissue accumulates in other organs, most notably the spleen and liver. This collagen fibrosis can also cause bone pain, intense fatigue, and loss of appetite.

The only cure for myelofibrosis has been stem cell transplantation. However, since the implication of a genetic mutation in this disease was discovered, there have been developments in drug treatment. In 2011, the first drug treatment ever for myelofibrosis, ruxolitinib (Jakafi, Incyte Corp.), was approved by the US Food and Drug Administration.

Ruxolitinib has shown results that are “unprecedented” in the treatment of this disorder, according to Dr. Harrison, who is one of the volunteers and one of the drug’s principal investigators.

While research continues, access to MPN specialists remains the surest means of securing optimal treatment, said Senyak.