Ramipril 10mg Tablet

1. Name Of The Medicinal Product

Ramipril 10mg tablet

2. Qualitative And Quantitative Composition

Ramipril 10mg tablets contain 10mg ramipril per tablet

For excipients, see 6.1

3. Pharmaceutical Form

Tablet

Ramipril 10mg: oblong shaped tablet (15 x 6.5mm), white, scoreline on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

      • manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

      • diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

      • Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

      • Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

      • Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use.

It is recommended that Ramipril is taken each day at the same time of the day.

Ramipril can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2). Ramipril has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with Ramipril; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Ramipril (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with Ramipril should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Ramipril should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

Ramipril may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

Ramipril should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of Ramipril is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of Ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg Ramipril once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of Ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of Ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg Ramipril after one or two weeks and then to 10 mg Ramipril after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of Ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

Ramipril should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with Ramipril must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg Ramipril.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

Ramipril is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

• Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

• History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

• Significant bilateral renal artery stenosis or renal artery stenosis in a single functioningkidney

• 2^nd and 3^rd trimester of pregnancy (see sections 4.4 and 4.6)

• Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

      • Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

      - patients with severe hypertension

      - patients with decompensated congestive heart failure

      - patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

      - patients with unilateral renal artery stenosis with a second functional kidney

      - patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

      - patients with liver cirrhosis and/or ascites

      - patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

- Transient or persistent heart failure post MI

- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

      • Elderly patients

See section 4.2.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, Ramipril must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including Ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of Ramipril should be considered prior to desensitization.

Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including Ramipril. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Ramipril: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of Ramipril is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

Ramipril is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Common	Uncommon	Rare	Very rare	Not known
Cardiac disorders		Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral
Blood and the lymphatic system disorders		Eosinophilia	White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased		Bone marrow failure, pancytopenia, haemolytic anaemia
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, ageusia, dysgeusia,	Tremor, balance disorder		Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia
Eye disorders		Visual disturbance including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impaired, tinnitus
Respiratory, thoracic and mediastinal disorders	Non-productive tickling cough, bronchitis, sinusitis, dyspnoea	Bronchospasm including asthma aggravated, nasal congestion
Gastrointestinal disorders	Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting	Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth	Glossitis		Aphtous stomatitis
Renal and urinary disorders		Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased
Skin and subcutaneous tissue disorders	Rash in particular maculopapular	Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis,	Photosensitivity reaction	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia
Musculoskeletal, connective tissue and bone disorders	Muscle spasms, myalgia	Arthralgia
Metabolism and nutrition disorders	Blood potassium increased	Anorexia, decreased appetite,			Blood sodium decreased
Vascular disorders	Hypotension, orthostatic blood pressure decreased, syncope	Flushing	Vascular stenosis, hypoperfusion, vasculitis		Raynaud's phenomenon
General disorders and administration site conditions	Chest pain, fatigue	Pyrexia	Asthenia
Immune system disorders					Anaphylactic or anaphylactoid reactions, antinuclear antibody increased
Hepatobiliary disorders		Hepatic enzymes and/or bilirubin conjugated increased,	Jaundice cholestatic, hepatocellular damage		Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).
Reproductive system and breast disorders		Transient erectile impotence, libido decreased			Gynaecomastia
Psychiatric disorders		Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence	Confusional state		Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE study: Main results

	Ramipril	Placebo	relative risk (95% confidence interval)	p-value
%	%
All patients	N = 4,645	N = 4,652
Primary combined events	14.0	17.8	0.78 (0.70-0.86)	< 0.001
Myocardial infarction	9.9	12.3	0.80 (0.70-0.90)	< 0.001
Death from cardiovascular causes	6.1	8.1	0.74 (0.64-0.87)	< 0.001
Stroke	3.4	4.9	0.68 (0.56-0.84)	< 0.001
Secondary endpoints
Death from any cause	10.4	12.2	0.84 (0.75-0.95)	0.005
Need for Revascularisation	16.0	18.3	0.85 (0.77-0.94)	0.002
Hospitalisation for unstable angina	12.1	12.3	0.98 (0.87-1.10)	NS
Hospitalisation for heart failure	3.2	3.5	0.88 (0.70-1.10)	0.25
Complications related to diabetes	6.4	7.6	0.84 (0.72-0.98)	0.03

The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least

The primary analysis showed that 117 (6.5 %) participants on ramipril and 149 (8.4 %) on placebo developed overt nephropathy, which corresponds to a RRR 24 %; 95 % CI [3-40], p = 0.027.

