Itracol

Itracol may be available in the countries listed below.

Ingredient matches for Itracol

Itraconazole

Itraconazole is reported as an ingredient of Itracol in the following countries:

• Slovenia

International Drug Name Search

Bumetanide Injection 0.5mg / ml, solution for injection (Leo Laboratories Ltd)

1. Name Of The Medicinal Product

Bumetanide Injection 0.5 mg/ml, solution for injection.

2. Qualitative And Quantitative Composition

Bumetanide Ph Eur 0.5 mg/ml.

3. Pharmaceutical Form

Solution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Bumetanide is indicated whenever diuretic therapy is required in the treatment of oedema, e.g. that associated with congestive heart failure, cirrhosis of the liver and renal disease including the nephrotic syndrome.

For those oedematous conditions where a prompt diuresis is required, Bumetanide Injection 0.5 mg/ml may be used, e.g. acute pulmonary oedema, acute and chronic renal failure. Bumetanide Injection 0.5 mg/ml can be given intravenously or intramuscularly to those patients who are unable to take Burinex Tablets or who fail to respond satisfactorily to oral therapy.

4.2 Posology And Method Of Administration

Route of administration: parenteral.

Pulmonary oedema : Initially 1 - 2 mg by intravenous injection. This can be repeated, if necessary, 20 minutes later.

In those conditions in which an infusion is appropriate, 2 - 5 mg may be given in 500 ml infusion fluid over 30 - 60 minutes. (See Section 4.4, special warnings and precautions for use).

When intramuscular administration is considered appropriate, a dose of 1 mg should be given initially and the dose then adjusted according to diuretic response.

Children: not recommended for children under 12 years of age.

Dosage in the elderly: adjust dosage according to response. A dose of 0.5 mg bumetanide per day may be sufficient in some elderly patients.

4.3 Contraindications

Although bumetanide can be used to induce diuresis in renal insufficiency, any marked increase in blood urea or the development of oliguria or anuria during treatment of severe progressing renal disease are indications for stopping treatment with bumetanide.

Hypersensitivity to any of the ingredients. Bumetanide is contra-indicated in hepatic coma and care should be taken in states of severe electrolyte depletion.

As with other diuretics, bumetanide should not be administered concurrently with lithium salts. Diuretics can reduce lithium clearance resulting in high serum levels of lithium.

4.4 Special Warnings And Precautions For Use

Excessively rapid mobilisation of oedema, particularly in elderly patients, may give rise to sudden changes in cardiovascular pressure-flow relationships with circulatory collapse. This should be borne in mind when bumetanide is given in high doses intravenously or orally. Electrolyte disturbances may occur, particularly in those patients taking a low salt diet. Regular checks of serum electrolytes, in particular sodium, potassium, chloride and bicarbonate should be performed and replacement therapy instituted where indicated.

Like other diuretics, bumetanide shows a tendency to increase the excretion of potassium which can lead to an increase in the sensitivity of the myocardium to the toxic effects of digitalis. Thus the dose may need adjustment when given in conjunction with cardiac glycosides.

Bumetanide may potentiate the effects of antihypertensive drugs. Therefore, the dose of the latter may need adjustment when bumetanide is used to treat oedema in hypertensive patients.

As with other diuretics, bumetanide may cause an increase in blood uric acid. Periodic checks on urine and blood glucose should be made in diabetics and patients suspected of latent diabetes.

Patients with chronic renal failure on high doses of bumetanide should remain under constant hospital supervision.

Pharmaceutical precautions

Bumetanide Injection 0.5 mg/ml is presented in amber glass containers to protect against deterioration due to exposure to light.

When an intravenous infusion is required, Bumetanide Injection 0.5 mg/ml may be added to Dextrose Injection BP, Sodium Chloride Injection BP or Sodium Chloride and Dextrose Injection BP.

