Sildenafil & Vigraz
Sildenafil is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
Mechanism of Action:
The physiologic mechanism of erection of the penis involves release of nitric oxide(NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate(cGMP),producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide(NO) by inhibiting phosphodiesterase type 5(PDE5),which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO,inhibition of PDE5 by Sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.Sildenafil at recommended doses has no effect in the absence of sexual stimulation. (PDR 2002)
Sildenafil is rapidly absorbed after oral administration,with absolute bioavailability of about 40% . Its pharmacokinetics are dose – proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism(mainly cytochrome P450 3A4)and is converted to an active metabolite with properties similar to the parent,Sildenafil .The concomitant use of potent cytochrome P450 3A4 inhibitors(e.g,erythromycin,ketoconazole, itraconazole)as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of Sildenafil.Both Sildenafil and the metabolite have terminal half- lives of about 4 hours.Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes(median 60 minutes)of oral dosing in the fasted state.Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma Proteins.Protein binding is independent of total drug concentrations.
After either oral or intravenous administration,Sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose)and to a lesser extent in the urine (approximately 13% of administered oral dose ) . (PDR 2002)
Pharmacokinetics in Special Populations:
Geriatrics:Healthy elderly volunteers (65 years or over ) had a reduced clearance of Sildenafil,with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers ( 18-45 years )
: In volunteers with mild and moderate renal impairment , the pharmacokinetics of a single oral dose of Sildenafil (50 mg) were not altered .In volunteers with severe renal impairment , Sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.
Pugh A and B) , Sildenafil clearance was reduced, resulting in increases in AUC ( 84% ) and Cmax ( 47%) compared to age-matched volunteers with no hepatic impairment .
Therefore,age>65, hepatic impairment and severe renal impairment are associated with increased plasma levels of Sildenafil . A starting oral dose of 25 mg should be considered in those patients. (PDR 2002)
Sildenafil is indicated for the treatment of erectile dysfunction. (PDR 2002)
Erectile dysfunction that is medication – induced or caused by endocrine problems , such as hypogonadism or hypothyroidism, or hyperthyroidism should be evaluated and appropriately treated before Sildenafil treatment is considered. (USP DI 2001)
Consistent with its known effects on the nitric oxide /cGMP pathway Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration to patients who are using organic nitrates, either regularly and / or intermittently, in any form is therefore contraindicated. After patients have taken Sildenafil , it is unknown when nitrates , if necessary , can be safely administered . Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet . (PDR 2002)
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore , treatments for erectile dysfunction, including Sildenafil should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.
Sildenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg),while this normally would be expected to be of little consequence in most patients , prior to prescribing Sildenafil physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. There is no controlled clinical data on the safety or efficacy of Sildenafil in the following groups : If prescribed , this should be done with caution. •Patients who have suffered a myocardial infarction, stroke , or life- threatening arrhythmia within the last 6 months .
Patients with resting hypotension ( BP <90/50 ) or hypertension (BP> 170/110).
Patients with cardiac failure or coronary artery disease causing unstable angina .
Patients with retinitis pigmentosa ( a minority of these patients have genetic disorders of retinal phosphodiesterases) .
Prolonged erection greater than 4 hours and priapism ( painful erections greater than 6 hours in duration ) have been reported infrequently since market approval of Sildenafil . In the event of an erection that persists longer than 4 hours , the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.
The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of Sildenafil (11–fold increase in AUC) . If Sildenafil is prescribed to patients taking ritonavir, caution should be used . Data from subjects exposed to high systemic levels of Sildenafil are limited. Visual disturbances occurred more commonly at higher levels of Sildenafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of Sildenafil ( 200-800 mg ) . To decrease the chance of adverse events in patients taking ritonavir, a decrease in Sildenafil dosage is recommended.
Pregnancy , Nursing Mothers and Pediatric Use:
Sildenafil is not indicated for use in newborns , children , or women .
Healthy elderly volunteers ( 65 years of over ) had a reduced clearance of Sildenafil .Since higher plasma levels may increase both the efficacy and incidence of adverse events , a starting dose of 25 mg should be considered. ( PDR 2002)
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assesment. Before prescribing Sildenafil , it is important to note the following : Patients on multiple antihypertensive medications were included in the pivotal clinical trials for Sildenafil . In a separate drug interaction study , when amlodipine, 5 mg or 10 mg , and Sildenafil , 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted. Controlled studies of drug interactions between Sildenafil and other antihypertensive medications have not been performed. The safety of Sildenafil is unknown in patients with bleeding disorders and patients with active peptic ulceration.
Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease),or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). The safety and efficacy of combinations of Sildenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
In humans, Sildenafil has no effect on bleeding time when taken alone or with aspirin. ( PDR 2002)
Information for patients:
Physicians should discuss with patients the contraindication of Sildenafil with regular and / or intermittent use of organic nitrates.
Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms(e.g,angina pectoris, dizziness,nausea ) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician.
Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Sildenafil . In the event of an erection that persists longer than 4 hours , the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
The use of Sildenafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV) , may be considered. (PDR 2002)
Concurrent use of other impotence therapy agents is not presently recommended. (USP DI 2001)
Cimetidine (800 mg),a nonspecific CYP inhibitor , caused a 56% increase in plasma Sildenafil concentrations when coadministered with Sildenafil (50 mg ) to healthy volunteers . When a single 100 mg dose of Sildenafil was administered with erythromycin,a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days) , there was a 182% increase in Sildenafil systemic exposure ( AUC ) . In addition , in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor , at steady state (1200 mg tid ) with Sildenafil (100 mg single dose ) resulted in a 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in Sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) . In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Sildenafil(100 mg single dose) resulted in a 300% (4 – fold )increase in Sildenafil Cmax and a 1000% (11- fold ) increase in Sildenafil plasma AUC. At 24 hours the plasma levels of Sildenafil were still approximately 200 ng/ml,compared to approximately 5 ng/ml when Sildenafil was dosed alone . This is consistent with ritonavir’s marked effect on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics.
Although the interaction between other protease inhibitors and Sildenafil has not been studied, their concomitant use is expected to increase Sildenafil levels.
It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of Sildenafil. Single doses of antacid (magnesium hydroxide /aluminum hydroxide) did not affect the bioavailability of Sildenafil .
Pharmacokinetic data from patients in clinical trials showed no effect on Sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide , warfarin), CYP2D6 inhibitors(such as selective serotonin reuptake inhibitors, tricyclic antidepressants),thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N- desmethyl Sildenafil was increased 62% by loop and potassium – sparing diuretics and 102% by nonspecific beta–blockers. These effects on the metabolite are not expected to be of clinical consequence. When Sildenafil 100 mg oral was coadministered with amlodipine, 5 mg or 10 mg oral , to hypertensive patients , the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg) , both of which are metabolized by CYP2C9 . Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg) .
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08% . In a study of healthy male volunteers, Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir , both of which are CYP3A4 substrates. Sildenafil potentiates the hypotensive effect of nitrates including nitroglycerin. (PDR 2002)
Pre – Marketing Experience:
The adverse events were generally transient and mild to moderate in nature.
In fixed–dose studies, the incidence of some adverse events increased with dose . The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage regimen,was similar to that for fixed–dose studies.When Sildenafil was taken as recommended in flexible dose, the following adverse events were reported:
Headache, flushing, dyspepsia, nasal congestion, urinary tract infection, abnormal vision, diarrhea , dizziness , rash. In fixed–dose studies , dyspepsia (17%) and abnormal vision (11%) were more common at 100 than at lower doses.At doses above the recommended dose rang, adverse events were similar to those detailed above but generally were reported more frequenly . (PDR 2002)
Post – Marketing Experience:
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and hypertension,have been reported post – marketing in temporal association with the use of Sildenafil .
Most,but not all, of these patients had preexisting cardiovascular risk factors.
Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Sildenafil, without sexual activity. Others were reported to have occurred hours to days after the use of Sildenafil and sexual activity .
Other events reported post–marketing to have been observed in temporal association with Sildenafil and not listed in the pre–marketing adverse reactions section above include.
Seizure and anxiety .
Prolonged erection , priapism and hematuria.
Diplopia,temporary vision loss/decreased vision ocular redness or bloodshot appearance , ocular burning ocular swelling/pressure, increased intraocuar pressure,retinal vascular disease or bleeding,vitreous detachment/traction and paramacular edema. (PDR 2002)
Dosage and Administration:
Usual adult dose:
50 mg (base) one hour (range , one half to four hours) before sexual intercourse once a day if needed .As tolerated, subsequent doses may be increased to 100 mg or decreased to 25 mg once a day .
