BISACODYL

BISACODYL

5mg coated Tablet

5mg, 10mg Suppository

DRUG CATEGORY: Stimulant Laxative

BRAND NAME: Dulcolax®

DESCRIPTION

Bisacodyl is a locally acting laxative from the diphenylmethane derivative group (4,4'-diacetoxy-diphenyl-(pyridyl-2)-methane).

As a contact laxative, Bisacodyl stimulates peristalsis of the colon and promotes accumulation of water in the colonic lumen which leads to stimulation of defecation, reduction of transit time and softening of stool.

INDICATIONS

Bisacodyl is indicated in patients suffering from constipation and for preparation of diagnostic procedures, in pre and post-operative treatment and in conditions which require defecation to be facilitated.

FORMULATION

1 coated tablet contains 5mg of Bisacodyl

1 suppository contains 10mg of Bisacodyl

1 pediatric suppository contains 5 mg Bisacodyl

PHARMACOLOGY

The laxative effect of Bisacodyl occurs upon contact with the colonic mucosa where it stimulates the sensory nerve endings that results to increase peristaltic contractions of the large intestines to produce soft well-formed stools. This results in a stimulation of defecation, reduction of transit time, and a softening of the stool. It is a reversible reaction wherein colonic function would return to its normal condition after defecation occurs.

The tablets usually exert a laxative effect within 6-12 hours after intake. The suppositories usually take effect in about 20 minutes (range 10 to 30 minutes); in some cases, it occurs 45 minutes after administration.

DOSAGE AND ADMINISTATION

Unless otherwise prescribe by the physician, the following dosages are recommended:

Adults and Children over 10 years old: 1 to 2 coated tablets (5 -10 mg) or 1 suppository (10 mg)

Children 4 – 10 years old: 1 coated tablet (5 mg) or 1 pediatric suppository (5mg)

Children under 4 years old: 1 pediatric suppository (5 mg)

Children should not take Bisacodyl without medical advice.

It is recommended to take the enteric coated tablets at night to promote bowel movement the following morning. They should be swallowed whole with an adequate amount of fluid.

The coated tablets should not be taken together with products reducing the acidity of the upper gastrointestinal tract, such as milk, antacids or proton pump inhibitors, in order not to prematurely dissolve the enteric coating.

Suppositories should be unwrapped and inserted into the rectum, pointed end first.

For preparation of diagnostic procedures, in pre- and post-operative treatment and in medical conditions which require defecation to be facilitated, Bisacodyl should be used under medical supervision.

Combination Therapy

Bisacodyl tablets should be combined with suppositories in order to achieve complete evacuation of the intestine.

Adults and Children over 10 years old: 2 – 4 tablets the night before and 1 adult suppository in the morning of the examination.

Children 4 – 10 years old: 1 tablet the night before and 1 pediatric suppository on the following morning.

CONTRAINDATIONS AND PRECAUTIONS

• Bisacodyl should not be given to patients with ileus, intestinal obstruction, acute abdominal conditions including appendicitis and acute inflammatory bowel disease and severe abdominal pain associated with nausea and vomiting which may be indicative of severe conditions.
• Bisacodyl is also contraindicated in severe dehydration and in patients with known hypersensitivity to Bisacodyl or any other component of the product.
• In cases of rare hereditary conditions that may be incompatible with an excipient of the product, the use of the product is contraindicated.
• As with all laxatives, Bisacodyl should not be taken on a continuous daily basis or for extended periods without investigating the cause of constipation.
• Prolonged excessive use may lead to fluid and electrolyte imbalance and hypokalemia.
• Intestinal loss of fluids can promote dehydration. Symptoms ma include thirst and oliguria. In patients suffering from fluid loss where dehydration may be harmful (e.g. renal insufficiency, elderly patients) Bisacodyl should be discontinued and only be restarted under medical supervision.
• Patients may experience hematochezia (blood in stool) that is generally mild and self-limiting.
• Dizziness and/or syncope have been reported in patients who have taken Bisacodyl. The details available for these cases suggest that the events would be consistent with defecation syncope (or syncope attributable to straining at stool), or with a vasovagal response to abdominal pain related to the constipation, and not necessarily to the administration of Bisacodyl.
• The use of suppositories may lead to painful sensations and local irritation, especially in anal fissure and ulcerative proctitis. Patients with rare hereditary conditions of galactose intolerance, e.g. galactosemia, and fructose intolerance should not take this medicine.
• No studies the effects of Bisacodyl on the ability to drive and use machines have been performed. However, patients should be advised that due to vasovagal response (e.g. to abdominal spasm) they may experience dizziness and/or syncope. If patients experience abdominal spasm, they should avoid potentially hazardous tasks such as driving or operating machinery.

DRUG INTERACTIONS

The concomitant use of diuretic and adrenocorticosteroids may increase the risk of electrolyte imbalance if excessive doses of Bisacodyl are taken.

If so, electrolyte imbalance may increase the sensitivity to cardiac glycosides.

PREGNANCY AND LACTATION

There are no adequate and well-controlled studies in pregnant women. Long experience has shown no evidence of undesirable or damaging effects during pregnancy. Nevertheless, as with all drugs, Bisacodyl should be taken during pregnancy only on medical advice.

Bisacodyl can be used during breast-feeding. No studies on the effect on human fertility have been conducted.

