Modified-release drug products

"Many terms are used to describe modified-release products including extended-release, prolonged-release, controlled-delivery, slow-release and sustained-release. These preparations, by definition, have a reduced rate of release of active substance. In general, these terms are interchangeable.



Delayed-release products are modified-release, but by definition are not extended-release. They involve the release of discrete amount(s) of drug some time after drug administration, e.g. enteric-coated products, and exhibit a lag time during which little or no absorption occurs...



Extended-release products contain a higher drug load and thus any loss of integrity of the release characteristics fo the dosage form has potential problems. While some extended-release products can be divided to provide half-d0ses..., others should only be taken whole... Modified-release products should never be crushed or chewed as the slow-release characteristics may be lost and toxicity may result. This is particularly important in patients unable to swallow whole tablets, a problem commonly affecting the elderly. The larger size of extended-release products may cause difficulties in ingestion or transit through the gut. These problems may result in some drugs... causing local tissue damage in patients who have a pathological or drug-induced reduction in gut motility."



Source: Oral extended-release products by Lloyd N. Sansom, Head, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide

(http://www.australianprescriber.com/magazine/22/4/88/90/)

Drug products that should not be broken, divided, chewed or crushed

Bisacodyl (Dulcolax) 5 mg Enteric Coated Tablet

Mfr./Dist: Interphil Labs., Inc.

Butamirate Citrate (Sinecod Forte) 50 mg Sustained-release Tablet

Mfr./Dist.: Interphil Labs., Inc./Novartis

Felodipine (Versant-XR) 5 mg Extended Release Tablet

Mfr./Distr.: Standard Chem.& Pharm.Co., Ltd./United Labs., Inc./L.R. Imperial, Inc.

Ferrous Sulfate (Sorbifer Durules) 500 mg Sustained Release Tablet

Mfr.: AstraZeneca

Furosemide 40 mg/Potassium Chloride 600 mg (Diumide-K) Continus Tablet (Controlled-Release)

Mfr./Dist: NAPP Lab., Inc/Pascual/Mundipharma

Gliclazide (Glubitor-OD) 30 mg Modified-Release Tablet

Mfr./United Lab., Inc./L.R Imperial, Inc.)

Nifedipine (Adalat GITS 30) 30 mg Extended Release Tablet

Mfr.: Bayer AG/Bayer Phils., Inc.

Nifedipine (Calcibloc OD) 30 mg Coated Tablet

Mfr.: Bayer AG/Bayer Phils., Inc./Therapharma

Oxycodone HCl (Oxycontin) 10 mg, 20 mg, 40 mg, 80 mg Controlled-Release Tablets

Mfr./Dist: Bard Pharmaceuticals, Ltd.Mundipharma/Pascual/Zuellig Pharma Corp.

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Drug products that may be divided (split) but should not be chewed or crushed

Isosorbide-5-Mononitrate (Imdur Durules) 30 mg and 60 mg Sustained Release Tablets

Mfr.: AstraZeneca

Theophylline (Theo-Dur) 200mg and 300 mg Sustained-Release Tablets

Mfr./Dist.: Valpharma S.A./AstraZeneca

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Note: The above list is incomplete.

Benzyl alcohol as preservative in drug products

Benzyl alcohol, another preservative, has been linked to "a number of neonatal deaths and severe respiratory and metabolic complications in low-birth-weight premature infants." Most drugs have very low levels of benzyl alcohol and are not suspected of causing infant complications, although the [American Academy of Pediatrics] note that "the effects of lower amounts... have not been adequately studied."

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Source: http://www.personalmd.com/news/a1997021009.shtml

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Benzyl alcohol gasping syndrome may occur due to a decrease in glycine conjugation seen in neonates and accumulation of benzoic acid.
Remember from class: Glycine conjugation is decreased in neonates and reaches adult levels at approximately 8 weeks of age. Because of decreased glycine conjugation, benzoic acid can accumulate in newborns given excess benzyl alcohol or benzoic acid.
Benzyl alcohol--> benzoic acid ----> glycine conjugation-----> hippuric acid.
This accumulation of benzoic acid results in the "benzyl alcohol gasping syndrome" with deterioration of multiple organ systems, severe metabolic acidosis and gasping respirations. This is a dose related syndrome and has been reported with doses of benzyl alcohol greater than 99 mg/kg. Because of this syndrome, the FDA now recommends that drugs containing benzyl alcohol or benzoic acid as preservatives should NOT be used in neonatal nurseries.
Therefore, one should USE PRESERVATIVE FREE MEDICATIONS FOR NEONATES.

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Source: http://www.uic.edu/classes/pmpr/pmpr652/Final/krauss/pedsdevcase.html

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Drug products containing benzyl alcohol as preservative:

Heparin Sodium (Heparin Leo Injection) 1,000 i.u., 5,000 i.u., 25,000 i.u.

Mfr./Distr.: Leo Pharmaceutical Products/Zuellig Pharma. Corp.