Usual adult prescribing limits :
100 mg once a day .
Usual geriatric dose:
Oral , 25 mg (base) one hour ( range,one half to four hours ) before sexual intercourse once a day if needed , as tolerated , subsequent doses may be increased . (USP DI 2001)
Store below at 30 º C .
Sildenafil 100 mg is available as blue,scored, barrel–shaped , film coated tablets in boxes of 2 .
1- PDR 2002
2-USP DI 2001
Tamsulosin Hcl is (-)-5-[2-[[2-(0-ethoxyphenoxy) ethyl] amino] propyl]-2- methoxybenzenesulfonamide, monohydrochloride. Its empirical formula is C20 H28 N2 O5 S.Hcl MW=448.98
Absorption: More than 90% Distribution: Animal syudies have found that tamsulosin is widely distributed to most tissues. It is minimally distributed into the brain, spinal cord and testes. Protein binding: Very high (94-99%) Biotrasformation: Tamsulosin is extensively metabolized by cytochrme P450 enzymes in the liver with <10% of the dose excerted in the urine unchanged.The metabolites undergo extensive conjugation to glucuronide or sulfate prior to renal excretion. Half life: Healthy individuals (fasting state): 9-13 hours. Target population : 14-15 hours. Time to peak concentration: 4-5 hours under fasting conditions and 6-7 hours when administered with food. Elimination: After 168 hours 76% of dose is recovered in the urine and 21% is recovered in the feces.
Mechanism of action:
Tamsulosin is an alpha-adrenegic blocking agen exhibiting selectivity for alpha receptors in the human prostate. Relaxation of smooth muscle in the bladder neck and prostate produced by alpha-adrenergic blockade results in improvement in urine flow rate and a reduction in symptoms of BPH.
Tamsulosion is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia(BPH)
Tamsulosin capsules are contraindicated in patients known to be hypersensitive to tamsulosin Hcl or any component of tamsulosin capsules.
Pregnancy and breast feeding:
Tamsulosin is not indicated for use in women. FDA Pregnancy category B.
Carcinoma of the prostate: Carcinoma of the prostate and BPH cause many of the same symptoms. These two disease frequently coexist. Patients should be evaluated parior to the start of tamsulosin capsules therapy to rule out the presence of carcinoma of the prostate.
Alpha-adrenergic blocking agents, other, such as doxazosin, phentolmine, prazosin and terazosin (concurrent administration may produce an additive effect). Cimetidin: Concurrent administration resulted in a 26% decrease in the clearance of tamsulosin and a 44% increase in tamsulosin AUC. Warfarin: Caution shpuld be exercised with concurrent administration because of inconclusive results from in vitro and in vivo studies.
Those indicating need for medical attention only if they continue or are bothersome: Incidence more frequent: Abnormal ejaculation, asthenia, black pain, diarrhea, dizziness, headache, rhinitis. Incidence less frequent: Chest pain, decresed libido, drowsiness, insomnia, nausea, orthostatic hypotension.
For more information on the management of overdose or unintentional ingestion, contact a poison control center.
Before using this drug:
Conditions affecting use, especially: Sensivity to tamsulosin or any component. Other medications especially alpha-adrenergic blocking agents or warfarin.
Proper use of theis medication:
Taking at the same time each day to help increase compliance. Not crushing, chewing or opening capsules, unless otherwise directed by a physician.
Missed dose : Taking as soon as Possible, not taking if almost time for next dose, not doubling doses.
Dosage and administration:
Usual adult dose: Oral, 0.4 mg once a day, approzimately one-half hour after the same meal each day. If there is no response after two to four weeks, the dose may be increased to 0.8 mg once a day
Packaging and storge:
Store below 30 c
Each film coated tablet contains 10 mg of Tadalafil .
