Pill-In-The-Pocket

The ‘Pill-in-the-pocket’ management of paroxysmal atrial fibrillation has been shown to be an effective and safe method of restoring a normal, sinus rhythm in a carefully selected group of patients. It involves taking a tablet, usually Flecainide or Propafenone, after recognizing the onset of AF on a PRN basis. Data from some studies show that the pill-in-the-pocket strategy with flecainide and propafenone is effective for all the arrhythmic episodes in more than 80 percent of patients with recurrent atrial fibrillation, after selection of patients on the basis of clinical features and the results of in-hospital treatment. Only some patients are suitable for the ‘Pill-in-the-Pocket’ method of treatment. They should:

• Be able to recognize the onset of the Atrial Fibrillation.

• Have attacks that happen no more frequently than at weekly or preferably monthly intervals.

• Have no significant underlying heart disease.

• Have no disabling symptoms during an attack (fainting, severe chest pain or breathlessness).

• Be able to understand the proper way of taking the medication.

Patients with infrequent SVT episodes may only need pharmacotherapy on an intermittent basis as well, or what has been described as the “pill-in-the-pocket” approach. Those experiencing SVT not more than a few times per year, but with episodes lasting one hour or longer, may be treated using this approach. This is typically done with verapamil (40 to 160 mg) in patients without pre-excitation or a beta blocker in patients without chronic obstructive pulmonary disease or asthma.

Topical treatment for Genital Warts

Drugs	Administration
Podophyllotoxin	Topical As 15% (Indian podophyllum) or up to 25% soln (American podophyllum): Apply weekly, leave for 1-6 hr then wash off. If there is no improvement after 6 wk, stop treatment.
Imiquimod 5 % w/w Cream (available in Blue Book)	As 5% cream: Apply 3 times wkly for up to 16 wk. Cream is applied at night and left on the skin for 6-10 hr. Wash with mild soap and water after each dose.
Sinecatechin ointment	Applied three times daily (0.5-cm strand of ointment to each wart) using a finger to ensure coverage with a thin layer of ointment until complete clearance of warts.
Pedophyllin resin 10%–25%	Applied to each wart and allowed to air-dry before the treated area comes into contact with clothing; over application or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas. The treatment can be repeated weekly, if necessary.
Trichloroacetic acid (TCA) or Bichloroacetic acid (BCA) 80%–90%	A small amount should be applied only to the warts and allowed to dry before the patient sits or stands, at which time a white frosting develops.

Acute Flare of Gout in ESRF

NSAIDS:

• In patients with residual kidney function, including patients on peritoneal dialysis, NSAIDs should be avoided because of the risk of worsening of renal function
• any use of NSAIDs in this setting should only be done in consultation with the patient’s nephrologist. 
• In patients on chronic hemodialysis, NSAIDs may be used as an alternative to glucocorticoids, particularly in patients with milder attacks in whom lower doses and shorter courses can be employed. 
• Other concerns in patients on hemodialysis include concomitant use of anticoagulation and risk of gastrointestinal toxicity.

Colchicine:

• Colchicine is generally avoided in hemodialysis patients with acute gout flares because it is not removed by dialysis, and therefore these patients have a heightened risk of colchicine toxicity.
• Its therapeutic index is narrow and side effects associated with colchicine treatment such as nausea, vomiting, abdominal pain and profuse diarrhoea can be so intense as to limit its usefulness.
• However, according to Lexicomp, it provides some guidelines on gout flare treatment:
• Gout flare treatment
• Treatment of gout flares is not recommended in patients with renal impairment who are receiving colchicine for prophylaxis.
• CrCl 30 to 80 ml/minute: Dosage adjustment not required; monitor closely for adverse effects
• CrCl <30mL/minute: Dosage reduction not required but may be considered; treatment course should not be repeated more frequently than every 14 days.
• Dialysis: 0.6 mg as a single dose; treatment course should not be repeated more frequently than every days. Not removed by dialysis
• Hemodialysis: Avoid chronic use of colchicine

Steroids:

• We generally treat patients with advanced chronic kidney disease (CKD) or end-stage renal disease requiring maintenance dialysis with intraarticular, oral, or parenteral glucocorticoids.
• We suggest the use of oral glucocorticoids for patients who cannot take NSAIDs or colchicine and who are not candidates for intraarticular glucocorticoid injection because of polyarticular disease. 
• We also suggest the use of oral glucocorticoids if a clinician with adequate expertise in these techniques is not readily available. 
• We use prednisone (or other equivalent glucocorticoid) in doses of 30 to 50 mg once daily or in two divided doses until flare resolution begins, and we then taper the dose of glucocorticoids, usually over 7 to 10 days (according to UpToDate).
• Oral Prednisolone up to 0.5 mg/kg/day or its equivalent can be given and tapered off over 4-10 days (according to Management of Gout CPG 2008)