ADVERSE DRUG REACTIONS

The most commonly reported adverse reactions during treatment with Bisacodyl are abdominal pain and diarrhea.

The following episodes may occure:

• Immune system disorders: anaphylactic reactions, angioedema, hypersensitivity.
• Metabolism and nutrition disorders: dehydration
• Nervous system disorders: dizziness, syncope. Dizziness and syncope occurring after taking Bisacodyl appear to be consistent with vasovagal response (e.g., to abdominal spasm, defecation).
• Gastrointestinal disorders: abdominal cramps, abdominal pain, diarrhea, nausea, hematochezia (blood in stool), vomiting, abdominal discomfort, anorectal discomfort, colitis.

OVERDOSAGE

High doses usually result to watery stools (diarrhea), abdominal cramps and clinically significant loss of fluid, potassium, and other electrolytes.

Bisacodyl, as with other laxatives, when taken in chronic overdose may cause chronic diarrhea, abdominal pain, hypokalemia, secondary hyperaldosteronism, and renal calculi. Renal tubular damage, metabolic alkalosis, and muscle weakness secondary to hypokalemia have also been described in association with chronic laxative abuse. After ingestion of oral forms of Bisacodyl, absorption can be minimized or prevented by inducing vomiting or gastric lavage. Replacement of fluids and correction of electrolyte imbalance may be required. This is especially important in the elderly and the young. Administration of antispasmodic may be of value.

STORAGE CONDITIONS

Store at temperatures not exceeding 30^oC.

SUCRALFATE

SUCRALFATE

1 g Tablet

DRUG CATEGORY: Cytoprotector

BRAND NAME:Iselpin®

FORMULATION

Each tablet contains 1 g of Sucralfate

DESCRIPTION

Sucralfate is a white, amorphous powder which is soluble in strong acids and in alkalis but practically insoluble in water and in alcohol. It is a basic, aluminum complex of sucrose octasulfate.

Sucralfate has the chemical name, α-D-Glucopyranoside β-D-fructofuranosyl, octakis (hydrogen sulfate), aluminum complex. Its molecular formula is C₁₂H_mAl₁₆O_nS₈ (m and n are approximately 54 and 75 respectively, resulting in an average molecular of about 2086 daltons).

PHARMACOLOGY

Sucralfate is a unique anti-ulcer agent in that it is chemically unrelated to antacids, anticholinergics, or H₂receptor antagonists. Although the exact mechanism of action of Sucralfate has been fully defined, the therapeutic effects of the drug are the result of a local action rather than a systemic effect.

Sucralfate exerts a generalized cytoprotective effect, thereby preventing injury to the gastrointestinal mucosa. Sucralfate binds to the surface of both gastric and duodenal ulcers. Studies in human subjects and animal models demonstrate that Sucralfate forms an ulcer adherent complex with the proteinaceous exudate at the ulcer site. These insoluble complexes form a protective barrier over the ulcer lesion which affords sustained protection against the penetration and action of gastric acid, pepsin and bile. Studies both in human and animals show that Sucralfate protects the gastric mucosa from various irritants such as alcohol, acetylsalicylic acid and sodium taurocholate.

Sucralfate inhibits the proteolytic effect of pepsin and has been shown to adsorb bile salts in vitro. This substance exhibits only weak antacid activity.

Sucralfate does not alter gastric emptying time or normal digestive function.

PHARMACOKINETICS

Sucralfate is minimally absorbed from the gastrointestinal tract following oral administration. Animal studies indicate that only 3-5% of an oral dose reaches the systemic circulation. It appears in the blood as sucrose sulfate which is formed in the stomach following the reaction of Sucralfate with hydrochloric acid. Binding to the ulcer site for up to 6 hours following oral administration has been demonstrated. This prolonged action is due to the drug's viscous adhesiveness, slow reaction with gastric acid, and high affinity for damaged mucosa. In animal models, more that 90% of an orally administered dose of sucrose sulfate is excreted unchanged in feces in 48 hours. The small amount of Sucralfate that is absorbed as sucrose sulfate is excreted unchanged in urine within 48 hours.

INDICATIONS

Sucralfate is indicated in the treatment of duodenal ulcer, gastric ulcer, and chronic gastritis.

PRECAUTIONS

While short-term (usually up to 8 weeks) treatment can completely heal the ulcer, this disease state is a chronic and recurrent one. Sucralfate cannot be expected to alter the post-healing frequency or severity of ulceration.

Carcinogenesis, Mutagenesis and Impairment of Fertility – There was no evidence of carcinogenesis in mice and rats receiving oral Sucralfate in dosages up to 1 g/kg daily (12 times the usual human dosage) for 2 years. Mutagenicity studies have not been conducted. A reproduction study in rats given 38 times the usual human dosage of Sucralfate did not reveal evidence of impaired fertility. The effect of Sucralfate of human fertility is not known.

Using During Pregnancy – Teratogenicity studies in mice, rats and rabbits using dosages of Sucralfate up to 50 times the usual human dosage have revealed no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Therefore, the safety of Sucralfate for use during pregnancy has not been established. It should not be used in pregnant women unless in the judgment of the physician, the expected benefits substantially outweigh the potential risk to the fetus.

Use During Lactation – it is not known if Sucralfate is excreted in breast milk. Because many drugs are excreted in breast milk, a decision should be made whether to discontinue nursing or to discontinue Sucralfate taking into account the importance of the drug to the mother and the potential risk to the infant.