The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at assessing the effect of treatment with ramipril on the rate of decline of glomerular function rate (GFR) in 352 normotensive or hypertensive patients (18-70 years old) suffering from mild (i.e. mean urinary protein excretion > 1 and < 3 g/24 h) or severe proteinuria (

The main analysis of patients with the most severe proteinuria (stratum prematurely disrupted due to benefit in ramipril group) showed that the mean rate of GFR decline per month was lower with ramipril than with placebo; -0.54 (0.66) vs. -0.88 (1.03) ml/min/month, p = 0.038. The intergroup difference was thus 0.34 [0.03-0.65] per month, and around 4 ml/min/year; 23.1 % of the patients in the ramipril group reached the combined secondary endpoint of doubling of baseline serum creatinine concentration and/or end-stage renal disease (ESRD) (need for dialysis or renal transplantation) vs. 45.5 % in the placebo group (p = 0.02).

Secondary prevention after acute myocardial infarction

The AIRE study included more than 2,000 patients with transient/persistent clinical signs of heart failure after documented myocardial infarction. The ramipril treatment was started 3 to 10 days after the acute myocardial infarction. The study showed that after an average follow-up time of 15 months the mortality in ramipril-treated patients was 16.9 % and in the placebo treated patients was 22.6 %. This means an absolute mortality reduction of 5.7 % and a relative risk reduction of 27 % (95 % CI [11-40 %]).

5.2 Pharmacokinetic Properties

Pharmacokinetics and Metabolism

Absorption

Following oral administration ramipril is rapidly absorbed from the gast

Fluconazole Injection

Dosage Form: injection
Fluconazole Injection USP,

For Intravenous Infusion Only.

Fluconazole Injection Description

Fluconazole, USP, the first of a new subclass of synthetic triazole antifungal agents, is available as a sterile solution for intravenous use in glass and in plastic containers.

Fluconazole, USP is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The structural formula is:

Fluconazole, USP is a white crystalline solid which is slightly soluble in water and saline.

Fluconazole Injection USP is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole, USP and 9 mg of sodium chloride, USP. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent. Injection volumes of 100 mL and 200 mL are packaged in glass and in plastic containers.

The plastic container is fabricated from a specially formulated medical grade film (Cryovac® M312 Pharmaceutical Solution Film). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Fluconazole Injection - Clinical Pharmacology

Pharmacokinetics and Metabolism

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean Cmax of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50 to 400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration time curve) are dose proportional.

The Cmax and AUC data from a food effect study involving administration of fluconazole tablets to healthy volunteers under fasting conditions and with a high fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole may be taken without regard to meals. (See DOSAGE AND ADMINISTRATION.)

Administration of a single oral 150 mg tablet of fluconazole to ten lactating women resulted in a mean Cmax of 2.61 mcg/mL (range: 1.57 to 3.65 mcg/mL).

Steady state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11 to 12%).

Following either single or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue: plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid: plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

Tissue or Fluid	Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration *
* Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation.
Cerebrospinal fluid†	0.5 to 0.9
Saliva	1
Sputum	1
Blister fluid	1
Urine	10
Normal skin	10
Nails	1
Blister skin	2
Vaginal tissue	1
Vaginal fluid	0.4 to 0.7

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.

The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. (SeeDOSAGE AND ADMINISTRATION.) A 3 hour hemodialysis session decreases plasma concentrations by approximately 50%.

In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response.