References: 

1. www.uptodate.com
2. lexicomp
3. CPG Management of Gout 2008

Paediatric Recurrent UTI

• routine surveillance of asymptomatic children did not enhance identification of true UTI episodes 
• suggest antimicrobial prophylaxis in children without vesicoureteral reflux (VUR) who have frequent recurrent UTIs (three febrile UTIs in six months or four total UTIs in one year).
•  Antimicrobial prophylaxis also may be warranted for children with more severe initial UTI episodes or those with additional UTI risk factors (eg, bladder and bowel dysfunction)

Choice of Antibiotic
Treatment:

Prophylaxis:

Agent	Single Daily Dose
Nitrofurantoin *	1-2 mg/kg PO
Sulfamethoxazole and trimethoprim (SMZ-TMP) *	5-10 mg/kg SMZ, 1-2 mg/kg TMP PO
Trimethoprim	1-2 mg/kg PO
*Do not use nitrofurantoin or sulfa drugs in infants younger than 6 weeks. Reduced doses of an oral first-generation cephalosporin, such as cephalexin at 10 mg/kg, may be used until the child reaches age 6 weeks. Ampicillin or amoxicillin are not recommended because of the high incidence of resistant E coli.

• Duration: for six months
• can be discontinued if no infection occurs during the period of prophylaxis
• if infection recurs, resumption of prophylaxis may be warranted

Evidence:

• most studies included only children with VUR
• A meta-analysis of individual data restricted to young children 2 to 24 months of age without VUR did not detect a benefit for prophylaxis in preventing recurrence
• In two companion studies of children with and without VUR who were followed prospectively for two years, the rate of reinfection was lowest in children with VUR who were randomized to prophylaxis (12 percent), highest in children with VUR randomized to placebo (25 percent)
• A study that evaluated 12 months of prophylaxis with sulfamethoxazole-trimethoprim (SMZ-TMP) compared with placebo to prevent UTI showed a small, but statistically significant, reduction in incidence but did not show any difference in renal scarring. In addition, a significant increase in UTI with SMZ-TMP ̶ resistant organisms occurred in the treatment group
• Until evidence-based guidelines about the use of suppressive antibacterial therapy after an initial febrile UTI are available, use of antibiotic prophylaxis is based on expert opinion

Cranberry Juice

• do not routinely suggest cranberry juice for the prevention of recurrent UTI in children. 
• In a meta-analysis of 13 studies including children and adults (n = 2462), cranberry products did not reduce the occurrence of symptomatic UTI compared with placebo, water, or no treatment
• Although cranberry juice in moderation is unlikely to be harmful, excessive intake may contribute to dental caries, diarrhea, and obesity

Circumcision

• Consider circumcision of male neonates. 
• The AAP policy statement on circumcision is that “the health benefits of newborn male circumcision outweigh the risks and that the procedure's benefits justify access to this procedure for families who choose it

References:

1. www.uptodate.com
2. http://emedicine.medscape.com/article/969643-treatment#d13
3. http://www.aafp.org/afp/2011/0215/p409.html

Chia Seeds and Interaction with medications

• Chia seeds are tiny, brown or black seeds, almost as small as poppy seeds.
• They come from a plant in the mint family
• People use chia seed for diabetes, high blood pressure, and for generally reducing the risk of heart disease and stroke (cardiovascular disease).
• Chia seeds contain a large amount of healthy omega-3 fatty acids and dietary fiber. Researchers think omega-3 fatty acids and fiber help reduce risk factors for heart disease

Evidences for Use:
Possibly not effective in Reducing Weight

• Consuming chia seeds mixed with water twice daily before meals for 12 weeks does not improve body composition or reduce blood pressure in people who are overweight or obese. 
• eating milled or whole chia seeds daily for 10 weeks does not improve body composition or blood pressure in overweight women

Insufficient evidences:

• some evidence that people with diabetes can lower their high risk by eating bread that contains a particular type of chia called Salba (Salba Nutritional Solutions). The dose of Salba that is needed to lower heart disease and stroke risk is 37 grams per day for 12 weeks. This dose seems to reduce blood pressure and lower the levels of C-reactive protein and von Willebrand factor in the blood
• Heart disease and stroke risk factors
• High blood pressure

Special Precautions & Warnings:

• Pregnancy and breast-feeding: 
• Not enough is known about the use of chia during pregnancy and breast-feeding. Stay on the safe side and avoid use.
• High triglycerides: 
• If you have high triglycerides, stick with using a specific variety of chia called Salba. Salba does not significantly increase triglyceride levels.
• Prostate cancer: 
• Chia contains a lot of alpha-linolenic acid. Some research suggests that large amounts of alpha-linolenic acid in the diet might increase the chance of getting prostate cancer. If you have prostate cancer or have a high risk of getting it, avoid eating large amounts of chia.

