Ontario Narcotic Strategy - List of Drugs

By Mary Nelson

Folic acid 5mg & obesity (BMI>30kg/m2)

At the CDA 2011 conference, folic acid 5mg/d is recommended for patients with Type 2 DM and obesity > 30kg/m2.  This is based on a theoretical "evidence" - where a larger volume of distribution requires a larger dose of folic acid.  Why 5mg?  Because it comes in a 5mg tablet (prescription only).  No direct evidence to support or refute this recommendation.

Hyperuricemia and Gout

By: Annette Vedelago


1) Natural history of gout

Unusual for gout to occur under age 30 in males or under age 50 in females

Four stages:        -   asymptomatic hyperuricemia
                             -   acute gouty arthritis

                             -   intercritical gout

                             -   chronic tophaceous gout

2) Pathophysiology

• Increase in UA from a decrease in urine  acid excretion or
• increase purine breakdown most commonly secondary to drugs (chemotherapy, diuretics, low dose aspirin), disease (malignancies, renal dysfunction, psoriasis), and dietary (beer, fish, red meat)

3) Asymptomatic hyperuricemia

• > 360 μmoL/L for females
• > 420 μmoL/L for males

The incidence of acute gout after 20 years of sustained hyperuricemia is:

• 0.1% – 0.5% for UA concentrations between 420 - 540 μmoL/L
• 5% for UA > 504 μmoL/L

4) Clinical pearl

Asymptomatic hyperuricemia usually does not require treatment with some exceptions. 

5) Drugs and conditions associated with hyperuricemia ¹

Drugs

•   alcohol
•  cyclosporine
•  cytotoxic chemotherapy
• diuretics
•  ethambutol
•  interferon + ribavirin
•  levodopa
•  nicotinic acid
•  pyrazinamide
•  salicylates, low-dose
•  tacrolimus
•  teriparatide

Conditions

•  alcohol consumption
•  atherosclerosis
•  diabetes
•  hyperlipidemia
•  hypertension
•  intrinsic renal disease
•  ischemic heart disease
•  metabolic syndrome
•  myeloproliferative disorders and some cancers  
•  obesity

What is the concern of diuretics with gout? ²

Loop (e.g. furosemide) and thiazide diuretics decrease the excretion and increase the concentration of uric acid.

hydrochlorothiazide-induced gout:    ~ 1%  increased when dose >25 mg/d

6) Diagnostic rule

• consider male gender
• previous patient reported arthritis attack
• onset within one day
• joint redness
• 1st MTP joint
• hypertension or > CVD risk and UA > 360 μmoL/L

Reference 1

7) What non-pharmacological therapies are recommended? ²

Acute attack: rest, elevate limb, ice, avoid contact

Maintenance: useful and may decrease the need for preventative medications

             Diet: compliance with low purine diets is poor, recommend one less portion of meat or fish per day; drink wine instead of beer; drink a glass of skimmed milk each day. Low fat dairy, fiber, vitamin C, and whole grains are associated with decreased gout.
Low calorie diet more beneficial/acceptable then low purine diet!

               Avoid: liver, kidney, shellfish, gravy, sardine, sweetbread, sugar drinks and yeast extract.

               Lifestyle: Weight loss, Smoking cessation, decrease alcohol binging (especially beer)

                                drink 2 L water/day (unless contraindicated), mild-moderate intensity exercise.

8) Indications for antihyperuricemic therapy ¹

• 2 attacks/year
•  severe or polyarticular attacks
•  presence of tophaceous gout
•  radiographic evidence of joint damage due to gout
•  severe/persistent hyperuricemia (> 720 μmoL/L)
•  hypoxanthine-guanine phosphoribosyl ransferase (HGPRT) deficiency or prhosphoribosyl perophosphate (PRPP) synthetase overactivity ( both ­ uric acid production)
•  uric acid nephropathy, nephrolithiasis (uric acid or calcium stones)
•  24-hour urinary uric acid excretion > 1000 mg, particularly in males < 25 years and premenopausal women
•  prophylaxis of hyperuricemia prior to administration of cytotoxic agents