When 25 mg bumetanide (as Bumetanide Injection 0.5 mg/ml) was added to 1 litre of these infusion fluids, no evidence of precipitation was observed over a period of 72 hours. Higher concentrations of bumetanide in these infusion fluids may cause precipitation. It is good practice to inspect all infusion fluids containing bumetanide from time to time. Should cloudiness appear, the infusion should be discarded.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

See Section 4.4 above.

4.6 Pregnancy And Lactation

Although tests in four animal species have shown no teratogenic effects, the ordinary precaution of avoiding use of bumetanide in the first trimester of pregnancy should at present be observed. Since it is not known whether bumetanide is distributed into breast milk, a nursing mother should either stop breast feeding or observe the infant for any adverse effects if the drug is absolutely necessary for the mother.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Reported reactions include skin rashes and muscular cramps in the legs, abdominal discomfort, thrombocytopenia and gynaecomastia. Bone marrow depression associated with the use of bumetanide has been reported rarely, but it has not been proven definitely to be attributed to the drug. Hearing disturbance after administration of bumetanide is rare and reversible. The possibility of hearing disturbance must be considered, particularly when bumetanide is injected too quickly and in high doses.

High Dose Therapy

In patients with severe chronic renal failure given high doses of bumetanide, there have been reports of severe, generalised, musculoskeletal pain sometimes associated with muscle spasm, occurring one to two hours after administration and lasting up to 12 hours. The lowest reported dose causing this type of adverse reaction was 5 mg by intravenous injection and the highest was 75 mg orally in a single dose. All patients recovered fully and there was no deterioration in their renal function.

The cause of this pain is uncertain but it may be a result of varying electrolyte gradients at the cell membrane level.

Experience suggests that the incidence of such reactions is reduced by initiating treatment at 5-10 mg daily and titrating upwards using a twice daily dosage regimen at doses of 20 mg per day or more.

4.9 Overdose

Symptoms would be those caused by excessive diuresis. General measures should be taken to restore blood volume, maintain blood pressure and correct electrolyte disturbance.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mode of action: bumetanide is a potent high ceiling diuretic with a rapid onset and a short duration of action.

5.2 Pharmacokinetic Properties

After intravenous injection, diuresis usually starts within a few minutes and ceases in about two hours.

In most patients, 1mg of bumetanide produces a similar diuretic effect to 40 mg furosemide. Bumetanide excretion in the urine shows a good correlation with the diuretic response. In patients with chronic renal failure, the liver takes more importance as an excretory pathway although the duration of action in such patients is not markedly prolonged.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Xylitol, disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate and water for injections.

6.2 Incompatibilities

None known

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

5 x 4 ml amber glass ampoules (OP), each ampoule containing 2mg bumetanide.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Leo Laboratories Limited

Longwick Road

Princes Risborough

Bucks HP27 9RR

UK

8. Marketing Authorisation Number(S)

PL 0043/0060

9. Date Of First Authorisation/Renewal Of The Authorisation

24 November 1978/13 January 1995.

10. Date Of Revision Of The Text

November 2005

LEGAL CATEGORY

POM

Avastin

Generic Name: Bevacizumab
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: Immunoglobulin G 1 (human-mouse monoclonal rhuMAb-VEGF γ-chain anti-human vascular endothelial growth factor), disulfide with human-mouse monoclonal rhuMAb-VEGF light chain, dimer
Molecular Formula: C₆₆₃₈H₁₀₁₆₀N₁₇₂₀O₂₁₀₈S₄₄
CAS Number: 216974-75-3

• GI Perforations


• 
  

  GI perforation reported in 0.3–2.4% of patients receiving bevacizumab; may be fatal.^a If GI perforation occurs, discontinue bevacizumab permanently.^a (See GI Perforations under Cautions.)

  
  

• Wound Healing Complications


• 
  

  Increased incidence of surgical and wound healing complications; may be serious and fatal.^a Discontinue bevacizumab if wound dehiscence occurs.^a (See Wound Healing Complications under Cautions.)