Interaction

• No clear evidence of interaction with medications
• Some study have shown that Salba (a type of Chia) is able to lower the levels of C-reactive protein and von Willebrand factor in the blood. 
• Thus recommend to avoid intake or close monitoring, especially with anticoagulant / blood thinning medications

References: 

1. http://www.webmd.com/vitamins-supplements/ingredientmono-1224-chia.aspx?activeingredientid=1224&activeingredientname=chia
2. https://www.nlm.nih.gov/medlineplus/ency/patientinstructions/000727.htm

Management of Viral Induced Wheeze

Inhaled bronchodilators

• often first-line therapy 
• effective rescue treatment in symptomatic patients, especially in children with established asthma
• have not been shown to improve clinical outcomes, decrease the rate of hospital admission, or decrease the duration of hospitalization in children with bronchiolitis

Inhaled hypertonic saline

• Limited data suggest that HS in combination with a short-acting beta2-agonist may be effective
• Similar limited findings have been reported for the treatment of bronchiolitis. 
• The use is based upon the hypothesis that viral infection, particularly with rhinovirus, leads to dehydration of the airway surface liquid and impaired mucus clearance

intermittent high-dose inhaled glucocorticoids

• if started at the onset of a URI and continued for up to 10 days, may decrease asthma-type symptoms and rescue oral glucocorticoid use in preschool children
• may be particularly effective in patients with asthma risk factors

Systemic glucocorticoids

• data are mixed regarding, although overall this approach does not appear to be effective in most patients 

Intermittent leukotriene-receptor antagonists 

• results are mixed, but the majority of studies do not favor the use 
• PREEMPT study examined intermittent montelukast compared with placebo in 220 children aged 2-14. Treatment was initiated at the onset of symptoms of a respiratory tract infection and continued for a minimum of a week or until symptoms had disappeared for 48 hours. The montelukast group had fewer unscheduled consultations for asthma and fewer days away from school.
• A three way comparison between standard treatment, intermittent montelukast, and intermittent nebulised budesonide (the only aerosolised steroid permitted by the FDA in preschool children) in 238 children aged 12-59 months showed minor and equivalent benefits for the two active treatments compared with standard treatment.

Recommendation For treatment 

• inhaled short-acting beta2-agonist (Grade 2B) such as albuterol via nebulizer (in NS) or metered dose inhaler (MDI) with spacer (table 1).
• suggest not using inhaled glucocorticoids (Grade 2B).
• suggest not using an oral glucocorticoid (Grade 2B). One exception is patients with severe acute wheezing symptoms and risk factors for persistent asthma (assessed by positive-modified asthma predictive indices)

Recommendation for prevention

• intermittent high-dose inhaled glucocorticoids (table 2), begun at the onset of a URI, before wheezing has occurred, and continued for up to 10 days (Grade 2B). Fluticasone propionate 750 mcg inhaled twice daily and budesonide 1 mg nebulized twice daily have both been studied in the prevention of virus-inducing wheezing in preschool children. 
• suggest not using an oral glucocorticoid at the onset of a URI before wheezing has occurred (Grade 2B). Exceptions include patients with a prior history of a severe virus-induced wheezing exacerbation requiring hospitalization, patients with asthma risk factors who are currently on daily inhaled glucocorticoids for frequent exacerbations, or those who have not responded to high-dose intermittent inhaled glucocorticoids in the past. 
• recommend daily inhaled glucocorticoids at standard doses in children who continue to experience severe or recurrent episodes of wheezing despite intermittent high-dose inhaled glucocorticoids (Grade 1A). 
• Intermittent or daily montelukast is an alternative, especially for patients who do not tolerate daily inhaled glucocorticoids.