Pharmacokinetics in Children

In children, the following pharmacokinetic data {Mean(%cv)} have been reported:

Age Studied	Dose (mg/kg)	Clearance (mL/min/kg)	Half-life (Hours)	Cmax (mcg/mL)	Vdss (L/kg)
9 Months to 13 years	Single-Oral 2 mg/kg	0.40 (38%) N = 14	25	2.9 (22%) N = 16	—
9 Months to 13 years	Single-Oral 8 mg/kg	0.51 (60%) N = 15	19.5	9.8 (20%) N = 15	—
5 to 15 years	Multiple IV 2 mg/kg	0.49 (40%) N = 4	17.4	5.5 (25%) N = 5	0.722 (36%) N = 4
5 to 15 years	Multiple IV 4 mg/kg	0.59 (64%) N = 5	15.2	11.4 (44%) N = 6	0.729 (33%) N = 5
5 to 15 years	Multiple IV 8 mg/kg	0.66 (31%) N = 7	17.6	14.1 (22%) N = 8	1.069 (37%) N = 7

Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg.

In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N = 7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N = 9) mL/min/kg six days later and 0.333 (56%, N = 4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later.

Pharmacokinetics in Elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg∙h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax.

In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0 to 24 hr, 22 %) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group.

A plot of each subject's terminal elimination half-life versus creatinine clearance compared with the predicted half-life – creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life – creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly.

Drug Interaction Studies

Oral contraceptives

Oral contraceptives were administered as a single dose both before and after the oral administration of fluconazole 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of fluconazole. The mean increase in ethinyl estradiol AUC was 6% (range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).

In a second study, twenty-five normal females received daily doses of both 200 mg fluconazole tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%). Both of these increases were statistically significantly different from placebo.

A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18 to 31%) and 13% (95% C.I. range 8 to 18%), respectively, relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC values of norethindrone decreased very slightly (< 5%) in 3 of the 21 subjects after fluconazole treatment.

Cimetidine

Fluconazole 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased 19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers.

Antacid

Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to a single dose of fluconazole 100 mg had no effect on the absorption or elimination of fluconazole.

Hydrochlorothiazide

Concomitant oral administration of 100 mg fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean ± SD increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31% (range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in renal clearance of 30% ± 12% (range: –10 to –50%).

Rifampin

Administration of a single oral 200 mg dose of fluconazole after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (SeePRECAUTIONS.)

Warfarin

There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral fluconazole 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). (SeePRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects experienced a 2 fold increase in his prothrombin time response.

Phenytoin

Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral fluconazole 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC.

The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. (SeePRECAUTIONS.)

Cyclosporine

Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24 hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased 60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (SeePRECAUTIONS.)

Zidovudine

Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC was 20% ± 32% (range: –27 to 104%).The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.

Theophylline

The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17% (range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (SeePRECAUTIONS.)

Terfenadine

Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg and 800-mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.)

Oral hypoglycemics

The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of fluconazole 100 mg daily for 7 days. In these three studies, 22/46 (47.8%) of fluconazole treated patients and 9/22 (40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (SeePRECAUTIONS.)

Tolbutamide

In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax increased 11% ± 9% (range: –6 to 27%). (SeePRECAUTIONS.)

Glipizide

The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean ± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23% (range: –11 to 79%). (SeePRECAUTIONS.)

Glyburide

The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean ± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19% (range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. (SeePRECAUTIONS.)

Rifabutin

There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (SeePRECAUTIONS.)

Tacrolimus

There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (SeePRECAUTIONS.)

Cisapride

A placebo-controlled, randomized, multiple dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (SeeCONTRAINDICATIONSandPRECAUTIONS.)

Midazolam

The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam.

A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. (SeePRECAUTIONS.)

Azithromycin

An open label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Voriconazole

Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes. Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 h of the last dose of fluconazole. (See PRECAUTIONS.)

Microbiology

Mechanism of Action

Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition.

Activity In Vitro and In Clinical Infections

Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.

Candida albicans

Candida glabrata (Many strains are intermediately susceptible)*

Candida parapsilosis

Candida tropicalis

Cryptococcus neoformans

*In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint (≥ 16 mcg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 mcg/mL, see Table 1), the highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative therapy is recommended.