Reference 1

Reference 1

Reference 1

Reference 1

Clinical pearls  – NSAIDs

• Contraindicated with decreased renal function (Clcr < 30 mL/min), GI) ulcer, heart failure, previous allergy to NSAID.
• Indomethacin is used historically, however others are also effective and cause less CNS adverse effects
• GI prophylaxis should be considered in the presence of a history of PUD/GI bleed or age > 70 (PPI or misoprostol 200 μg TID – QID)
• High doses for 1^st 24-72 hours, then stop or use lowest effective dose x 1-2 weeks

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Clinical pearls  – Colchicine

Dose:  1.2 mg stat then 0.6 mg 1 hour later (FDA); no further doses for 3 days (CPS) other dosing schedules have been used: 0.6 mg bid x 1-3 days, then daily x1-2 weeks

Limiting dose to less than 3 tablets on day 1 then 1-2 tablets/day will greatly decrease diarrhea/GI side effects

Use ½ dose if taking concomitant strong CYP3A4 inhibitor and normal renal/hepatic function (CPS) see CPS for other doses

Monitor:  CBC (neutropenia), CK (rhabdomyolysis may increase with statins/fibrates), renal function q6 months

Prophylaxis when starting allopurinol:  0.6 daily – bid (or 1 mg daily) x 3 – 6 months.

NOT COVERED ON ODB
Vitamin C   

1000 – 1500 mg/day may reduce relative risk of gout by 34 – 45%

However, doses over 1000 mg increases risk of kidney stones (oxalate or uric acid) in those who have had a previous kidney stone

•       May increase excretion of uric acid.

Clinical pearls  – Allopurinol

Wait 1-2 weeks after inflammation subsides before initiating NEVER START OR STOP ALLOPURINOL DURING AN ACUTE ATTACK

Prophylax with colchicine (0.6 daily – bid) or NSAID low dose x 3 – 6 months while titrating allopurinol

D/C if rash since rash may precede serious hypersensitivity reactions (20-30% mortality)

Start low:  100 – 200 mg daily and increase by 100 mg weekly based on UA levels (CPS)  or start at 100 mg daily and increase q2 – 4 weeks (RxFiles)

Maximum 800 mg daily if normal renal function, otherwise reduced.

If eGFR < 50 mL/min, start at 50 mg/day and titrate by 50 mg doses, maximum 300 mg/day.  (http://www.rxfiles.com/)

CrCl 10 – 20 mL/min max. maintenance dose 100 mg daily

CrCl < 10 mL/min max maintenance dose 100 mg q2-3 days

Divided doses if > 300 mg daily (improved GI tolerability)

After food

↑INR possible with warfarin – monitor

↑toxicity of azathioprine

Before starting:  LFT; Cr (CrCl); CBC

Febuxostat (Uloric ©)

80 mg daily more effective than allopurinol 300 mg daily in bringing UA to goal (<360 μmoL/L)

May be used if CrCl > 30 mL/min

Alternative to allopurinol if hypersensitive to allopurinol

BUT – more expensive, NOT COVERED ON ODB, if normal renal function, allopurinol dose may be increased above 300 mg (800 mg max)

Contraindicated with azathioprine, mercaptopurine or theophylline!

Conclusions

Treat acute gout before deciding upon need for UA lowering Tx

Consider iatrogenic causes (ie. Drugs)

Never start or stop allopurinol (or febuxostat) during acute attack

Use prophylaxis with colchicine or NSAID x 3-6 months while titrating dose of allopurinol (or            
               febuxostat

References

1.  Therapeutic choices. Canadian pharmacists Association, 2011

2.  www.RxFiles.ca (Accessed Oct 17, 2011)

Annette's Phun Pharmacy Phacts - Narcotic Safety and Awareness Act

Citalopram (Celexa) & Abnormal Heart Rhythms

On August 24, 2011, the US FDA has recommended the following:


RECOMMENDATION: Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day. Citalopram should not be used in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing Torsade de Pointes.