References;

1. www.uptodate.com
2. https://www.epocrates.com/dacc/1404/WheezePreschoolChildrenBMJ1404
3. http://www.aacijournal.com/content/10/1/21
4. http://pediatrics.aappublications.org/content/129/2/e285.full

Promethazine For Procedural Sedation

Availability

• Promethazine 5mg/5ml syrup
• Promethazine HCL 50mg/2ml injection

General

• phenothiazine antihistamine with sedative, antiemetic, and anticholinergic effects. It is a competitive histamine (H1) and alpha-adrenergic receptor antagonist
• The clinical effects of promethazine generally occur within 5 minutes after an IV dose and 20 minutes after an IM dose in adults. 
• The average duration of action is 4 to 6 hours, but effects may persist for up to 12 hours
• Use of promethazine as a sedative agent spread rapidly after its approval. 
• While often producing a satisfactory level of sedation, the combination was associated with respiratory depression, hypotension, extrapyramidal effects, and prolonged recovery times. 
• Due to this, American Academy of Pediatrics published a statement in 1995 discouraging the use of these agents as sedatives in children

Apnea and Respiratory Depressant

•  direct central respiratory depressant effect, antagonism of central dopaminergic receptors resulting in increased levels of endogenous opioids capable of producing respiratory depression, or potentiation of the respiratory depressant effects of concomitantly administered opioids
• Respiratory depression may be more pronounced in infants, particularly premature neonates, who may not be able to metabolize promethazine as well as older children and adults due to lower levels of CYP2D6 activity or reduced sulfur stores

Tissue Injury

• Promethazine injection has a pH of 4 to 5.5 and IV administration may lead to severe injection site reactions. 
• These range from burning, pain, and erythema at the site of injection to thrombophlebitis, venous thrombosis, abscess formation, tissue necrosis, and gangrene. 
• Nerve injury, including paralysis, has been reported after parenteral administration into or near a nerve. 
• Subcutaneous (SC) administration has also resulted in chemical irritation of the tissues with subsequent necrosis. The SC route is now contraindicated

Others

• the most frequently observed adverse effects are sedation, somnolence, blurred vision, dry mouth, and confusion. 
• Extrapyramidal adverse effects may present as oculogyric crisis, torticollis, and tongue protrusion. 
• These effects are typically the result of an acute overdose, but may occur after therapeutic doses
• Other side effects such as thickening of bronchial secretions, and pharyngitis have been reported with the use of this medication

Evidences Against Use

• Ketamine/Midazolam combination provided sufficient sedative effect in lower doses compared to Midazolam/Promethazine (sedative agents in pediatric dentistry)
• chloral hydrate can be considered as a safe and more effective drug in sedation induction for sleep EEG in children compared to Promethazine (orally 70 mg/kg chloral hydrate VS promethazine 1 mg/kg for sedation during electroencephalography (EEG) in children). However, in terms of side effects, both results were comparable.

Evidences Supporting Use

• combination of midazolam and promethazine not only speeds up the sedation induction, but also decreases unresponsiveness to the treatment and the need for a rescue dose (oral midazolam + Promethazine vs Oral Midazolam only)
• Preanesthetic sedation of preschool children: Comparison of intranasal midazolam versus oral promethazine showed both were comparable for numerous elective surgery
• Chloral hydrate and promethazine, when used in combination, have been shown to be more effective than i.v. midazolam in providing maintenance sedation in critically ill children

Usual Pediatric Dose for Sedation (>2 years)

• Sedation: oral, IM, IV, or rectal: 0.5 to 1 mg/kg/dose (not to exceed 25 mg) every 6 hours as needed
• Preoperative analgesia/hypnotic adjunct: IM, IV: 1.1 mg/kg once in combination with an analgesic or hypnotic (at reduced dosage) and with an atropine-like agent (at appropriate dosage). 
• Note: Promethazine dosage should not exceed half of suggested adult dosage

References:

1. http://www.medscape.com/viewarticle/720608_10
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283976/
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574988/
4. http://ispub.com/IJA/12/2/6492
5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173384/
6. http://www.drugs.com/dosage/promethazine.html
7. http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf
8. http://dentistryasleepny.com/pdf/Article3_Considerations_for_the_Use_of_Enteral_Sedation_in_Pediatric_Dentistry

Anti-Tuberculosis Dosing

References:
CPG Management of Tuberculosis (3rd edition)

Saxagliptin to Sitagliptin Conversion

Conversion to saxagliptin (Onglyza) should be made once both the provider and patient have been informed and that proper patient education is provided.  

Patients may remain on alternate therapy if there are clinical reasons where switching may be inappropriate.

Saxagliptin Dose

• The recommended dosage of saxagliptin is 2.5 mg or 5 mg once daily taken regardless of meals.
• No dosage adjustment for saxagliptin is recommended for patients with mild renal impairment (creatinine clearance [CrCl] >50 mL/min).
• The dosage of saxagliptin is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min) [saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis.
• The dosage of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5  inhibitors**

The following dosing table may be used to assist converting patients from another DPP-4 inhibitor to saxagliptin. 