The following in vitro data are available, but their clinical significance is unknown.

Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 mcg/mL or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Candida dubliniensis

Candida guilliermondii

Candida kefyr

Candida lusitaniae

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

Susceptibility Testing Methods

Cryptococcus neoformans and filamentous fungi

No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi.

Candida species

Broth Dilution Techniques

Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided inTable 1.

Diffusion Techniques

Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 mcg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided inTable 1.

Table 1: Susceptibility Interpretive Criteria for Fluconazole

	Broth Dilution at 48 hours (MIC in mcg/mL)			Disk Diffusion at 24 hours (Zone Diameters in mm)
Antifungal agent	Susceptible (S)	Intermediate (I) *	Resistant (R)	Susceptible (S)	Intermediate (I) *	Resistant (R)
* The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. † Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale.
Fluconazole†	≤ 8	16 to 32	≥ 64	≥ 19	15 to 18	≤ 14

The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 mcg disks should provide the following range of values noted in Table 2.

NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results

QC Strain	Macrodilution (MIC in mcg/mL) @ 48 hours	Microdilution (MIC in mcg/mL) @ 48 hours	Disk Diffusion (Zone Diameter in mm) @ 24 hours
* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies.
Candida parapsilosis ATCC 22019	2 to 8	1 to 4	22 to 33
Candida krusei ATCC 6258	16 to 64	16 to 128	*
Candida albicans ATCC 90028	*	*	28 to 39
Candida tropicalis ATCC 750	*	*	26 to 37

Activity In Vivo

Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans.

In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immuno suppressed mice. The clinical significance of results obtained in these studies is unknown.

Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.

Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Drug Resistance

Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms.

Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles.

Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell.

The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles.

Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 mcg/mL), the highest fluconazole dose is recommended.

Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

Indications and Usage for Fluconazole Injection

Fluconazole Injection USP is indicated for the treatment of:

1. Vaginal candidiasis (vaginal yeast infections due to Candida).


2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.


3. Cryptococcal meningitis. Before prescribing fluconazole for AIDS patients with cryptococcal meningitis, please seeCLINICAL STUDIESsection. Studies comparing fluconazole to amphotericin B in non-HIV infected patients have not been conducted.

Prophylaxis

Fluconazole is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Clinical Studies

Cryptococcal meningitis

In a multicenter study comparing fluconazole (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality among high risk patients was 33% and 40% for amphotericin B and fluconazole patients, respectively (p = 0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p = 0.48). Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et al. N Engl J Med 1992; 326:83–9.)

Vaginal candidiasis

Two adequate and well-controlled studies were conducted in the U.S. using the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month posttreatment evaluation.

The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal products group.

	Fluconazole PO 150 mg tablet	Vaginal Product qhs × 7 days
Enrolled	448	422
Evaluable at Late Follow-up	347 (77%)	327 (77%)
Clinical cure	239/347 (69%)	235/327 (72%)
Mycologic eradication	213/347 (61%)	196/327 (60%)
Therapeutic cure	190/347 (55%)	179/327 (55%)

Approximately three-fourths of the enrolled patients had acute vaginitis (< 4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg fluconazole tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (≥ 4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis.

Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group. Most of the events were mild to moderate. Because fluconazole was given as a single dose, no discontinuations occurred.

Zithromax Intravenous

Generic Name: azithromycin (Intravenous route)

ay-zith-roe-MYE-sin

Commonly used brand name(s)

In the U.S.

• Zithromax

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antibiotic

Chemical Class: Macrolide

Uses For Zithromax

Azithromycin injection is used to treat bacterial infections in many different parts of the body. It is also used to prevent Mycobacterium avium complex (MAC) disease in patients infected with the human immunodeficiency virus (HIV).

Azithromycin belongs to the class of drugs known as macrolide antibiotics. It works by killing bacteria or preventing their growth. However, this medicine will not work for colds, flu, or other virus infections. Azithromycin injection may be used for other problems as determined by your doctor.

This medicine is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, azithromycin is used in certain patients with the following medical condition:

• Trachoma (treatment).