Polyethoxylated castor oil in Vitamin K products

Studies in animals given polyethoxylated castor oil have shown a severe anaphylactic reaction associated with histamine release. Strong circumstantial evidence implicates polyethoxylated castor oil in similar reactions in humans. Polyethoxylated castor oil, when given to patients over a period of several days, can also produce abnormal lipoprotein electrophoretic patterns, alterations in blood viscosity and erythrocyte aggregation (red blood cell clumping).

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Source: Vitamin K: A literature review by Karin Rothville DipCBEd (http://www.whale.to/a/rothville.html

Vitamin K product containing polyethoxylated castor oil as non-ionic surfactant:

Phytomenadione (Cycomin) 10 mg/mL Injection

Mfr./Distr.:Rotexmedica, GmbH/Duopharma Trade Phils., Inc.

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Note: If you know of any drug product containing polyethoxylated castor oil that is available in the Philippines, kindly e-mail at pinoypharmacist@yahoo.com. Your contribution will be highly appreciated.

Aspartame-Containing Drug Products

Acetylcysteine (Fluimucil) 100 mg and 200 mg granulates (Zambon Switzerland Ltd./The Cathay Drug Co., Inc.)

Acetylcysteine (Fluimucil) 600 mg effervescent tablets (Zambon Switzerland Ltd./The Cathay Drug Co., Inc)

CalciumCarbonate (Calsan) 1.25 g (500 mg elemental calcium) chewable tablet (Interphil Laboratories/Diethelm Phils. Inc)

Ranitidine (Zantac FR) 150 mg effervescent tablet (GlaxoSmithKline) - contains 30 mg aspartame

Ranitidine (Zantac FR) 300 mg effervescent tablet (GlaxoSmithKline) - contains 45 mg aspartame

Sodium-Containing Drug Products

Calcium Carbonate (Calsan) 1.25 g (500 mg elemental Calcium) chewable tablet (Interphil Laboratories, Inc./Diethelm Phils., Inc.) - contains 4.29 mg (0.18 mmol) of Sodium

Piperacillin Sodium/Tazobactam Sodium (Tazocin) 2g/250 mg vial (Wyeth) - contains 4.69 mEq (108 mg) of Sodium

Piperacillin Sodium/Tazobactam Sodium (Tazocin) 4g/500 mg vial (Wyeth) - contains 9.39 mEq (216 mg) of sodium

Ranitidine (Zantac FR) 150 mg effervescent tablet (GlaxoSmithKline) - contains 14.3 mEq (328 mg) of sodium

Ranitidine (Zantac FR) 300 mg effervescent tablet (GlaxoSmithKline) - contains 20.8 mEq (479 mg) of sodium

Iberet FT and Iberet Active

...IBERET FT and IBERET ACTIVE are one and the same. There has been no reformulation whatsoever, simply a change in packaging and name. Just like Iberet FT, Iberet Active contains:

525 mg Ferrous Sulfate (elemental iron, 105 mg)
6 mg Thiamine (Vitamin B1)
6 mg Riboflavin (Vitamin B2)
30 mg Nicotinamide
5 mg Pyridoxine (vitamin B6)
25 mcg Cyanocobalamin (Vitamin B12)
10 mg Calcium Pantothenate
500 mg Ascorbic Acid (Vitamin C)

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Source: Letter of Mr. Bernardo L. Pacheco of Abbott Laboratories addressed to the pharmacists of the the Philippine General Hospital dated March 1, 2007.

Tartrazine-containing drug products

Patients who are sensitive to aspirin may also be sensitive to tartrazine, a yellow dye used in medicines and foods. Symptoms of an allergic reaction (urticaria, rhinitis, or asthma) may occur after exposure to many chemicals used to colour, flavour, or preserve food and drugs, but tartrazine (FD & C yellow No. 5) is the colour most frequently incriminated. Intolerance to tartrazine was first reported in 1959, and its part in induction of intractable urticaria has been recognised since 1975. Non-thrombocytopenic purpura is also reported to be due to hypersensitivity to tartrazine---which suggests the possibility that tartrazine may act as a hapten bound to the endothelial cells of small blood vessels.

Source: "Sensitivity to tartrazine" at
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1500754&blobtype=pdf

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Tartrazine-containing Drug Products Available in the Philippines*

Metronidazole (Pharex Metronidazole) 250 mg and 500 mg tablet

Mfr/Dist..: Pascual Lab., Inc./Pharex HealthCorp

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* If you know of a drug product containing tartrazine available in the Philippines, kindly inform the pinoypharmacist through your comment or by e-mail (pinoypharmacist@yahoo.com)

All about drug-induced hyponatraemia

Articles about drug-induced hyponatraemia:

"Managing drug-induced hyponatraemia in adults"
at http://www.australianprescriber.com/magazine/26/5/114/7/

"Drug-induced hyponatraemia" (Letters) at http://www.australianprescriber.com/magazine/27/2/28/33/


Drugs that can cause hyponatraemia:*

"Tramadol and hyponatraemia" (Medicinal mishap) at http://www.australianprescriber.com/magazine/27/4/artid/495/

"Severe hyponatraemia associated with omeprazole" (Medicinal mishap) at
http://www.australianprescriber.com/magazine/28/2/48/9/

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* Not a complete list.