Examples:

• Patient with severe renal impairment (CrCl<30mL/min) who is currently receiving sitagliptin 25mg once daily can be switched to saxagliptin 2.5mg once daily.
• Patient currently receiving linagliptin 5mg and has moderate renal impairment (CrCl ≥30<50mL/min) would receive saxagliptin 2.5mg once daily.

Drug Name	Usual Dose	Dosage Adjustment in Renal Insufficiency			Dosage adjustment with concomitant use of strong CYP3A4/5 inhibitors**
		Mild (CrCl ≥ 50mL/min)*	Moderate (CrCl ≥ 30 to < 50 mL/min) *	Severe (CrCl< 30 mL/min) or ESRD requiring dialysis
Saxagliptin	2.5mg or 5mg once daily	No dosage adjustment needed	2.5mg once daily	2.5mg once daily following hemodialysis	2.5mg once daily
Sitagliptin	100mg once daily	No dosage adjustment needed	50mg once daily	25mg once daily without regard to time of dialysis	No dosage adjustment needed
Linagliptin	5mg once daily	No dosage adjustment needed	No dosage adjustment needed	No dosage adjustment needed	Use of CYP3A4 or P-gp inducers with linagliptin is not recommended
Alogliptin	25mg once daily	No dosage adjustment needed	12.5mg once daily	6.25mg once daily without regard to tome of dialysis	No dosage adjustment needed

*CrCl cutoffs for aloglitpin for mild renal insufficiency is CrCl ≥ 60mL/min; moderate renal insufficiency CrCl ≥ 30 to < 60mL/min

**Examples of strong CYP 3A4/5 inhibitors include but are not limited to: ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin

Metoclopramide in Children

Concerns

• well-known risks of neurological effects such as short-term extrapyramidal disorders- muscle spasms (often involving the head and neck), and tardive dyskinesia (uncontrollable movements such as grimacing and twitching). 
• The risk of acute (short-term) neurological effects is higher in children
• tardive dyskinesia is reported more often in the elderly, and the risk is increased at high doses or with long-term treatment. 
• The evidence indicated that these risks outweighed the benefits of metoclopramide in conditions requiring long-term treatment. 
• There have also been very rare cases of serious effects on the heart or circulation, particularly after injection

Recommendations from EMA (European Medicines Agency) 
Adult

• remains indicated for prevention of post-operative nausea and vomiting (PONV), radiotherapy-induced nausea and vomiting and delayed (but not acute) chemotherapyinduced nausea and vomiting
• indicated for symptomatic treatment of nausea and vomiting including that associated with acute migraine (where it may also be used to improve absorption of oral analgesics)
• conventional formulations (all routes) is 10 mg up to 3 times daily (max 30mg/day or 0.5mg/kg day)

Children

• only be used as a second-line option for prevention of delayed chemotherapy-induced nausea and vomiting and treatment of established PONV. 
• Use is contraindicated in children under 1 year of age.
• recommended dose is 0.1 to 0.15 mg per kg body weight, repeated up to three times daily

General

• Intravenous doses should be administered as a slow bolus over at least 3 minutes to reduce the risk of adverse effects
• Given very rare reports of serious cardiovascular reactions associated with metoclopramide, particularly via the intravenous route, special care should be taken in populations likely to be at increased risk, including the elderly, patients with cardiac conduction disturbances, uncorrected electrolyte imbalance or bradycardia, and those taking other drugs known to prolong QT interval
• should only be prescribed for short-term use (up to 5 days). 
• Patients who are currently taking regular metoclopramide should have their treatment reviewed at a routine (non-urgent) medical appointment.

Evidences for Recommendations

• no evidence of consistent benefit in gastroparesis, gastro-oesophageal reflux disease and dyspepsia, all of which are chronic conditions requiring prolonged treatment which puts patients at risk of chronic neurological side effects. 
• Evidence to support a role as an adjunct in surgical and radiological procedures was also lacking.
• reporting rate for these disorders was calculated to be 6 times higher in children than in adults
• Cardiovascular reaction reports associated with metoclopramide appeared to be very rare, and mainly associated with intravenous formulations given to patients with underlying risks for cardiac disease; they included hypotension, shock, syncope, bradycardia or atrioventricular block, and cardiac arrest.
• evidence also indicated efficacy in nausea and vomiting associated with acute migraine, but seemed to indicate that doses above 10 mg do not result in increased efficacy

References

1. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146614.pdf
2. http://www.who.int/medicines/publications/Pharm_Newsletter2_2015.pdf
3. MADRAC ADR Newsletter 2007 - September - BPFK
4. Drug Doses