Use in Children – the safety and effectiveness of Sucralfate in children have not been established; its use in this age group is therefore not recommended.

CONTRAINDICATIONS

1. Individuals with a known hypersensitivity to any of the ingredients.
2. Patients receiving dialysis (Long-term administration of this product may result in aluminum accumulation and toxicity. Aluminum toxicity has been implicated in encephalopathy and osteomalacia).

CAREFUL ADMINISTRATION

Patients with renal impairment (Long-term administration of this product may result in aluminum accumulation and toxicity. Aluminum toxicity has been implicated in encephalopathy and osteomalacia. Blood levels such as aluminum, phosphate, calcium, and alkaline phosphatase should be monitored periodically).

DRUG INTERACTIONS

1. Since this product may inhibit absorption of new quinolones such as ciprofloxacin hydrochloride and norfloxacin, this product should not be administered concomitantly with new quinolones.
2. Since this product may alter absorption and excretion of some co-administered drugs, this product should be carefully administered in concomitant therapy.

ADVERSE REACTIONS

Adverse reactions to Sucralfate in clinical trials were minor and rarely led to discontinuation of the drug. In studies including over 2500 patients treated with Sucralfate, adverse effects were only reported in 121 (4.7%). The most frequent complaint was constipation (2.2%). Other adverse effects, reported in not greater that 1 in every 350 patients treated were diarrhea, nausea, gastric discomfort, indigestion, dry mouth, rash, pruritus, back pain dizziness, drowsiness, and vertigo.

ADMINISTRATION TO THE ELDERLY

Since physiologic function are usually reduced in elderly patients, caution must be exercised with careful consideration give to dosage.

DOSAGE AND ADMINISTRATION

The recommended adult oral dosage is 1 g four times a day on an empty stomach (1 hour before each meal and at bedtime).

Antacids may be used as needed for relief of pain but should not be taken within 30 minutes before or after Sucralfate.

Although healing with Sucralfate may occur during the first week or two, continuation of treatment is suggested for 4-8 weeks unless healing has been demonstrated by X-ray or endoscopic examination. In resistant cases, up to 12 weeks may be needed.

OVERDOSAGE

There is limited information available on eh acute toxicity of Sucralfate. Following oral administration of a single 12 g dose to healthy adults, no serious toxicity was observed. Acute oral toxicity studies in animals with doses to 12 g/kg could not establish a lethal dose. Risks associated with overdosage should, therefore, be minimal.

STORAGE CONDITIONS

Store at a temperature not exceeding 25^oC. Keep bottle tightly closed.

HYOSCINE-N-butylbromide

HYOSCINE-N-butylbromide

10 mg sugar-coated Tablet

20 mg/ml Injection

DRUG CATEGORY: Antispasmodic/Anticholinergic

BRAND NAME:Buscopan®

FORMULATION

1 sugar coated tablet contains 10 mg of Hyoscine-N-butylbromide.

1 ampoule of 1 ml contains 20 mg of Hyoscine-N-butylbromide.

INDICATIONS

Acute gastrointestinal, biliary and genitourinary spasm, including biliary and renal colic.

As an aid in diagnostic and therapeutic procedures, where spasm may be a problem, e.g. gastro-duodenal endoscopy, and in radiology.

DOSAGE AND ADMINISTRATION

Oral Tablet

Unless otherwise prescribed by your physician, the following doses are recommended:

Adults and children over 6 years: 1-2 sugar-coated tablets 3-5 times daily. The tablet should be swallowed whole with adequate fluid.

Parenteral Injection

Adults and adolescents over 12 years:

1-2 ampules of Hyoscine-N-butylbromide (20-40 mg) may be administered by slow intravenous, intramuscular or subcutaneous injection several times daily.

The maximum daily dose of 100 mg should not be exceeded.

Infants and children:

In severe cases: 0.3-0.6 mg/kg body weight, to be administered by slow intravenous, intramuscular or subcutaneous injection several times daily. The maximum daily dose of 1.5 mg/kg body weight should not be exceeded.

Hyoscine-N-butylbromide should not be taken on a continuous daily basis or for extended periods without investigating the cause of abdominal pain.

CONTRAINDICATIONS

Hyoscine-N-butylbromide is contraindicated in:

• patients who have demonstrated prior hypersensitivity to Hyoscine-N-butylbromide or any other components of the product
• untreated narrow-angle glaucoma
• hypertrophy of the prostate with urinary retention
• mechanical stenosis in the gastrointestinal tract retention
• tachycardia
• megacolon
• myasthenia gravis

By intramuscular injection, Hyoscine-N-butylbromide ampules are contraindicated:

• in patients being treated with anticoagulant drugs since intramuscular haematoma may occur. In these patients, the subcutaneous or intravenous routes may be used.

In case of rare hereditary conditions that may be incompatible with an excipient of the product, the use of the product is contraindicated.

SPECIAL WARNINGS AND PRECAUTIONS

In case severe, unexplained abdominal pain persists or worsens, or occurs together with symptoms like fever, nausea, vomiting, changes in bowel movements, abdominal tenderness, decreased blood pressure, fainting or blood in stool, appropriate diagnostic measures are needed to investigate the etiology of the symptoms.