Prescriptions for intravenous potassium chloride

"The pharmacist who receives a prescription for intravenous potassium chloride must be careful and check the amount of potassium chloride in the prescription and the infusion rate at which the drug is to be administered to the patient. The usual additive dilution of potassium chloride is 40 mEq/liter of intravenous fluid. The maximum desirable concentration is 80 mEq/liter of potassium chloride, although severe emergencies may dictate greater concentrations. The maximum infusion rate should not exceed 40 mEq per hour with a maximum24-hour dose not exceeding 400 mEq of potassium chloride. Because of its potent ECG effects, when infused it is wise to monitor the patient's ECG, and to check the patient's serum potassium level after the first 50 to 100 mEq of potassium chloride are administered."

Source: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. by Ansel, Howrd C., et. al., page 325.


"The risks associated with intravenous potassium chloride are well known. If it is injected too rapidly or in too high a dose, it may cause cardiac arrest within minutes. The effect of hyperkalaemia on the heart is complex - virtually any arrhythmia may be observed."

Source: "High-risk medication alert: intravenous potassium chloride" at http://www.australianprescriber.com/magazine/28/1/14/6/


Example of prescriptions for intravenous potassium chloride we encountered:

Potassium Chloride 120 mEq in PNSS 1L x 12 H
Potassium Chloride 200 mEq in PNSS 200 cc x 16 H

Lactose-containing drug products

"We should remember that we are NOT just prescribing the active ingredient when we prescribe. There is the issue of varying particle size and varying excipients that may make a difference. For example, I once had a psychotic patient with lactose intolerance and I had to work to identify which brands (or even which strengths of the same brand) of antipsychotics were lactose free..." -- R.J. Taylor, Psychiatrist

Source: http://www.australianprescriber.com/magazine/28/4/84/7/

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LACTOSE-CONTAINING DRUG PRODUCTS AVAILABLE IN THE PHILIPPINES*

Amphotericin B USP, 5% (w/w) (Amphocil) 50 mg (50,000 I.U.); 100 mg (100,000 I.U. vial

Mfr./Dist.: Ben Venue Laboratories Inc./Mayne Pharma Pty. Ltd.

Celecoxib (Coxid) 100 or 200 mg capsule

Mfr./Dist.: Searle Ltd./Biomedis

Clarithromycin (Klaricid O.D.) 500 mg Modified Release tablet

Mfr.: Abbott

Domperidone (Motilium) 10 mg film-coated tablet

Mfr./Distributor: Interphil Laboratories, Inc./JANSSEN PHARMACEUTICA

Gabapentin (Neurontin) 100 mg, 300 mg or 400 mg capsule

Mfr.:Pfizer

Lactulose (Duphalac) 3.3 g/5 mL Syrup (Contains , 0.9 g of lactose per 15 mL)

Mfr./Interphil Laboratories, Inc./Solvay Pharma, Inc., Phils

Methylergometrine hydrogen maleate (Methergin) 0.125 mg sugar-coated tablet

Mfr.: Novartis

Moxifloxacin (Avelox) 400 mg film-coated tablet

Mfr.: Bayer

Nifedipine (Calcibloc OD) 30 mg coated tablet

Mfr./Dist.: Bayer/Therapharma

Risperidone (Risperdal) 1 mg, 2 mg, 3 mg or 4 mg tablet

Mfr./Dist.: JANSSEN-CILAG SpA/Zuellig Pharma Corp.

Tramadol HCl (Tramundin IR) 50 mg immediate-release tablet

Mfr./Dist.: Mundipharma GmgH/Zuellig

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*Note: The above list is incomplete. If you know of a lactose-containing drug product, feel free to inform me through your comments or by writing me through my e-mail address at pinoypharmacist@yahoo.com. Your contributions will be highly appreciated.

Chlorhexidine-toothpaste interaction

"... The efficacy of chlorhexidine may be reduced by toothbrushing and rinsing because of a chemical interaction. The interval between toothbrushing and rinsing should therefore be at least 30 minutes."

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Source: "Management of drug-induced gingival enlargement" at http://www.australianprescriber.com/magazine/26/1/11/3/

Epinephrine products expressed as ratio strengths

Medication errors have occurred due to confusion with epinephrine products expressed as ratio strengths (eg 1:1000 vs 1:10,000.

Epinephrine 1:000 = 1mg/mL and is most commonly used SubQ.

Epinephrine 1:10,000 = 0.1 mg/mL and is used I. V.

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Source: Lexi-Comp's Pediatric Dosage Handbook, 12th ed. by Carol K. Taketomo, PharmD, et al. 2005, p. 486.