Neutropenia and Thalassemia

• patients with thalassemia frequently experience transient episodes of mild or moderate neutropenia irrespective of the chelation therapy they are on

Neutropenia due to Thalassemia

• Splenomegaly invariably develops in the symptomatic thalassemias. Splenomegaly can worsen the anemia and occasionally cause neutropenia and thrombocytopenia.
• neutropenia occurs significantly more often in patients with thalassemia who have not undergone splenectomy than in those who have
• some viral infections, particularly parvovirus, may cause neutropenia independent of chelation therapy
• Splenectomy does not causes neutropenia generally. Patients without a functioning spleen have a severe impairment in their ability to cope with specific infections [Pneumococcus, Meningococcus and Haemophilus influenzae]
• In some cases (Felty’s Syndrome) splenectomy is actually able to reverse profound neutropenia

Neutropenia due to Iron Chelators

• Approximately 6% of patients with thalassemia receiving deferiprone develop neutropenia
• Due to the risk of agranulocytosis and associated rare deaths, weekly white blood cell counts are required for all patients receiving this drug.
• Some studies showed that not all cases of mild neutropenia during deferiprone therapy develop into agranulocytosis, and suggests that many episodes of neutropenia may not be caused by deferiprone

Management

• In deferiprone-treated thalassemia patients who develop agranulocytosis, therapy must always be interrupted
• Neutropenia may precede the development of agranulocytosis. 
• Measure the absolute neutrophil count (ANC) before starting deferiprone therapy and monitor the ANC weekly during therapy. 
• Interrupt deferiprone therapy if neutropenia develops. 
• If infection develops, interrupt deferiprone and monitor the ANC more frequently. 
• Advise patients taking deferiprone to report immediately any symptoms indicative of infection
• The present practice is to always discontinue therapy in all patients who experience a decline in neutrophils below 1.5 X 109 /L, irrespective of the potential cause of the neutropenia
• For agranulocytosis (ANC < 0.5 x 109 /L), Consider hospitalization and other management as clinically appropriate. Do not resume Ferriprox in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients

References:

1. http://www.aafp.org/afp/2009/0815/p339.html
2. http://www.tema.unina.it/index.php/jop/article/view/1282/1394
3. http://thalassemia.com/documents/SOCGuidelines2012.pdf
4. http://www.ncbi.nlm.nih.gov/pubmed/24330079
5. http://thalassemia.com/documents/articles.El-Beshlawy-2014-deferiprone.pdf
6. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021825lbl.pdf

Metformin & Hyperpigmentation

Does it CAUSE Hyperpigmentation?

• Generally does not have any adverse reactions related to skin
• Very rare (1 in 10,000) may experience skin reactions such as rash, itching or flushing
• Some case reports:
• Leukocytoclastic vasculitis and psoriasiform drug eruption are the two most common presentations of metformin allergy
• lichenoid reaction of the oral mucosa may also occur
• Grinspan's syndrome (the triad of oral lichen planus, diabetes mellitus, and hypertension) could be seen in metformin allergy

Metformin & Vitamin B12 Deficiency

• Chronic metformin use results in vitamin B12 deficiency in 30% of patients.
•  Exhaustion of vitamin B12 stores usually occurs after twelve to fifteen years of absolute vitamin B12 deficiency. 
• may present without anemia and as a peripheral neuropathy, is often misdiagnosed as diabetic neuropathy, although the clinical findings are usually different.
• A retrospective and prospective study of 63 individuals with vitamin B12 deficiency-related neurological syndromes in India showed that 41 % had skin and mucosal changes, hyperpigmentation in 19 % subjects
• mechanism of hyperpigmentation due to vitamin B12 deficiency is an increase in melanin synthesis

Application as TREATMENT for Hyperpigmentation?

• Lehraiki et al. report that metformin, an antidiabetic drug, inhibited melanogenesis, in vitro and in vivo, and they suggest that metformin may be used to treat hyperpigmentation disorders.
• topical application of metformin induced tail whitening in mice
• metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and cAMP-responsive element-binding protein phosphorylation
• showed antimelanogenic effect of metformin on reconstituted human epidermis and on human skin biopsies

1. References:
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081469/
3. http://www.ehealthme.com/ds/metformin/skin+hyperpigmentation
4. http://www.uv.es/bagan/Docencia/ampliacion/reaccionesfarmacos.pdf
5. http://www.medscape.com/viewarticle/719043_2

Daflon In Pregnancy

Availability: 
Diosmin 450mg/ Hesperidin 50mg
Indication

• Treatment of symptoms related to venolymphatic insufficiency (heavy legs, pain, early morning restless legs), 
• Treatment of functional symptoms related to acute hemorrhoidal attack and chronic hemorrhoids

Contraindication

• Hypersensitivity

Precaution/Warning 

• Pregnancy and Lactation

Pregnancy

• Experimental studies in animals have not demonstrated any teratogenic effect in animals. 
• Furthermore, no adverse effects have been reported to date in humans. 