Parenteral Injection

Elevation of intraocular pressure may be produced by administration of anticholinergic agents such as Hyoscine-N-butylbromide in patients with undiagnosed and therefore untreated narrow-angle glaucoma. Therefore, patients should seek urgent develop a painful, red eye with loss of vision after the injection of Hyoscine-N-butylbromide.

After parenteral administration of Hyoscine-N-butylbromide, cases of anaphylaxis including episodes of shock have been observed. As with all drugs causing such reactions, patients receiving Hyoscine-N-butylbromide by injection should be kept under observation.

Oral Tablet

Because of potential risk of anticholinergic complications, caution should be used in patients prone to narrow-angle glaucoma as well as patients susceptible to intestinal or urinary outlet obstruction and in those inclined to tachyarrhythmia.

One sugar-coated tablet of 10 mg contains 41.2mg sucrose, resulting in 411.8 mg sucrose per maximum recommended daily dose. Patients with the hereditary condition of fructose intolerance should not take this medicine.

Abdominal cramps may be temporary or signal the presence of a more serious problem. Consult your doctor if the pain is severe or does not improve within 48 hours of taking Hyoscine-N-butylbromide.

INTERACTIONS

The anticholinergic effect of drugs such as tri- and tetracyclic antidepressants, antihistamines, antipsychotics, quinidine, amantadine, disopyramide and other anticholinergics (e.g. tiotropium, ipratropium, atropine-like compounds) may be intensified by Hyoscine-N-butylbromide.

Concomitant treatment with dopamine antagonists such as metoclopramide may result in diminution of the effects of both drugs on the gastrointestinal tract.

The tachycardic effects of beta-adrenergic agents may be enhanced by Hyoscine-N-butylbromide.

FERTILITY, PREGNANCY AND LACTATION

There is limited data from the use of Hyoscine-N-butylbromide in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (please refer to “toxicology”).

There is insufficient information on the excretion of Hyoscine-N-butylbromide and its metabolites in human milk.

As a precautionary measure, it is preferable to avoid the use of Hyoscine-N-butylbromide during pregnancy and lactation.

No studies on the effects on human fertility have been conducted (please refer to “toxicology”).

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as accommodation disorder or dizziness during treatment with Hyoscine-N-butylbromide. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience accommodation disorder or dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.

SIDE EFFECTS

Many of the listed undesirable effects can be assigned to the anticholinergic properties of Hyoscine-N-butylbromide. Anticholinergic side effects of Hyoscine-N-butylbromide are generally mild and self-limited.

Immune system disorders

Anaphylactic shock including fatal outcome, anaphylactic reactions, dyspnea, skin reactions (e.g. urticaria, rash erythema, pruritus) and other hypersensitivity.

Eye disorders

Accommodation disorders, mydriasis, increased intraocular pressure.

Cardiac disorders

Tachycardia

Vascular disorders

Blood pressure decreased, dizziness, flushing.

Gastrointestinal disorders

Dry mouth

Skin and subcutaneous tissue disorders

Dyshidrosis

Renal and urinary disorders

Urinary retention

OVERDOSAGE

Symptoms

In the case of overdosage, anticholinergic effects may be observed.

Therapy

If required, parasympathomimetic drugs should be administed. Ophthalmological advice should be sought in cases of glaucoma urgently. Cardiovascular complications should be treated according to usual therapeutic principles. In case of respiratory paralysis: intubation, artificial respiration should be considered. Catheterization may be required for urinary retention. In addition, appropriate supportive measures should be used as required.

PHARMACOLOGICAL PROPERTIES

Hyoscine-N-butylbromide exerts a spasmolytic action on the smooth muscle of the gastrointestinal, biliary and genitourinary tracts. As a quaternary ammonium derivative, Hyoscine-N-butylbromide does not enter the central nervous system. Therefore, anticholinergic side effects at the central nervous system do not occur. Peripheral anticholinergic action results from a ganglion-blocking action within the visceral wall as well as from an anti-muscarinic activity.

PHARMACOKINETICS

Absorption and distribution

After intravenous administration, Hyoscine-N-butylbromide is rapidly distributed (t_{1/2 α}= 4 min, t_{1/2 β} = 29 min) into the tissues. The volume of distribution (Vss) is 128 L (corresponding to approx. 1.7 L/kg). Because of its high affinity for muscarinic receptors and nicotinic receptors, Hyoscine-N-butylbromide is mainly distributed on muscle cells of the abdominal and pelvic area as well as in the intramural ganglia of abdominal organs. Plasma protein binding (albumin) of Hyoscine-N-butylbromide is approximately 4.4%. Animal studies demonstrate that Hyoscine-N-butylbromide does not pass the blood-brain barrier, but no clinical data to this effect is available. Hyoscine-N-butylbromide (1 mM) has been observed to interact with the choline transport (1.4 nM) in epithelial cells of human placenta in vitro.

Metabolism and elimination

The main metabolic pathway is the hydrolytic cleavage of the ester bond. The half-life of the terminal elimination phase (t_{1/2 γ}) is approximately 5 hours. The total clearance is 1.2 L/min. Clinical studies with radiolabeled Hyoscine-N-butylbromide show that after intravenous injection 42 to 61% of the radioactive dose is excreted renally and 28.3 to 37% faecally.

The portion of uchanged active ingredient excreted in the urine is approximately 50%. The metabolites excreted via the renal route bind poorly to the muscarinic receptors and are therefore not considered to contribute to the effect of the hyoscine-N-butylbromide.