Before Using Zithromax

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of azithromycin injection in children and teenagers younger than 16 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of azithromycin injection in the elderly. However, elderly patients are more likely to have age-related heart problems, which may require caution in patients receiving azithromycin injection.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Cisapride


• Dihydroergotamine


• Dronedarone


• Ergoloid Mesylates


• Ergonovine


• Ergotamine


• Mesoridazine


• Methylergonovine


• Methysergide


• Pimozide


• Sparfloxacin


• Thioridazine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acecainide


• Alfuzosin


• Amiodarone


• Amitriptyline


• Amoxapine


• Apomorphine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azimilide


• Bretylium


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Dasatinib


• Desipramine


• Disopyramide


• Dofetilide


• Dolasetron


• Droperidol


• Erythromycin


• Flecainide


• Fluconazole


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Ibutilide


• Iloperidone


• Imipramine


• Lapatinib


• Levofloxacin


• Lopinavir


• Lumefantrine


• Mefloquine


• Methadone


• Moxifloxacin


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Paliperidone


• Pazopanib


• Perflutren Lipid Microsphere


• Posaconazole


• Procainamide


• Prochlorperazine


• Promethazine


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Salmeterol


• Saquinavir


• Sematilide


• Simvastatin


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Sunitinib


• Tedisamil


• Telithromycin


• Terfenadine


• Tetrabenazine


• Toremifene


• Trazodone


• Trifluoperazine


• Trimipramine


• Vandetanib


• Vardenafil


• Vemurafenib


• Voriconazole


• Ziprasidone

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atorvastatin


• Digoxin


• Fentanyl


• Lovastatin


• Nelfinavir


• Rifabutin


• Theophylline


• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Congestive heart failure or


• Diarrhea or


• Heart disease or


• Heart rhythm problems (e.g., prolonged QT interval), history of or


• Liver disease or


• Myasthenia gravis (severe muscle weakness)—Use with caution. May make these conditions worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body. .

• Liver disease, history of—Should not be used in patients with this condition.

Proper Use of Zithromax

A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins. This medicine is given slowly, so the needle will remain in place for about an hour.

Your doctor may give you a few doses of this medicine until your condition improves, and then you may be switched to an oral medicine that works the same way. If you have any concerns about this, talk to your doctor.

Precautions While Using Zithromax

Your doctor will check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it. Blood tests may be needed to check for unwanted effects.

If your symptoms do not improve within a few days, or if they become worse, check with your doctor.

This medicine may cause serious allergic reactions, including anaphylaxis, which can be life-threatening and require immediate medical attention. Call your doctor right away if you have a rash; itching; hives; hoarseness; shortness of breath; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth after you receive this medicine.

Serious skin reactions can occur with this medicine. Stop using this medicine and check with your doctor right away if you have blistering, peeling, or loosening of the skin; red skin lesions; severe acne or skin rash; sores or ulcers on the skin; or fever or chills while you are using this medicine.

Stop using this medicine and check with your doctor right away if you have pain or tenderness in the upper stomach; pale stools; dark urine; loss of appetite; nausea; unusual tiredness or weakness; or yellow eyes or skin. These could be symptoms of a serious liver problem.

Azithromycin injection may cause diarrhea, and in some cases it can be severe. It may occur 2 months or more after you stop using this medicine. Do not take any medicine to treat diarrhea without checking first with your doctor. Diarrhea medicines may make the diarrhea worse or make it last longer. If you have any questions about this or if mild diarrhea continues or gets worse, check with your doctor.

Tell your doctor if you have bleeding, blistering, burning, discoloration of the skin, itching, lumps, pain, rash, redness, or swelling at the injection site.