Studies & Evidences

• 3 pregnant females who presented with congestive haemorrhoidal disease and responded favourably to Daflon in a study in Saudi Arabia
• In another study for a median of 8 weeks before delivery and 4 weeks after delivery, in 50 women with acute hemorrhoids, Treatment was well accepted, and did not affect pregnancy, fetal development, birth weight, infant growth and feeding

Alternatives

• help relieve the itch or discomfort of haemorrhoids, but do not treat the underlying varicose veins. 
• Suppository and ointment formulations are both safe to use in pregnancy
• A haemorrhoid preparation will contain some of the following medications.
• Hydrocortisone and prednisolone (corticosteroids) - reduce inflammation and itching.
• Lignocaine and cinchocaine (local anaesthetics) - reduce pain and irritation.
• Witch hazel (hamamelis), aluminium acetate and allantoin - reduce inflammation.
• Zinc oxide – protective.
• Peru balsam and benzyl benzoate – mild antiseptic and anti-itching action

Other non-Pharmacological Advice

• Take high fibre diet and drink lots of water
• Warm (but not hot) sitz baths are a traditional therapy for piles: sit in about 8 cm of warm water for 15 minutes, several times a day, especially after a bowel movement
• Try not to sit for hours at a time. If you have to, take breaks: once every hour, get up and move around for at least five minutes. A doughnut-shaped cushion can make sitting more comfortable and ease haemorrhoid pressure and pain.
• Insert petroleum jelly just inside the anus to make bowel movements less painful.
• Consider dabbing witch hazel (a soothing anti-inflammatory agent) on irritated haemorrhoids to reduce pain and itching.
• Resist the temptation to scratch haemorrhoids
• If you need a pain reliever, consider using paracetamol.
• Bathe regularly to keep the anal area clean, but be gentle: excessive scrubbing, especially with soap, can intensify burning and irritation.
• Don't sit on the toilet for more than five minutes at a time, and when wiping, be gentle. If toilet paper is irritating, try dampening it first, or use cotton balls or alcohol-free baby wipes
• When performing any task that requires exertion, be sure to breathe evenly. It's common to hold your breath during exertion, and if you do, you're straining and contributing to haemorrhoid swelling.

Recommendation

• As the use in pregnancy is still in ‘Precaution/Warning’ category, it is advisable not to initiate patient on the therapy
• Other symptomatical approach such as listed above would be preferred as first line
• Consider management and advice for constipation and exertion
• Discuss with respective specialist on usage of agent if needed and no improvement with other managemnet

References

1. http://www.rcsed.ac.uk/RCSEDBackIssues/journal/svol2_6/206005.html
2. http://www.servier.com.ve/sites/default/files/spc-pil/spc-daflon500.pdf
3. http://www.ncbi.nlm.nih.gov/pubmed/9184951
4. http://www.just.edu.jo/DIC/AZLibrary/Diosmin%20and%20Hespiridin.pdf
5. http://www.webmd.boots.com/digestive-disorders/piles-haemorrhoids?page=2
6. http://www.seslhd.health.nsw.gov.au/mothersafe/documents/HaemorrhoidsinPregnancyandBreastfeeding2013_new.pdf

Dermatological Reaction to Anti-Tuberculosis Drugs

Evaluate other potential etiologies of rash and pruritus:

• Scabies and insect bites may masquerade as a drug rash. 
• Contact dermatitis (question patient about use of new lotions, soaps, perfumes, etc.). 
• Phototoxicity (may respond to sunscreens, but these may cause contact dermatitis). 
• Other drugs, especially new agents, should be evaluated as possible etiologies. 
• Other dermatologic causes; psoriasis, pityriasis, atopic dermatitis, etc.
•  Dry skin, especially in diabetic patients, may be the cause of pruritus. Consider liberal use of lotions, such as petroleum jelly and lanolin (may be purchased in a feed supply store where it is less expensive). Dry skin is a serious problem with clofazimine. Drugs should not be continued if there are systemic symptoms, fever, urticaria, mucous membrane involvement, blistering of the skin, edema of the lips or eyes, or wheezing or compromise of the airway. 
• Hypothyroidism. 
• Acneiform lesions may fl are with the use of INH, ethionamide, and clofazimine. This will usually resolve after several months, often with improvement in the patient’s acne. Standard topical antibiotic treatment may be helpful in the meantime. 
• Unusual skin lesions may be associated with HIV infection.