TOXICOLOGY

Acutely, hyoscine-N-butylbromide has a low index of toxicity: oral LD₅₀values were 1000-3000 mg/kg in mice, 1040-3300 mg/kg in rats, and 600 mg/kg in dogs. Toxic signs were ataxia and decreased muscle tone, additionally, in mice tremor and convulsions, in dogs mydriasis, dry mucous membranes and tachycardia. Deaths from respiratory arrest occurred within 24 hours. The intravenous LD₅₀values of hyoscine-N-butylbromide were 10-23 mg/kg in mice and 18 mg/kg in rats.

In repeated oral dose toxicity studies over 4 weeks, rats tolerated 500 mg/kg = “ no observed adverse effect level (NOAEL)”. At 2000 mg/kg, by the action on parasympathetic ganglia of visceral area, hyoscine-N-butylbromide paralyzed the gastrointestinal function resulting in obstipation. Eleven out of 50 rats died.

Hematology and clinical chemistry results did not show dose-related variations.

Over 26 weeks, rats tolerated 200 mg/kg, while at 250 and 1000 mg/kg, the gastrointestinal function was depressed and deaths occurred. The NOAEL of the 30-week oral (capsule) dog study was 30 mg/kg. The majority of clinical findings was attributable to acute effects of hyoscine-N-butylbromide at high dosages (200 mg/kg). No adverse histopathological findings were observed.

A repeated intravenous dose of 1 mg/kg was well tolerated by rats in a 4-week study. At 3 mg/kg, convulsions occurred immediately after injection. Rats dosed with 9 mg/kg died from respiratory paralysis.

Dogs treated intravenously over 5 weeks at 2 x 1, 2 x 3 and 2 x 9 mg/kg, showed a dose-dependent mydriasis in all treated animals, in addition at 2 x 9 mg/kg, ataxia, salivation and decreased body weight and food intake were observed. The solution were locally well tolerated.

After repeated IM injection, the dose of 10 mg/kg was systemically well tolerated, but lesions of muscles at the site of injection were distinctly increased if compared to control rats. At 60 and 120 mg/kg, mortality was high and local damages were dose-dependently increased. Hyoscine-N-butylbromide was neither embryotoxic nor teratogenic at oral doses of up to 200 mg/kg in the diet (rat) and 20 mg/kg by gavage or 50 mg/kg SC (rabbit). Fertility was not impaired at doses of up to 200 mg/kg p.o..

Like other cationic drugs, hyoscine-N-butylbromide interacts with choline transport system of human placental epithelial cell in vitro. Transfer of hyoscine-N-butylbromide to the fetal compartment has not been proved.

In special studies concerning local tolerability, a repeated IM injection of 25 mg/kg hyoscine-N-butylbromide over 28 days was studied in dogs and monkeys. Small focal necroses at the site of injection were seen only in dogs. Hyoscine-N-butylbromide was well tolerated in arteries and veins of the rabbit's ear. In vitro, 2% hyoscine-N-butylbromide injectable solution showed no hemolytic action when mixed with 0.1 ml human blood.

Hyoscine-N-butylbromide revealed no mutagenic or clastogenic potential in the Ames test, in the in vitro gene mutation assay in mammalian V79 cells (HPRT test) and in an in vitro chromosome aberration test in human peripheral lymphocytes. In vivo, hyoscine-N-butylbromide was negative in the rat bone marrow micronucleus assay.

There are no in vivo carcinogenicity studies. Nevertheless, hyoscine-N-butylbromide did not show a tumorigenic potential in two oral 26-week-studies in rats given up to 1000 mg/kg.

STORAGE CONDITIONS

Store at temperature not exceeding 30^oC.

ISOSORBIDE dinitrate

ISOSORBIDE dinitrate

5 mg and 10 mg Oral Tablet

5 mg Sublingual Tablet

DRUG CATEGORY: Anti-angina

BRAND NAME:Isordil®

DESCRIPTION

Isosorbide dinitrate is a white, crystalline, odorless compound. It is sparingly soluble in water and freely soluble in alcohol. The chemical name of Isosorbide dinitrate is 1,4:3,6-dianhydro-sorbitol-2,5-dinitrate.

ANIMAL PHARMACOLOGY

Isosorbide dinitrate, a direct-acting vasodilator, relaxes vascular smooth muscle. When administered intravenously to dogs, Isosorbide dinitrate decreases systolic and diastolic blood pressure. Hindlimb vascular resistance is decreased after femoral artery injection. Coronary blood flow increases secondary to vasodilation in the rabbit heart. The parent drug was found to be a more potent vasodilator than its mononitrate metabolites.

In addition to vascular smooth muscle, Isosorbide dinitrate relaxes bronchial, biliary, gastrointestinal, ureteral, and uterine smooth muscle. Nitrates are physiological antagonists of norepinephrine, acetylcholine, and histamine.

CLINICAL PHARMACOLOGY

The exact mechanism of action of the nitrates in the relief of angina pectoris is not fully understood. They appear to relieve classic angina pectoris by reducing myocardial oxygen demand, i.e. by decreasing heart's “afterload” and “preload” through dilatation of peripheral venous capacitance and, to a lesser extent, arteriolar resistance vessels. Nitrates may cause a redistribution of coronary blood flow to ischemic areas by selectively dilating large coronary vessels or collateral vessels which may develop secondary to myocardial ischemia.