Data Summary 

FDA has received post-marketing reports of QT interval prolongation and Torsade de Pointes associated with Celexa and its generic equivalents. In addition, FDA has evaluated the results of a thorough QT study assessing the effects of 20-mg and 60-mg doses of citalopram on the QT interval in adults. In this randomized, multi-center, double-blind, placebo-controlled, crossover study, 119 subjects received citalopram 20 mg per day (Day 9), citalopram 60 mg per day (Day 22), and placebo. The overall summary of findings is presented in Table 1 

Table 1: Increase in the Corrected QT Interval for Citalopram (FDA Analysis) 

Citalopram Dose	Increase in QT Interval (ms)	90% Confidence Interval (ms)
20 mg/day	8.5	(6.2, 10.8)
60 mg/day	18.5	(16.0, 21.0)
40 mg/day	12.6*	(10.9, 14.3)*

*Estimate based on the relationship between citalopram blood concentration and QT interval.

Compared to placebo, maximum mean prolongations in the individually corrected QT intervals were 8.5 and 18.5 milliseconds (ms) for 20 mg and 60 mg citalopram, respectively. For 40 mg citalopram, prolongation of the corrected QT interval was estimated to be 12.6 ms. 

As a result of this thorough QT study, FDA has determined that citalopram causes dose-dependent QT interval prolongation and should no longer be used at doses above 40 mg per day. Important safety information about the potential for QT interval prolongation and Torsade de Pointes with drug dosage and usage recommendations are being added to the package inserts of Celexa and its generic equivalents.

What does this mean for our patients with depression and anxiety that have felt a benefit from the increased dose of citalopram 60mg?

Consider the following:

1.  Discuss with the patient the US FDA recommendations and possible increase risk of QT prolongation.

2.  Suggest monitor ECG, serum K+ and Mg+ (regularly if maintaining dose of 60mg)

3.  If tapering to citalopram 40mg, follow up with the patient accordingly to ensure no relapse (e.g., within the month)

4.  If relapse occurs, consider switching to sertraline (max dose = 200mg/d) or augmenting with bupropion (depending on the diagnosis of treatment)  {e.g., if depression+anxiety, consider sertraline.  If major depressive disorder only, consider adding bupropion (bupropion may increase anxiety)}

If you have any other suggestions or comments, please feel free to share on this blog!

References:
1.  http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm269481.htm
2. http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm

With all the controversy over the benefits vs costs of home blood glucose monitoring in patients with type 2 diabetes who are not receiving insulin, what are you recommending to your patients?

Thanks for the question. This topic has been a hot issue for the past 3-4 years.

Most of the controversy relates to patients not taking any agents that are likely to cause hypoglycemia.

Over all, it depends on the therapy and the A1c and assumes that someone (patient or clinician) will actually look at the data, identify trends, and act on the analysis of the data by either making lifestyle modifications or modifying pharmacotherapy. There are 5 bodies that have made recommendations regarding self-monitoring of blood glucose, the CDA (Canadian Diabetes Association), ADA (American Diabetes Association), COMPUS, the UK’s National Institute for Health and Clinical Excellence (NICE),  and IDF (International Diabetes Federation).

I have compiled for you the recommendations from the different groups (Appendix 1).

My own perspective

For patients following lifestyle modifications only

For newly diagnosed diabetic with an A1c below 7.0%, the emphasis is mostly related to letting them experience the impact of nutritional changes, exercises, and weight loss. What can they do to better control their diabetes without medications? To find out portion sizes of specific carbohydrates or meals that they can tolerate.

I recommend to patients that they use their glucometer to see how they react to certain foods or exercise. To test a food or type of meal, to take their blood glucose before and 2h after that food or meal. If it is below 7.0 before the meal, it should be below 10.0 mMol/L 2 hours after. If it is above 10.0 than the amount of carbohydrate was too much. Next time that they have that food try a smaller portion to see if you can tolerate it and keep your 2h post meal BG under 10.0  In these patients, following their blood glucose twice a week is more than enough.

Later on, when they have a good understanding of the effect of different foods and exercise on their BGs and if they are stable and well controlled, there might be little need for any blood glucose monitoring at all and just follow the A1c every 3 months. They should have the option to monitor their BGs if they wish as so people are feel more empowered that way. Also, they may want to monitor if they do not feel well and may have symptoms consistent with either hypo or hyperglycemia.

For patients with an A1c close to 7.0%, they may want to monitor their blood sugar twice a week once before breakfast and the other time 2h after their biggest meal of the day because those are the 2 times of the day likely to cause problems.