  
  


• 
  

  Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery required to decrease risk of wound dehiscence not established.^a However, manufacturer recommends discontinuing therapy ≥28 days prior to elective surgery and resuming therapy only after surgical incision has fully healed.^a

  
  


• 
  

  Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.^a

  
  

• Hemorrhage


• 
  

  Severe, sometimes fatal hemorrhagic events (e.g., hemoptysis, epistaxis, GI hemorrhage, CNS hemorrhage, vaginal hemorrhage) reported.^a Do not administer to patients with serious hemorrhage or recent hemoptysis.^a (See Hemorrhage under Cautions.)

  
  

Introduction

Antineoplastic agent; a recombinant humanized monoclonal antibody.^{1 2 3 4 5}

Uses for Avastin

Colorectal Cancer

Used in combination with IV fluorouracil-based chemotherapy for the first-line treatment of metastatic cancer of the colon or rectum.^{1 2 3 4 9} Analysis of pooled data suggests that use of bevacizumab in combination with fluorouracil and leucovorin is associated with prolonged survival.²⁰

Has also been used in combination with oxaliplatin-containing regimens as first-line therapy for metastatic colorectal cancer†.³⁸

Used in combination with IV fluorouracil-based chemotherapy for the second-line treatment of previously treated metastatic cancer of the colon or rectum.¹ Interim analysis of data from one study indicated bevacizumab monotherapy† was associated with decreased survival compared with combination regimen consisting of fluorouracil, leucovorin, and oxaliplatin.¹

Under investigation for use as adjuvant therapy following surgery for early-stage (i.e., stage I or II) colon cancer†.²⁸

Non-small Cell Lung Cancer

Used in combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.^{1 10 11 33 d e}

Some clinicians consider combination of bevacizumab, carboplatin, and paclitaxel as a regimen of choice in the initial treatment of advanced NSCLC for eligible patients (i.e., performance status of 0–2, nonsquamous histology, no history of hemoptysis, absence of CNS metastases, and no concomitant anticoagulant therapy).²⁷

Breast Cancer

Used in combination with paclitaxel for initial treatment of metastatic HER2-negative breast cancer.¹ Efficacy is based on prolonged progression-free survival; currently, no data available that demonstrate prolonged overall survival or amelioration of disease-related symptoms.¹ In December 2010, after reviewing data from 4 clinical studies, FDA recommended to remove this indication from bevacizumab’s approved labeling because of lack of benefit on overall survival and unfavorable risk-benefit ratio.^{58 59 60} A public hearing was held on June 28–29, 2011.⁶¹ FDA’s final decision regarding approval status for this indication was pending at the time this drug monograph was finalized for publication.

Bevacizumab is not indicated for use in the treatment of breast cancer that has progressed following the use of an anthracycline and taxane regimen for metastatic disease.¹

Brain Tumors

Used as a single agent for treatment of glioblastoma in patients whose disease has progressed following previous therapy.^a Efficacy is based on increased objective response rate; currently, no data available that demonstrate prolonged overall survival or amelioration of disease-related symptoms.^a

Renal Cell Carcinoma

Used in combination with interferon alfa for treatment of metastatic renal cell carcinoma.^a

Ovarian Cancer

Under investigation for use in treatment of ovarian cancer†.²⁶

Prostate Cancer

Under investigation for use in treatment of prostate cancer†.^{23 24}

Neovascular Age-related Macular Degeneration

Has been used by intravitreal injection† in treatment of neovascular age-related macular degeneration†.³⁴

Avastin Dosage and Administration

General

• 
  

  Use in combination with other chemotherapeutic agents.¹ (See Dosage under Dosage and Administration.)

  
  


• 
  

  Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.¹ (See Wound Healing Complications under Cautions.)

  
  


• 
  

  Discontinue therapy ≥28 days prior to elective surgery; do not resume until surgical incision is fully healed.¹ (See Wound Healing Complications under Cautions.)