After therapeutic doses of the drug, systemic arterial pressure is usually decreased; heart rate is unchanged or undergone a slight compensatory increase. In the absence of heart failure, cardiac output transiently increases and then decreases. Pulmonary vascular resistance and pulmonary pressure are decreased.

The anti-angina effects of sublingual Isosorbide dinitrate generally occur within 2-5 minutes after administration and last for 1-2 hours. The hemodynamic effects of the oral tablets are observed within 20-60 minutes and last for 4-6 hours.

PHARMACOKINETICS

Gastrointestinal absorption of Isosorbide dinitrate tablets is rapid and complete. The drug undergoes an extensive first-pass effect with some intepatient variation. Isosorbide dinitrate is metabolized to two mononitrates which subsequently undergo glucuronidation. Less that 1% of Isosorbide dinitrate is bound to plasma proteins. Plasma concentrations of Isosorbide dinitrate and mononitrates were compared after administration of sublingual (2 x 5 mg)and oral (2 x 10 mg) tablets to volunteers. The sublingual dosage form was more rapidly absorbed than the oral formulation, as evidenced by the earlier peak concentrations of the parent drug was 0.2 and 0.5 hours for the sublingual and oral tablets, respectively. For 2-isosorbide mononitrate, the half-life was 2.0 hours for both dosage forms. For 5-isosorbide mononitrate, the half-life of the sublingual tablets was 5.8 hours while that of the oral tablets was 4.5 hours. With chronic administration, significant plasma accumulation of the parent compound occurs, presumably the result of saturation of the intrahepatic biotransformation process.

The elimination phase after both acute and chronic administration of Isosorbide dinitrate appears to be at least bioexponential. Essentially all of the drug is eliminated by the kidneys, principally as isosorbide glucuronide.

INDICATIONS

Angina Pectoris

Isosorbide dinitrate Oral Tablets:

For the prophylaxis of ischemic heart pain associated with coronary insufficiency. Isosorbide dinitrate may reduce the frequency, duration and severity of anginal attacks. Exercise tolerance may be improved and the need for nitroglycerin may be reduced. The oral tablets are not indicated for the treatment of an anginal attack.

Isosorbide dinitrate Sublingual Tablets:

For treatment of angina pectoris and for prophylaxis in situations likely to provoke an anginal attack, i.e. physical or emotional stress.

Congestive Heart Failure

Acute and chronic congestive heart failure (including that associated with myocardial infarction). Based on concurrent knowledge, Isosorbide dinitratie should be considered only as an adjunct to the more conventional modes of therapy (cardiac glycosides and diuretics); however, in refractory cases, it may be used alone or concomitantly with other vasodilators. Isosorbide dinitrate is particularly effective in patients with increased left ventricular end diastolic pressure (LVEDP)- “backward failure”- and normal or approximately normal cardiac output in whom pulmonary congestion or edema is the primary problem. Isosorbide dinitrate is especially recommended when coronary artery disease is the cause of congestive heart failure, in which case its anti-angina effect is of additional value.

CONTRAINDICATIONS

Hypersensitivity or idiosyncrasy to Isosorbide dinitrate or related compounds.

WARNINGS

As with other vasodilator, Isosorbide dinitrate may cause paradoxical side effects in sensitive patients, which may increase ischemia and may even lead to extension of myocardial damage and advanced congestive heart failure. If one elects to use organic nitrates in the early infarction, hemodynamic monitoring and frequent clinical assessment should be used because of the potential deleterious effects of hypotension. Sildenafil may amplify the vasodilatory effects of nitrates such as Isosorbide dinitrate and can result in severe hypotension. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose.

PRECAUTIONS

Severe hypotensive response, particularly with upright posture, may occur with even small doses of Isosorbide dinitrate. Paradoxical bradycardia and increased angina pectoris may accompany nitrate-induced hypotension. The drug should be used with caution in subjects who may have blood volume depletion from diuretic therapy or in subjects who have low systolic blood pressure (e.g. below 90 mm Hg).

In the treatment of acute or chronic cardiac failure, pulmonary capillary pressure should not be allowed to fall below 15 mm Hg or systolic blood pressure below the physiological range in normal or hypentensive patients. Systolic pressure should be preserved in patients with pre-existing hypotension in the range of 90 – 100 mm Hg.

Marked symptomatic, orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustment of either class of agents may be necessary.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

Tolerance to this drug and cross tolerance to other nitrates and nitrites may occur.. The importance of tolerance to the appropriate use of Isosorbide dinitrate in the management of patients with angina pectoris has not been determined.

In clinical trials in angina patients, there are reports of anginal attacks being more easily provoked and or rebound in the hemodynamic effects soon after nitrate withdrawal. It seems prudent therefore, to gradually withdraw patients from Isosorbide dinitrate when therapy is being terminated, rather than stopping the drug abruptly.

Carcinogenesis, Mutagenesis, Impairment of Fertility – No long term studies in animals have been performed to evaluate the carcinogenic potential of this drug. A modified two-litter reproduction study in rats fed Isosorbide dinitrate at 25 o 100 mg/kg/day did not reveal any effects on fertility or gestation or any remarkable growth pathology in any parent or offspring fed Isosorbide dinitrate as compared with rats fed a basal-controlled diet.