Patients on agents not likely to cause hypoglycemia

The same as above would apply in respect to testing to see the impact of food and exercise PLUS you want to assess the efficacy of the medication and titrate according to response. Here, I ask patients to test once or twice daily at different times of the day so that I can have some information to titrate the dosage of their medications until I reach target average pre and post-meal blood glucose results. Obviously, they should also test if they have symptoms consistent with hypoglycemia. 

In patients with well controlled and stable A1c (well under 7.0%) who have implemented good lifestyle changes, the value of regular testing may not be that great in this situation. Monitoring the A1c Q3months may be a reasonable option. Otherwise, testing twice a week would be quite sufficient.

When the A1c is above 7.0%, you want to monitor more frequently (e.g., once a day at different times of the day) so that you can titrate the oral anti hyperglycemic agents. You would do that until you reach target. When the A1c is controlled and stable that you can relax the monitoring as long as the patient does not gain weight and maintains is lifestyle changes.

Patient on oral agents that can potentially cause hypoglycemia

Same as above regarding the effect of lifestyle modifications and titration of therapy PLUS patients should monitor their BGs when they are not feeling well and may be experiencing a hypoglycemic episode. More frequent testing (up to 4 times daily) may be necessary when ill. Testing during physical activity or during changes to routine, as necessary, may be beneficial.

Appendix 1

1.      COMPUS Optimal Therapy Report 2009

1.1 ADULTS WITH TYPE 2 DIABETES ON INSULIN

For adults with type 2 diabetes using insulin with or without oral antidiabetes drugs, COMPUS Expert Review Committee (CERC) recommends that the optimal daily frequency of SMBG be individualized. CERC suggests that the maximum weekly frequency of SMBG is 14 tests per week for most of these patients.

This population is heterogeneous regarding the dose and frequency of insulin administration. Given a lack of evidence, the following reflects CERC clinical opinion and accepted standards of practice:

Patients at increased risk of hypoglycemia or its consequences may benefit from performing SMBG more than 14 times per week. These include individuals:

·         using multiple daily insulin injections (i.e., three or more per day)

·         with a history of hypoglycemia

·         working in an occupation where hypoglycemia poses safety concerns or where testing is mandated by an employer (e.g., pilots, air-traffic controllers, critical positions in railways)

·         private and commercial drivers who should abide by jurisdictional regulations concerning SMBG, hypoglycemia, and operation of motor vehicles.

Other populations which may benefit from performing SMBG more than 14 times per week include those:

·         newly initiated on insulin

·         experiencing acute illness

·         undergoing changes in insulin dose/regimen or significant changes in routine

·         with poorly controlled or unstable blood glucose levels

·         who are pregnant or planning a pregnancy.

Patients who are not identified in the populations above may benefit from performing SMBG less than 14 times per week.

1.2 ADULTS WITH TYPE 2 DIABETES WHO USE ORAL ANTIDIABETES DRUGS

Most adults with type 2 diabetes managed on oral anti-diabetes drugs do not require routine self-monitoring of blood glucose. Periodic testing in selected patients (e.g., those with unstable changes, risk of hypoglycemia with insulin secretagogues like glyburide) should be linked to specific patient actions (e.g., prevention or management of hypoglycemia, self-directed dosage adjustment).

Routine use of blood glucose test strips for SMBG is not recommended by CERC for most adults with type 2 diabetes using oral antidiabetes drugs

Given a lack of evidence, the following reflects CERC’s clinical opinion and accepted standards of practice:

·         Patients treated with insulin secretagogues may benefit from routine use of SMBG to reduce the risk of hypoglycemia.

·         Other populations that may benefit from SMBG include those:

o   at increased risk of hypoglycemia (e.g., due to a history of severe hypoglycemia or hypoglycemia unawareness, instances of inadequate caloric intake, unforeseen or unplanned physical activity)

o   experiencing acute illness

o   undergoing changes in pharmacotherapy or significant changes in routine

o   with poorly controlled or unstable blood glucose levels

o   who are pregnant or planning a pregnancy.

1.3 ADULTS WITH TYPE 2 DIABETES WHO DO NOT USE ANTIDIABETES DRUGS

Most adults with type 2 diabetes controlled by diet alone should not require routine self-monitoring of blood glucose.

Given a lack of evidence, the following reflects CERC clinical opinion and accepted standards of practice:

·         Women with type 2 diabetes who are not using insulin and are considering a planned pregnancy may benefit from SMBG testing.