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹ Do not administer by rapid IV injection (e.g., IV push or bolus.¹

Dilution

Do not shake vial prior to dilution.¹

Withdraw appropriate dose of bevacizumab and dilute in 100 mL of 0.9% sodium chloride.¹ Do not administer or mix with dextrose solutions.¹

Rate of Administration

Administer initial dose over 90 minutes.¹ (See Infusion Reactions under Cautions.)

If well tolerated, administer second dose over 60 minutes.¹

If second dose is well tolerated, administer subsequent doses over 30 minutes.¹

Has been administered safely over shorter infusion times (0.5 mg/kg per minute).⁴³

Dosage

Consult respective manufacturers or published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.³

Adults

Colorectal Cancer

First-line Treatment of Metastatic Colorectal Cancer

IV

5 mg/kg every 14 days; continue until disease progression or unacceptable toxicity occurs.¹

Use in combination with IV fluorouracil-based chemotherapy.¹ In clinical studies, bevacizumab was used in combination with the IFL regimen (irinotecan 125 mg/m², fluorouracil 500 mg/m², and leucovorin 20 mg/m², administered by IV injection once weekly for 4 out of every 6 weeks)^{1 4} or the 5-FU/LV regimen (leucovorin 500 mg/m² by IV infusion over 2 hours, then fluorouracil 500 mg/m² by slow IV injection [1 hour after initiation of leucovorin] given once weekly for the first 6 weeks out of every 8-week cycle).^{1 2 3}

Second-line Treatment of Metastatic Colorectal Cancer

IV

10 mg/kg every 14 days; continue until disease progression or unacceptable toxicity occurs.¹

Use in combination with IV fluorouracil-based chemotherapy.¹ In clinical studies, bevacizumab was administered on day 1 of the treatment cycle prior to the FOLFOX4 regimen (oxaliplatin 85 mg/m² and leucovorin 200 mg/m² concurrently IV, then fluorouracil 400 mg/m² by direct IV injection, followed by fluorouracil 600 mg/m² by continuous IV infusion on day 1; and leucovorin 200 mg/m² IV, then fluorouracil 400 mg/m² by direct IV injection, followed by fluorouracil 600 mg/m² by continuous IV infusion on day 2; treatment cycles repeated every 2 weeks).¹

Non-small Cell Lung Cancer

IV

15 mg/kg every 3 weeks; continue until disease progression or unacceptable toxicity occurs.^{1 e f}

Use in combination with IV paclitaxel and carboplatin (PC regimen).^{1 f} In clinical studies, bevacizumab was administered 1 hour after the PC regimen (paclitaxel 200 mg/m² by IV infusion over 3 hours, then carboplatin [at dose required to obtain AUC of 6 mg/mL per minute] by IV infusion over 15–30 minutes beginning 60 minutes after completion of paclitaxel; treatment cycles repeated every 3 weeks).^{1 11 d e f} In these studies, patients received up to 6 cycles of bevacizumab in combination with the PC regimen, after which bevacizumab monotherapy (15 mg/kg every 3 weeks) was continued until disease progression or unacceptable toxicity occurred.^{1 11 d e f} A median of 7 treatment cycles (including cycles of bevacizumab monotherapy) was administered.¹¹

Breast Cancer

IV

10 mg/kg every 14 days; continue until disease progression or unacceptable toxicity occurs.¹

Use in combination with IV paclitaxel (90 mg/m² IV once weekly for 3 out of 4 weeks).¹

Brain Tumors

Glioblastoma

IV

10 mg/kg every 14 days; continue until disease progression or unacceptable toxicity occurs.¹

Renal Cell Carcinoma

IV

10 mg/kg every 14 days; continue until disease progression or unacceptable toxicity occurs.¹

Use in combination with interferon alfa (9 million units sub-Q 3 times weekly).^a