Dermatological Reactions
Flushing Reactions 

• Flushing and/or itching reactions of the skin without a rash usually involve the face and scalp, and occur 2 to 3 hours after medications. Redness and watering of the eyes may also occur. 
• This is usually due to rifampin (RIF) or pyrazinamide (PZA). 
• It is usually mild and resolves in time without therapy. 
• If it is bothersome to the patient, an antihistamine may be administered to treat or to prevent the reaction. 
• Patients taking INH may experience flushing and/or itching of the skin with or without a rash, plus possible hot flashes, palpitation, or headache 2 to 3 hours after consuming tyramine-containing foods (cheese, salami, red wine) or certain fish (tuna). 
• Advise patients not to ingest foods that precipitate the reaction while they are receiving INH. 

Phototoxicity 

• Warn patients about the potential for phototoxicity if they are taking PZA, clofazimine, or fluoroquinolones. 
• Caution patients to limit sun exposure and to use sunscreens. 
• Phototoxicity may occur for prolonged periods even after the causative drug is stopped. Pseudojaundice (brownish discoloration of the skin) has been reported due to rifabutin. 

Lichenoid Drug Reactions 

• Pruritic, flat-topped, violaceous papules may occur anywhere, but most commonly involve the wrists, shins, and back. 
• Mucous membranes and the scalp may also be involved. 
• Differentiation from lichen planus may be made by a biopsy showing eosinophilic infiltration. 
• Lesions may resolve while medication continues. 
• Topical hydrocortisone or antihistamines may be helpful to control pruritus. 
• Medication should not be discontinued unless an equally effective drug is available for substitution. 
• Identifying the medication responsible in a multidrug regimen may be difficult because lesions resolve slowly and EMB, INH, streptomycin, and cycloserine have all been identified as causing these lesions. 

Hives, Urticaria

• Hives and urticaria may be caused by nearly any drug in the regimen. 
• They more commonly are due to INH, RIF, PZA, ethionamide, fl uoroquinolones, and EMB

Petechial rash 

• pinpoint sized red dots under the surface of the skin caused by leakages of capillaries
• Rifampin (RIF) hypersensitivity is suspected. 
• A platelet count (CBC without differential) should be ordered. 
• If the platelet count is below normal (normal range: 150,000-450,000 platelets per microliter), stop RIF and never restart it again. Monitor the platelet count until it returns to baseline. 

Erythematous rash with fever, and/or mucous membrane involvement. 

• STOP ALL drugs immediately 
• Rule out anaphylaxis reactions (angioedema, swollen tongue and throat, flushed face, airway constriction, wheezing, difficulty breathing, hypotension). 
• Rule out Stevens-Johnson Syndrome: systemic shedding of mucous membrane and fever. It can be life threatening. Immediate urgent care is required. 

Pharmacological Interventions

• They can be given prior to the anti-tuberculosis drug or as needed. 
• Diphenhydramine (Benadryl) 
• 25 to 50 mg PO, IV, or IM given before the medication, and then every 4 to 6 hours as needed may lessen skin irritation. 
• If patients become drowsy, caution them not to drive or operate machinery. 
• Other antihistamines: Chlorpheniramine 
• 4 mg PO before the medication and then every 4 to 6 hours as needed; hydroxyzine (Atarax) 25 mg PO or IM QID (can be increased to 50 mg QID); or loratadine (Claritin) 10 mg PO before the medication. 
• Hydrocortisone cream
• can be used topically. 
• Low-dose prednisone 
• (10 to 20 mg/day) for several weeks can be tried if other measures are not helpful.

Re challenge Therapy

• If treatment of TB can not be interrupted (severely ill with tuberculosis), try three new drugs (different class of drugs). Second-line anti-TB drugs such as 4 injectable aminoglycosides (streptomycin, amikacin) and 2 oral agents can be used. 
• If rash has improved substantially, anti-TB drugs can be restarted one by one every 2-3 days. 
• First, start with RIF because of its efficacy and is the least likely to cause rash. 
• Second, INH can be added after 3 days. 
• Third, PZA or EMB can be added after 3 days of INH. 
• Monitor signs and symptoms of rash. If rash recurs at any point; the last agent added should be removed.

References:

1. http://www.currytbcenter.ucsf.edu/sites/default/files/mdr_07advreact.pdf
2. http://www.uphs.upenn.edu/TBPA/treatment/managingsideeffects.pdf
3. http://health.utah.gov/epi/diseases/TB/resources/treatment/management_common_side.pdf