This medicine can cause changes in heart rhythms, such as a condition called QT prolongation. It may change the way your heart beats and cause fainting or serious side effects in some patients. Contact your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Zithromax Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Pain, redness, and swelling at the injection site

Less common

• Difficult or labored breathing


• loose stools


• shortness of breath


• tightness in the chest


• wheezing

Rare

• Abdominal or stomach cramps or pain (severe)


• abdominal or stomach tenderness


• diarrhea (watery and severe, which may be bloody)


• fever


• joint pain


• skin rash


• swelling of the face, mouth, neck, hands, and feet

Incidence not known

• Agitation


• black, tarry stools


• bleeding gums


• blistering, peeling, or loosening of the skin


• bloating


• blood in the urine or stools


• bloody or cloudy urine


• blurred vision


• chest pain or discomfort


• chills


• coma


• confusion


• constipation


• convulsions


• cough


• darkened urine


• decreased urine output


• depression


• difficulty with swallowing


• dizziness


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• fainting


• fast, pounding, or irregular heartbeat or pulse


• fever with or without chills


• general feeling of discomfort or illness


• greatly decreased frequency of urination or amount of urine


• headache


• hives


• hostility


• increased thirst


• indigestion


• irregular heartbeat recurrent


• irregular or slow heart rate


• itching


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• lethargy


• light-colored stools


• loss of appetite


• muscle pain


• muscle twitching


• nausea or vomiting


• pain


• pains in the stomach, side, or abdomen, possibly radiating to the back


• pinpoint red spots on the skin


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• rapid weight gain


• red skin lesions, often with a purple center


• red, irritated eyes


• shortness of breath


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• stupor


• sweating


• swelling of the hands, ankles, feet, or lower legs


• tightness in the chest


• unusual bleeding or bruising


• unusual tiredness or weakness


• wheezing


• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Diarrhea (mild)


• nausea


• stomach pain or discomfort (mild)


• weight loss

Less common or rare

• Acid or sour stomach


• belching


• burning feeling in the chest or stomach


• cracked lips


• excess air or gas in the stomach or intestines


• full feeling


• heartburn


• passing gas


• sleepiness or unusual drowsiness


• sore mouth or tongue


• stomach discomfort, upset, or pain


• white patches in the mouth, tongue, or throat

Incidence not known

• Attack, assault, or force


• bad, unusual, or unpleasant (after) taste


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• change in taste


• continuing ringing or buzzing or other unexplained noise in the ears


• difficulty with moving


• discoloration of the tongue


• dizziness or lightheadedness


• feeling of constant movement of self or surroundings


• hearing loss


• itching of the vagina or genital area


• lack or loss of strength


• loss of sense of smell


• muscle pain or stiffness


• pain during sexual intercourse


• sensation of spinning


• thick, white vaginal discharge with no odor or with a mild odor


• trouble sitting still

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Zithromax Intravenous side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Zithromax Intravenous resources

• Zithromax Intravenous Side Effects (in more detail)
• Zithromax Intravenous Use in Pregnancy & Breastfeeding
• Drug Images
• Zithromax Intravenous Drug Interactions
• Zithromax Intravenous Support Group
• 48 Reviews for Zithromax Intravenous - Add your own review/rating

Compare Zithromax Intravenous with other medications

• Babesiosis
• Bacterial Endocarditis Prevention
• Bacterial Infection
• Bartonellosis
• Bronchitis
• Cervicitis
• Chancroid
• COPD, Acute
• Cystic Fibrosis
• Gonococcal Infection, Uncomplicated
• Granuloma Inguinale
• Legionella Pneumonia
• Lyme Disease, Erythema Chronicum Migrans
• Mycobacterium avium-intracellulare, Prophylaxis
• Mycobacterium avium-intracellulare, Treatment
• Mycoplasma Pneumonia
• Nongonococcal Urethritis
• Otitis Media
• Pelvic Inflammatory Disease
• Pharyngitis
• Pneumonia
• Sinusitis
• Skin Infection
• Tonsillitis/Pharyngitis
• Toxoplasmosis
• Typhoid Fever
• Upper Respiratory Tract Infection

Foli-Iron Caplets

Pronunciation: VYE-ta-min/FOE-lik AS-id/EYE-urn
Generic Name: Vitamin B Complex/Vitamin C/Folic Acid/
Brand Name: Examples include Foli-Iron and I-Fol Plus

Accidental overdose of products that contain iron is a leading cause of fatal poisoning in children younger than 6 years old. Keep this and all medicines out of the reach of children. In case of accidental ingestion, call the poison control center or a doctor at once.