Dosage Modification for Toxicity

Dosage reductions not recommended in any patient;¹ instead, temporarily or permanently discontinue therapy based on causality.¹

Discontinue therapy permanently if GI perforation (i.e., GI perforation, fistula formation in GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence (requiring medical intervention), severe bleeding (requiring medical intervention), severe arterial thromboembolic event, nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy occurs.^{1 7}

Discontinue therapy if reversible posterior leukoencephalopathy syndrome (RPLS) occurs.^{1 31 32 a} (See Reversible Posterior Leukoencephalopathy Syndrome [RPLS] under Cautions.) Risk of reinitiating therapy in patients previously experiencing RPLS not known.^{1 32}

Discontinue therapy temporarily in patients with evidence of moderate to severe proteinuria pending further evaluation, in patients with severe hypertension not controlled by medical management, or in patients with severe infusion reactions.¹ (See Cautions.)

Special Populations

No dosage adjustment required in geriatric patients.¹

Cautions for Avastin

Contraindications

• 
  

  None.^{1 3}

  
  

Warnings/Precautions

Warnings

Consider the usual cautions, precautions, and contraindications of any other antineoplastic agents included in the therapeutic regimen.³

GI Perforations

Potentially fatal GI perforation reported; generally manifested as abdominal pain, nausea, vomiting, constipation, and/or fever; usually occurs within the first 50 days following initiation of bevacizumab.^{1 3 a}

GI perforation sometimes associated with or complicated by fistula formation (see Fistula Formation under Cautions) and/or intra-abdominal abscess.^{1 4 a}

If GI perforation occurs, discontinue bevacizumab permanently.¹

Wound Healing Complications

Impaired wound healing, bleeding complications, and/or wound dehiscence, sometimes fatal, reported.¹ Discontinue bevacizumab in patients with wound healing complications requiring medical intervention.^a (See Boxed Warning.)

Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.¹

Discontinue bevacizumab ≥28 days prior to elective surgery.^{1 a} Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery not established, but consider long half-life of bevacizumab.¹ (See Half-life under Pharmacokinetics.) Manufacturer recommends resuming therapy only after surgical incision has fully healed.¹

Hemorrhage

Severe, sometimes fatal, hemorrhagic events (e.g., pulmonary hemorrhage, hemoptysis, hematemesis, epistaxis, severe GI hemorrhage, CNS hemorrhage, intracranial hemorrhage) reported.¹ (See Boxed Warning.)

Risk of severe pulmonary hemorrhage in patients with non-small cell lung cancer.^a Serious or fatal pulmonary hemorrhage reported in 31% of patients with squamous cell histology and in 4% of patients with non-squamous cell histology.^a

Risk of CNS hemorrhage in patients with CNS metastases.^a Intracranial hemorrhage reported in patients with glioblastoma.^a

Mild hemorrhagic events, most commonly grade 1 epistaxis, also reported.¹

Do not administer to patients with recent hemoptysis (≥½ teaspoon of red blood).¹ If severe hemorrhage (i.e., requiring medical intervention) occurs, discontinue therapy and manage aggressively.¹

Thromboembolism

Serious, sometimes fatal, arterial thromboembolic events (e.g., cerebral infarction, TIA, MI, angina) reported.^{1 7 8 16 17} Increased risk in patients with a history of arterial thromboembolic events or patients ≥65 years of age.^{1 7} Weigh risks against benefits of therapy.¹⁷ Discontinue therapy permanently if severe arterial thromboembolic event occurs;^{1 7} safety of resuming therapy after resolution of an arterial thromboembolic event not studied.¹

Grade 3 or 4 venous thromboembolic events (e.g., DVT, intra-abdominal venous thrombosis) reported.¹ Increased risk of developing second thromboembolic event reported in patients with metastatic colorectal cancer receiving bevacizumab with chemotherapy despite use of full-dose warfarin therapy following an initial venous thromboembolic event.¹