Mechanism of Action :
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells . Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by Tadalafil has no effect in the absence of sexual stimulation . [PDR 2007]
Tadalafil is well absorbed after a dose by mouth . Peak plasma concentration are attained within 2 hours . The rate of absorption is not affected by food. Tadalafil is widely distributed into tissues and is approximately 94% bound to plasma proteins . It is metabolised in the liver primarily by the cytochrome P450 isoenzyme CYP3A4 . The major metabolite, the methylcatechol glucuronide, is inactive . The mean half- life of Tadalafil is about 17.5 hours . Tadalafil is excreted, predominantly as metabolites, in the feces (61% of the dose ) and to a lesser extent the urine (36% of the dose) . Clearance may be reduced in the elderly and in patients with renal impairment . [Martindale 2007]
Tadalafil is indicated for the treatment of erectile dysfunction. [PDR 2007]
Tadalafil should be used with caution in cardiovascular diseases, anatomical deformation of the penis (e.g.angulation, cavernosal fibrosis, peyronie’s disease) and in those with a predisposition to prolonged erection. Tadalafil also should be used with caution in hepatic and renal impairment . [BNF 2006]
There are no adequate and well controlled studies of Tadalafil in pregnant women . It is not indicated for use in women . [PDR 2007]
Breast feeding :
Use of Tadalafil in nursing mothers is not recommended . [PDR 2007]
Drug interactions :
– Cytochrom P450 inhibitors : Ketoconazole, HIV protease inhibitors (such as ritonavir), erythromycin, itraconazole, grapefruit juice . – Cytochrom P450 inducers : Rifampin, carbamazepine, phenytoin, phenobarbital – Antacids – Alcohol – Anti-hypertensives : α- blockers ( Doxazosin, Tamsulosin), Amlodipine, Metoprolol, Enalapril (PDR 2007)
– Tadalafil is contraindicated for patients with a known hypersensitivity to Tadalafil or any component of the tablet . [PDR 2007] – Administration with nitrates and nitric oxide donors – Coadministration with alpha-blockers other than 0.4 mg/day Tamsulosin. [Fact 2007] – Hypotension , recent stroke, unstable angina , myocardial infarction, moderate heart failure , uncontrolled arrhythmias, uncontrolled hypertension. [BNF 2006]
– Priapism – Cardiovascular The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy : – Patients with an MI within the last 90 days – Patients with unstable angina or angina occurring during sexual intercourse. – Patients with New York Heart Association class 2 or greater heart failure in the last 6 months . – Patients with uncontrolled arrhythmias , hypotension (BP less than 90/50 mm Hg) or uncontrolled hypertension (BP greater than 170/100 mm Hg) – Patients with a stroke within the last 6 months . [Fact 2007]
Adverse Reactions :
– Cardiovascular : Hypertension , MI – CNS : Dizziness – Dermatologic : Rash – GI : Diarrhea , gastroesophageal reflux, GGTP increased, loose stools, nausea , upper abdominal pain . – Gu : Erection increased, spontaneous penile erection . – Musculoskeletal : Arthralgia, neck pain . – Respiratory : Epistaxis , dyspnea , pharyngitis . Special senses : Conjunctivitis , eye pain , blurred vision , conjunctival hyperemia , eyelid swelling , lacrimation increased , change in color vision . Miscellaneous : Asthenia , face edema, pain, fatigue [Fact 2007]
Dosage and administration :
The recommended starting dose of Tadalafil in most patients is 10mg, taken prior to anticipated sexual activity . The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability . The maximum recommended dosing frequency is once per day . Tadalafil may be taken without regard to food . [PDR 2007]
Store below 30° C. [PDR 2007]
How Supplied :
Tadalafil 10 mg is available as brown, barrel-shape film-coated tablet. There are blisters of 4’s, boxes of one blister.
Martindale, 2007 PDR, 2007 Fact, 2007 USP DI, 2005 BNF, 2006
Chemically it is [( + )- 5 – [[ 4 – [ 2 – ( 5 – ethyl – 2 – pyridinyl) ethoxy]phenyl]methyl-2,4-]thiazolidinedione monohydrochloride . The empirical formula is c19H20N2O3S.HCl and a molecular weight of 392.90 .
- Absorption : Rapid
- Distribution:0.63 L/kg
- Protein binding : Very high (>99%)
- Biotransformation:Pioglitazone is extensively metabolized in the liver to several active metabolites. Cytochrome (CYP ) P450 iso forms involved in the hepatic metabolism of pioglitazone are cyP2C8 and cyP3A4 .
- Half – life :3-7 hours
- Time to peak concentration :2 hours .