Use During Pregnancy - Isosorbide dinitrate has been shown to cause a dose-released increase in embryotoxicity (increase in mummified pups) in rabbits at oral doses 35 and 150 times the maximum recommended human daily dose. There are no adequate and well-controlled studies in pregnant women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use During Lactation - it is not known if Isosorbide dinitrate is excreted in breast milk. Because many drugs are excreted in breast milk, a decision should be made whether to discontinue nursing or to discontinue Isosorbide dinitrate, taking into account the importance of the drug to the mother and the potential risk to the infant.

Use in Children - The safety and effectiveness of Isosorbide dinitrate in children has not been established.

Geriatric Use – Clinical studies of Isosorbide dinitrate Sublingual and Oral Tablets did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients.

In general dose selections for an elderly patients should be cautious, usually staring at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE EFFECTS

1. Cutaneous vasodilation with flushing may occur.
2. Vascular headache is common and may be severe and persistent. Headache is usually relieved by the use of suitable analgesics, or by a temporary reduction in dosage, and tends to disappear after the first week or two of use.
3. Transient episodes of dizziness and weakness, as well as other signs of cerebral ischemia associated with postural hypotension, may occasionally develop. Occasional individuals may exhibit marked sensitivity to the hypotensive effects of nitrates, even with the usual therapeutic dosage. Severe responses such as nausea, vomiting, weakness, restlessness, pallor, perspiration, and collapse can be manifested. Alcohol may intensify this effect. Measures which facilitate venous return (e.g. head-low of Trendelenburg position, deep breathing movement of extremities will usually reverse the syndrome.
4. Drug rash and/or exfoliative dermatitis may occasionally occur.
5. Nausea and vomiting appear to be uncommon.

DRUG INTERACTIONS

Nitrates may cause hypotension as a result of peripheral vasodilatation. Alcohol may enhance this effect. Patients who are prescribed Isosorbide dinitrate should be cautioned accordingly.

Patients receiving antihypentensive drugs, beta adrenergic blockers, or phenothiazines with nitrates should be observed for possible additive hypotensive effects.

Sildenafil – See Warnings.

DOSAGE AND ADMINISTRATION

The initial dose should be not more than 5 mg since a severe hypotensive response occasionally occurs.

Angina Pectoris

Sublingual Tablets: (Tablets dissolve within 20 seconds) 5 mg to 10 mg sublingually every 2 to 3 hours for the prophylaxis of acute angina; this may be supplemented by a dose of 5 mg to 10 mg prior to stressful situations likely to provoke an attack of angina.

Congestive Heart Failure

In acute and chronic congestive heart failure, both sublingual and oral forms may be used. The selection of sublingual or oral Isosorbide dinitrate should be made on the basis of duration of action rather than the magnitude of response, since this is the major difference observed for these dosage forms.

In order to obtain full therapeutic effect, it is important that the dosage of sublingual and oral forms be individualized in accordance with each patient's needs, clinical response and hemodynamic monitoring.

Isosorbide dinitrate therapy should begin with the lowest effective dose and further adjusted as necessary, based on the left ventricular performance. The initial dose really depends on the assessment of how severe the heart failure is. For the treatment of acute congestive heart failure, the rapidly acting sublingual form of Isosorbide dinitrate is preferred and should first be administered to stabilize the patient's symptoms or to determine the magnitude of hymodynamic response; then it should be followed by the oral form for maintenance therapy.

The average recommended doses for acute and chronic congestive heart failure are the following:

Acute Congestive Heart Failure

Sublingual tablet: 5 to 10 mg every two hours or as needed.

Chronic Congestive Heart Failure

Initial dosage, sublingual tablet: 5 to 10 mg every two hours or as needed.

Maintenance dosage, oral tablet: 20 to 40 mg four times daily or as needed.

OVERDOSAGE

Symptoms of nitrate overdosage may include the following: a prompt fall in blood pressure, persistent and throbbing headache, vertigo, palpitation, visual disturbances, flushed and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright position), methemoglobinemia with cyanosis and anoxia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracanial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions and possibly death due to circulatory collapse.

It is not known what dose of the drug is associated with symptoms of overdosing or what dose of the drug would be life-threatening. The acute oral LD₅₀of Isosorbide dinitrate in rats was found to be approximately 1100 mg/kg of body weight. These animal experiments indicate that approximately 500 times the usual therapeutic dose would be required to produce such toxic symptoms in humans. It is not known whether the drug is dialyzable.

Suggested treatment of overdosage: Prompt removal of the ingested material by gastric lavage, if ingestion was recent and the patient is conscious. Keep the patient recumbent in a shock position and comfortably warm. Passive movements of the extremities may aid venous return. Administer oxygen and artificial respiration if necessary. If methemoglobinemia is present, administer methylene blue (1% solution), 1 to 2 mg/keg intravenously.

Epinephrine is ineffective in reversing the severe hypotension events associated with overdose. It and related compounds are contraindicated in this situation.

STORAGE CONDITIONS

Isosorbide dinitrate Oral Tablets: Store at a temperature not exceeding 25^oC.

Isosorbide dinitrate Sublingual Tablets: Store at a temperature not exceeding 30^oC.

DIPHENHYDRAMINE

DIPHENHYDRAMINE

25 mg capsule, 50 mg capsule

12.5 mg/5 ml syrup

DRUG CATEGORY: Antihistamine

BRAND NAME: Benadryl®

FORMULATION

Each 25 mg capsule contains 25 mg Diphenhydramine Hydrochloride.