Foli-Iron Caplets are used for:

Preventing and treating low iron levels in the body. It may also be used for other conditions as determined by your doctor.

Foli-Iron Caplets are an iron, vitamin, and folic acid combination. It works by providing iron, vitamins, and folic acid to the body.

Do NOT use Foli-Iron Caplets if:

• you are allergic to any ingredient in Foli-Iron Caplets


• you have high levels of iron in the blood (eg, hemochromatosis, hemosiderosis)


• you have pernicious anemia

Contact your doctor or health care provider right away if any of these apply to you.

Before using Foli-Iron Caplets:

Some medical conditions may interact with Foli-Iron Caplets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have any other type of anemia (eg, hemolytic anemia)


• if you have stomach or bowel problems (eg, Crohn disease, inflammation, ulcer), metabolism problems, the blood disease porphyria, or other blood problems (eg, thalassemia)


• if you have a bleeding problem, have had multiple blood transfusions, or are receiving dialysis

Some MEDICINES MAY INTERACT with Foli-Iron Caplets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Fluorouracil because the risk of its side effects may be increased by Foli-Iron Caplets


• Doxycycline, hydantoins (eg, phenytoin), mycophenolate, penicillamine, or thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Foli-Iron Caplets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Foli-Iron Caplets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Foli-Iron Caplets:

Use Foli-Iron Caplets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Foli-Iron Caplets by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• If you also take bisphosphonates (eg, alendronate), cefdinir, methyldopa, a quinolone antibiotic (eg, ciprofloxacin), or a tetracycline antibiotic (eg, minocycline), ask your doctor or pharmacist how to take it with Foli-Iron Caplets.


• If you miss a dose of Foli-Iron Caplets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Foli-Iron Caplets.

Important safety information:

• Do not take more than the recommended dose without checking with your doctor.


• Do not take large doses of vitamins (megadoses or megavitamin therapy) while you use Foli-Iron Caplets unless your doctor tells you to.


• Foli-Iron Caplets has pyridoxine (vitamin B₆), folic acid, and iron in it. Before you start any new medicine, check the label to see if it also has pyridoxine, folic acid, or iron in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Foli-Iron Caplets may interfere with certain lab tests, such as tests used to check for blood in the stool. Be sure your doctor and lab personnel know you are taking Foli-Iron Caplets.


• Foli-Iron Caplets should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Foli-Iron Caplets while you are pregnant. Foli-Iron Caplets are found in breast milk. If you are or will be breast-feeding while you use Foli-Iron Caplets, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Foli-Iron Caplets:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; dark or green stools; diarrhea; nausea; stomach pain; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry, or bloody stools; severe or persistent stomach pain.

This is not a complete list of all side effects that may occur. If you have questions or need medical advice about side effects, contact your doctor or health care provider. You may report side effects to FDA at 1-800-FDA-1088 (1-800-332-1088) or at http://www.fda.gov/medwatch.

See also: Foli-Iron side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include black, tarry, or bloody stools; blue or unusually pale skin; drowsiness or dizziness; fast heartbeat; increased thirst or urination; seizures; severe or persistent nausea, vomiting, diarrhea, or stomach pain; sluggishness; vomiting blood; weakness.

Proper storage of Foli-Iron Caplets:

Store Foli-Iron Caplets at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Foli-Iron Caplets out of the reach of children and away from pets.

General information:

• If you have any questions about Foli-Iron Caplets, please talk with your doctor, pharmacist, or other health care provider.


• Foli-Iron Caplets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Foli-Iron Caplets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Foli-Iron resources

• Foli-Iron Side Effects (in more detail)
• Foli-Iron Use in Pregnancy & Breastfeeding
• Foli-Iron Drug Interactions
• Foli-Iron Support Group
• 0 Reviews for Foli-Iron - Add your own review/rating

Compare Foli-Iron with other medications

• Vitamin/Mineral Supplementation and Deficiency