- Elimination:It is assumed that most of a dose is excreted into bile as active drug or metabolites and is eliminated in the feces. Renal : 5 –30%
Mechanism of actions :
Pioglitazone is a thiazolidinedione antidiabetic agent that is effective only in the presence of insulin. Its primary action is to decrease insulin resistance at peripheral sites and in the liver , resulting in increased insulin – dependent glucose disposal and decreased hepatic glucose output.
These effects are accomplished through selective binding at the peroxisome proliferator – activated receptor – gamma, which is found in adipose tissue ,skeletal muscle, and the liver. Activation of these receptors modulates transcription of several insulin – responsive genes that control glucose and lipid metabolism . Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. (USP DI 2007)
Indications and usage :
Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Pioglitazone is indicated for monotherapy. Pioglitazone is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control . Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.
Pioglitazone is indicated in patients with known hypersensitivity to this product or any of its components.
FDA Pregnancy Category C.
It is recommended that insulin alone be used during pregnancy for maintenance of blood glucose concentrations that are as close to normal as possible.Abnoraml maternal blood glucose concentrations have been associated with a higher incidence of congenital anomalies and increased neonatal morbidity and mortality. (USP DI 2007)
Nursing mothers: Pioglitazone is not recommended for use by nursing mothers. (USP DI 2007)
- Precaution: – Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore pioglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
- Hypoglycemia: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.
- Ovulation: Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women . Then ,these patients may be at an increased risk for pregnancy .
- Hematologic: Pioglitazone may cause decreses in hemoglobin and hematocrit.
- Edema: Pioglitazone should be used with caution in patients with edema.
- Cardiac: In preclinical studies pioglitazone cause plasma volme expansion and pre- load – induced cardiac hypertrophy .
- Hepatic effects: Therapy with pioglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal .
Drug interactions :
1 – Oral contraceptives
2 – Glipizide
3 – Digoxin
4 – Warfarin
5 – Ketoconazole
Adverse effects :
Those indicating need for medical attention :
- Incidence more frequent : Tooth disorders (5.3%)
- Incidence less frequent : Peripheral edema (4.8%)
- Incidence more frequent : Headache (9.1%) , myalgia (5.4%) pharyngitis ( 5.1%) , sinusitis ( 6.3%) , upper respiratory tract infection (13.2%)
Those indicating need for medical attention only if they continue or are bothersome .
دFor more information on the management of over dose or unintentional ingestion, contact a poison control center .
Dosage and administration :
Usual adult dose :
- – As monotherapy : Oral initially 15 or 30 mg once a day the dose may be increased in increments up to 45 mg once daily.
- – In combination with insulin . Oral , initially 15 or 30 mg once daily.
- – In combination with metformin: Oral , initially 15 or 30 mg once dialy.
- – In combination with sulfonylurea : Oral, initially 15 or 30 mg once daily.
Usual adult prescribing limits :
45 mg daily .
Usual pediatric dose :
Safety and efficacy have not been established.
Packaging and storage :
- Store below 30ºC in a tightly closed container. Protect from moisture and humidity .
- Keep out of children .
Antiacid , Antihyperphosphatemic
Each tablet contains Aluminum hydroxide 300 mg
Al ( OH ) 3
Absorption : small amounts of the aluminum in aluminum hydroxide are absorbed from the intestine .
Onset and duration of action : Slow , prolonged
Elimination : Renal and fecal ; 15 to 30 % of the salts formed are absorbed and are then excreted by the kidneys.
Mechanism of action :
- Antacid – these medications react chemically to neutralize or buffer existing quantities of stomach acid but have no direct effect on its output. This action results increased pH value of stomach contents , thus providing relief of hyperacidity symptoms . Also , these medications reduce acid concentration within the lumen of the esophagus . This causes an increase in intra-esophageal pH and a decrease in pepsin activity .
- Antihyperphosphatemic – Aluminum hydroxide reduce serum phosphate levels by binding with phosphate ions in the intestine to form insoluble aluminum phosphate , which passes through the intestinal tract unabsorbed .
- Antihypocalcemic – Aluminum hydroxide may increase the release of calcium from bone as a result of the decreased serum phosphate levels .
- Antidiarrheal – Aluminum hydroxideۥs constipating properties help decrease the fluidity of stools .
Indications and usage :
- For Antacid use : the dose of antacid needed to neutralize gastric acid varies among patients , depending on the amount of acid secreted and the buffering capacity of the particular preparation . It is estimated that 99% of the gastric acid will be neutralized when a gastric pH of 3.3 is achieved .