1.4 FINANCIAL IMPLICATIONS

Should these recommendations on self-monitoring of blood glucose using test strips became the practice in Canada, health outcomes for those living with diabetes would not be compromised, but more than $150 million annually could be redirected to other health sector priorities.

2.      IDF Guideline on Self-Monitoring of Blood Glucose in Non-Insulin Treated Type 2 Diabetes

Although further studies are needed to better assess the benefits, optimal use and cost-effectiveness of SMBG, the following recommendations are proposed to guide individuals with non-insulin-treated diabetes and their healthcare providers in the use of SMBG.

1.      SMBG should be used only when individuals with dia­betes (and/or their care-givers) and/or their healthcare providers have the knowledge, skills and willingness to incorporate SMBG monitoring and therapy adjustment into their diabetes care plan in order to attain agreed treatment goals.

2.      SMBG should be considered at the time of diagnosis to enhance the understanding of diabetes as part of individuals’ education and to facilitate timely treatment initiation and titration optimization.

3.      SMBG should also be considered as part of ongoing diabetes self-management education to assist people with diabetes to better understand their disease and provide a means to actively and effectively participate in its control and treatment, modifying behavioural and pharmacological interventions as needed, in consulta­tion with their healthcare provider.

4.      SMBG protocols (intensity and frequency) should be individualized to address each individual’s specific edu­cational/behavioural/clinical requirements (to identify/ prevent/manage acute hyper- and hypoglycemia) and provider requirements for data on glycemic patterns and to monitor impact of therapeutic decision making.

5.      The purpose(s) of performing SMBG and using SMBG data should be agreed between the person with dia­betes and the healthcare provider. These agreed-upon purposes/goals and actual review of SMBG data should be documented.

6.      SMBG use requires an easy procedure for patients to regularly monitor the performance and accuracy of their glucose meter.

3.      Canadian Diabetes Association Practice Guidelines 2008

For individuals using insulin, SMBG should be recommended as an essential part of diabetes self-management [Grade A, Level 1, for type 1 diabetes; Grade C, Level 3, for type 2 diabetes] and should be undertaken at least 3 times per day [Grade C, Level 3] and include both pre- and postprandial measurements [Grade C, Level 3].

In those with type 2 diabetes on once-daily insulin in addition to oral antihyperglycemic agents, testing at least once a day at variable times is recommended [Grade D, Consensus].

For individuals treated with oral antihyperglycemic agents or lifestyle alone, the frequency of SMBG should be individualized depending on glycemic control and type of therapy and should include both pre- and postprandial measurements [Grade D, Consensus].

In many situations, for all individuals with diabetes, more frequent testing should be undertaken to provide information needed to make behavioural or treatment adjustments required to achieve desired glycemic targets and avoid risk of hypoglycemia [Grade D, Consensus].

4. American Diabetes Association

·         SMBG should be carried out three or more times daily for patients using multiple insulin injections or insulin pump therapy.

·         For patients using less-frequent insulin injections, noninsulin therapies, or medical nutrition therapy (MNT) alone, SMBG may be useful as a guide to the success of therapy.

·         To achieve postprandial glucose targets, postprandial SMBG may be appropriate.

·         When prescribing SMBG, ensure that patients receive initial instruction in, and routine follow-up evaluation of, SMBG technique and their ability.

The frequency and timing of SMBG should be dictated by the particular needs and goals of the patient. SMBG is especially important for patients treated with insulin to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia.

For most patients with type 1 diabetes and pregnant women taking insulin, SMBG is recommended three or more times daily. For these populations, significantly more frequent testing may be required to reach A1C targets safely without hypoglycemia.

The optimal frequency and timing of SMBG for patients with type 2 diabetes on noninsulin therapy is unclear. A meta-analysis of SMBG in non–diabetes concluded that some regimen of SMBG was associated with a reduction in A1C of 0.4%. However, many of the studies in this analysis also included patient education with diet and exercise counseling and, in some cases, pharmacologic intervention, making it difficult to assess the contribution of SMBG alone to improved control. Several recent trials have called into question the clinical utility and cost-effectiveness of routine SMBG in non–insulin-treated patients. Because the accuracy of SMBG is instrument and user dependent, it is important to evaluate each patient’s monitoring technique, both initially and at regular intervals thereafter. In addition, optimal use of SMBG requires proper interpretation of the data. Patients should be taught how to use the data to adjust food intake, exercise, or pharmacological therapy to achieve specific glycemic goals, and these skills should be reevaluated periodically.