Each 50 mg capsule contains 50 mg Diphenhydramine Hydrochloride.

Each 5ml contains 12.5 mg of Diphenhydramine Hydrochloride.

DESCRIPTION

Diphenhydramine is 2-(diphenylmethoxy)-N,N-dimethylethylamine hydrochloride, and occurs as a white, crystalline powder, and is freely soluble in water and alcohol.

ACTIONS

Diphenhydramine Hydrochloride is an antihistamine with anticholinergic (drying) and sedative side effects. Antihistamines appear to compete with histamine for cell receptor sites on effector cells.

INDICATIONS

ORAL: Diphenhydramine in the oral form is effective for the following indications.

• ANTIHISTAMINIC: For perennial and seasonal (hay fever) allergic rhinitis; vasomotor rhinitis, allergic conjunctivis due to inhalant allergens and foods; amelioration of allergic reactions to blood or plasma, dermatographism; as therapy for anaphylactic reactions adjunctive to epinephrine and other standard measures after the acute manifestations have been controlled.
• MOTION SICKNESS: For active and prophylactic treatment of motion sickness.
• ANTIPARKINSONISM: For parkinsonism (including drug-induced extrapyramidal reactions) in the elderly unable to tolerate more potent agents; mild cases of parkinsonism (including drug-induced) in other age groups; in other cases of parkinsonism (including drug-induced) in combination with centrally acting anticholinergic agents.

CONTRAINDICATIONS

Use in Newborn or Premature Infants: This drug should not be used in newborn or premature infants.

Use in Breastfeeding Mother: Because of the higher risk of antihistamines fro infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in breastfeeding mothers. For pregnant women, consult your doctor before using this product.

Use in Lower Respiratory Disease: Antihistamine should NOT be used to treat lower respiratory tract symptom including asthma.

Antihistamines are also contraindicated in the following conditions: Hypersensitivity to diphenhydramine hydrochloride and other antihistamines of similar chemical structure; monoamine oxidase inhibitor therapy.

WARNINGS

Antihistamines should be used with considerable caution in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, sympatomatic prostatic hypertrophy, or bladder-neck obstruction.

Use in Children: In infants and children, especially, antihistamine, in over-dosage may cause hallucinations, convulsions or death. As in adults, antihistamines may diminish mental alertness in children. In the young child, particularly, they may produce excitation.

Use in Pregnancy: Experience with this drug in pregnant women is inadequate to determine whether there exists a potential for harm to the developing fetus.

Use with CNS Depressants: Diphenhydramine hydrochloride has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.)

Use in activities requiring mental alertness: Patients should be warned about engaging in activities requiring mental alertness, such as driving a car or operating appliances, machinery, etc.

Use in the Elderly (approximately 60 years or older): Antihistamines are more likely to cause dizziness, sedation and hypotension in elderly patients.

PRECAUTIONS

Diphenhydramine hydrochloride has an atropine-like action, and therefore, should be used with caution in patients with history of brochial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension.

DRUG INTERACTIONS

MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines.

ADVERSE REACTIONS

The most frequent adverse reactions are underscored.

1. General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of mouth, nose and throat.
2. Cardiovascular System: Hypotension, headache, palpitations, tachycardia, extrasystoles.
3. Hematologic System: Hemolytic anemia, thrombocytopenis, agranulocytosis.
4. Nervous System: Sedation, sleepiness, dizziness, disturbed coordination, fatique, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, hysteria, neuritis, convulsions.
5. GI System: Epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation.
6. GU System: Urinary frequency, difficult urination, urinary retention, early menses.
7. Respiratory System: Thickening of bronchial secretions, tightness of chest and wheezing nasal stuffiness.

OVERDOSAGE

Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms like dry mouth, fixed dilated pupils; flushing and gastrointestinal symptoms may also occur. If vomiting has not occurred spontaneously, the patient should be induced to vomit. This the best done by having the patient drink a glass of water or milk, after which the patient should be mad to gag. Precautions against aspiration must be taken, especially in infants and children.

If vomiting is unsuccessful, gastric lavage is indicated within 3 hours after ingestion and even later if large amounts of milk or cream were given before hand.

Isotonic or ½ isotonic saline is the lavage solution of choice.

Saline cathartics, as milk or magnesia, by osmosis, draw water into the bowel and therefore are valuable for their action in rapid dilution of bowel content.

Stimulants should not be used.

Vasopressors may be used to treat hypotension.

DOSAGE AND ADMINISTRATION

A single oral dose of diphenhydramine hydrochloride is quickly absorbed, with maximum activity occurring in approximately one hour. The duration of activity following an average dose of diphenhydramine is from 4 to 6 hours.

The usual adult dosage is 50 mg three or four times daily. Children (over 20 lbs): 12.5 to 25 mg, three or four times daily. Maximum daily dosage not to exceed 300 mg. Based upon body weight, the recommended dosage is 5 mg/kg/24 hours. In motion sickness, full dosage is recommended for prophylactic use, the first dose to be given 30 minutes before exposure to motion and similar doses before meals and upon retiring for duration of exposure.

STORAGE CONDITION

Diphenhydramine hydrochloride should be stored at temperatures not exceeding 30^oC and protected from light.