- For use in peptic ulcer : In the treatment of peptic ulcer disease , to achieve adequate antacid effect in the stomach at the optimum time , most antacids are administered 1 and 3 hours after meals for prolonged acid-neutralizing effect and at bedtime.However,when taken at bed time , their affect is not prolonged because of rapid gastric emptying. Additional doses of antacids may be administered to relieve the pain that may occur between the regularly scheduled doses. Antacid therapy should be continued for at least 4 to 6 weeks after all symptoms have disappeared , since there is no correlation between disappearance of symptoms and actual healing of the ulcer .
- For antihyper phosphatemic use .
– This medication should not be used when intestinal obstruction exist .
– Risk-benefit should be considered when the following medical problems exist :
1) Alzheimerۥs disease ( may be exacerbated )
3) Bleeding , gastrointestinal or rectal , undiagnosed
4) Bone fractures Aluminum hydroxide has the ability to form the insoluble complex of aluminum phosphate , which is excreted in the feces . This may lead to lowered serum phosphate concentrations and phosphorus mobilization from the bone .
5) Constipation or fecal impaction
6) Chronic diarrhea( possible increase danger of phosphate depletion with aluminum containing antacids )
7) Gastric outlet obstruction
10) Renal function impairment
11) Sensitivity to aluminium
Pregnancy : Antacide are generally considered safe as long as chronic high doses are avoided .
Breast feeding : problems in humans have not been documented; although some aluminum may be distributed into breast milk , the concentration is not great enough to produce an effect in the neonate .
pediatrices : Antacids should not be given to young children (up to 6 years of age ) unless prescribed by a physician . Since children are not usually able to describe their symptoms precisely , proper diagnosis should precede the use of an antacid .
Use of aluminum-containing antacids is contraindicated in very young children because there is a risk of aluminum toxicity,especially in dehydrated infants and children or infants and children with renal failure .
Geriatrics : Metabolic bone disease commonly seen in the elderly may be aggravated by the phosphorus depletion , hypercalciuria and inhibition of absorption of intestinal fluoride caused by the chronic use of aluminum containing antacids. Also , elderly patients are more likely to have age related renal function or impairment , which may lead to aluminum retention .
Although it is not known whether high intake of aluminum leads to Alzheimer’s disease , the use of aluminum – containing antacids in Alzheimer’s patients is not generally recommended .
- Acidifiers , urinary such as : Ammonium chloride , Ascorbic acid potassium or sodium phosphate , Racemethionine .
- Amphetamines or Quinidine
- Anticholinergics or other medications with anticholinergic activity .
- Digitalis glycosides
- Enteric coated medications such as bisacodyl
- Folic acid
- Histamine H2 – receptor antagonists
- Iron preparations ( oral )
- Izoniazide ( oral )
- Phosphate , (oral )
- Sodium fluoride
- Tetracycline ( oral )
Adverse reactions :
- – With long – term use in chronic renal failure in dialysis patients ( Neuorotoxicity )
- With large doses : fecal impaction , swelling of feet or lower legs .
- with long – term use : hypercalcemia associated with milk alkali syndrome , Osteomalacia and osteoporosis due to phosphat depletion,
- phosphorus depletion syndrome.
- Chalky taste
- stomach cramps
Dosage and administration :
For use in peptic ulcer :
In the treatment of peptic ulcer disease , to achieve adequate antacid effect in the stomach at the optimum time , most antacids are administered 1 and 3 hours after meats for prolonged acid-neutralizing effect and at bedtime .
In the treatment of peptic ulcer , 960 mg to 3.6 grams are given orally every one or two hours during waking hours , the dosage being adjusted as needed . For extremely severe symptoms of peptic ulcer ( hospitalized patients ) , 2.6 to 4.8 grams diluted with two to three parts of water may be given intragastrically every thirty minutes for periods of twelve or more hours a day .
For antihyper phosphatemic use :
1.9 to 4.8 grams of aluminum hydroxide are given orally three or four times a day in conjunction with dietary phosphate restriction . In children, a does of 50 to 150 mg/kg of body weight is given in four to six divided doses in conjunction with dietary phosphate restriction .
Store below 30° C . in a well-closed container . Protect from moisture .
USP DI 2004