5.   NICE (UK)

Combined insulin and hypoglycemic agents

• Fasting blood glucose should be tested once daily during basal insulin dose titration.
• People with diabetes who use insulin and oral hypoglycemic agents should be encouraged to self-monitor at least once daily, varying the time between fasting, pre-meal and post-meal, to identify trends.
• People with diabetes showing that they use blood testing to inform their lifestyle activities should be able to choose to self-monitor as a means of monitoring lifestyle changes, based on their diabetes control.

Healthy eating and physical activity with or without additional metformin +/-  glitazone

• Glycemic control is best monitored through regular HbA1c testing based on NICE guidelines:
  - 6 monthly if stable
  - 2 to 3 monthly if unstable and/or changing treatment.
• SMBG once or twice weekly at different times should be used to inform if deterioration of control is occurring, if this is the method of monitoring preferred by the person with diabetes.
• If HbA1c is suboptimal, monitoring should be used to identify problems and inform treatment, particularly prior to reviews as appropriate.
• People with diabetes who prefer to monitor their blood glucose to proactively review and inform lifestyle changes should be able to do so.

Sulphonylureas alone or in combination with other oral antidiabetic agents

• SMBG should be used to reveal if hypoglycaemia is being experienced by those using sulphonylureas or combination therapy.
• Initial regular testing (1 or 2 times daily) is recommended during titration of dose.
• More frequent testing (up to 4 times daily) may be necessary when ill.
• Testing during physical activity or during changes to routine, as necessary, may be beneficial.
• SMBG prior to a review if HbA1c is suboptimal to identify any problems and inform treatment changes as appropriate.

Antony Gagnon, PharmD, CDE

Pharmacy Program Manager

Hamilton FHT

Monogenic Diabetes Lecture at the American Diabetes Association San Diego June 24 - 28 2011

Lecture presented by Fabrizio Barbetti summarized below:
A sometimes overlooked cause of neonatal diabetes is monogenic, or a mutation in one gene.  Neonatal diabetes is defined as diabetes occurring up to 180 days of life and has an incidence of 1:210,000 births.   There may be a resulting defect in the beta cell, or a genetic defect in insulin action.
One type results from complete glucokinase deficiency due to a mutation in the gene encoding ATP-sensitive K+ channel subunit Kir6.2.  In patients with this KCNJ11 mutation, many may be successfully weaned from insulin to a sulfonylurea such as glyburide or gliclazide.  Doses up to 45 mg/day glyburide or 720 mg/day gliclazide have been used in adults.  (Up to 2 - 2.5 mg/kg/day glyburide)  Glyburide may be dissolved in water at 5 mg/mL and mixed in formula or mother's milk for infants.
An interesting link between monogenic DM and motor/developmental delay was discussed.  The subunit Kir6.2 is found on other cells(other than the beta cell) such as neuronal cells.  Some patients weaned from insulin do much better in regards to motor co-ordination when on glyburide.  Genetic testing appears to be worthwhile, although our capability here in North America was not discussed.

Melatonin

During the retreat for mental health workers, one of the most common questions during the Complementary & Alternative Medicine presentation/workshop was...

What are the benefits and risks of melatonin in children?

Answer:

CHILDREN: POSSIBLY UNSAFE ...when used orally or parenterally. Melatonin has been used with apparent safety in short-term clinical trials in a small number of children. However, there is concern that melatonin supplementation has the potential to adversely affect children. Young people up to the age of 20 years produce melatonin endogenously in high levels. Melatonin levels are inversely related to gonadal development. Theoretically, exogenously administered melatonin might adversely affect gonadal development; use with caution.  Efficacy and safety for longer than 4 weeks has not been evaluated.

References: 

1. Natural Medicine - Comprehensive Database

2. http://www.bestbets.org/bets/bet.php?id=1749

3. http://www.nyrdtc.nhs.uk/docs/dud/DU_44_melatonin_a.pdf