Hypertension

Severe hypertension (grade 3 or 4) reported.¹ Complications include potentially fatal hypertensive encephalopathy and CNS hemorrhage.¹

Monitor BP every 2–3 weeks or more frequently if hypertension develops.¹ Hypertension may respond to antihypertensive therapy.^{1 6} Temporarily discontinue therapy in patients with severe hypertension not controlled with medical management.¹ If therapy is discontinued because of hypertension, monitor BP at regular intervals thereafter.¹ Discontinue therapy permanently if hypertensive crisis or hypertensive encephalopathy occurs.¹

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS (a brain-capillary leak syndrome) reported.^{1 29 30 32} May manifest with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances; mild to severe hypertension also may occur.^{1 32} Manifestations occurred from 16 hours to 1 year after initiation of bevacizumab.^{1 32} Magnetic resonance imaging (MRI) is necessary to confirm diagnosis of RPLS.^{1 32}

Closely monitor and maintain strict control of BP during and following bevacizumab infusion.³⁰ If RPLS develops, discontinue bevacizumab and initiate treatment of hypertension as clinically indicated.^{1 31 32} Symptoms usually lessen or resolve within days of drug discontinuance, but some patients have experienced ongoing neurologic sequelae.^{1 32} Risk of reinitiating bevacizumab in patients previously experiencing RPLS not known.^{1 32}

Neutropenia and Infection

Severe neutropenia, febrile neutropenia, and serious infection (including pneumonia, catheter infections, and wound infections), sometimes fatal, reported at higher incidence in patients receiving bevacizumab in combination with chemotherapy compared with those receiving chemotherapy alone.¹

Proteinuria

Increased incidence and severity of proteinuria reported.¹ Severity ranges from clinically silent to nephrotic syndrome.⁶ Proteinuria with findings of thrombotic microangiopathy on renal biopsy reported in patients receiving bevacizumab alone or in combination with other antineoplastic agents for various cancers.³⁷

Monitor patients for development or worsening of proteinuria with serial urinalysis.¹ Further assessment (e.g., 24-hour urine collection) recommended if ≥2+ urine dipstick reading occurs.^a Interrupt bevacizumab therapy for moderate proteinuria (≥2 g per 24 hours); resume therapy when proteinuria is <2 g per 24 hours.^a Safety of continuing or temporarily discontinuing therapy in patients with moderate to severe proteinuria not known.¹

Discontinue therapy in patients with nephrotic syndrome.¹ In clinical studies, proteinuria associated with nephrotic syndrome decreased in severity several months following discontinuance of bevacizumab in some patients but did not completely resolve.¹

Fistula Formation

GI tract fistula formation reported in patients with colorectal and other types of cancer (e.g., NSCLC) receiving bevacizumab.^{1 g} (See GI Perforations under Cautions.)

Non-GI fistula formation, sometimes fatal and usually occurring within first 6 months of treatment, reported.¹ Non-GI fistula sites include tracheo-esophageal, bronchopleural, biliary, vaginal, and bladder.¹ If fistula formation involving an internal organ occurs, discontinue bevacizumab permanently.¹

Infusion Reactions

Infusion reactions (e.g., hypertension, hypertensive crisis associated with neurologic manifestations, wheezing, oxygen desaturation, grade 3 hypersensitivity, chest pain, headache, rigor, diaphoresis) reported.¹

Infuse initial doses slowly, increasing rate of infusion as tolerated.¹ (See Rate of Administration under Dosage and Administration.)

If severe infusion reactions occur, interrupt infusion and administer appropriate medical therapy.¹ Adequate information on rechallenge not available.¹

Microangiopathic Hemolytic Anemia

Microangiopathic hemolytic anemia reported in patients with solid tumors receiving bevacizumab and sunitinib†;^{35 36} cases were reversible within 3 weeks following discontinuance of both drugs without other interventions.^{35 36} Use of bevacizumab in combination with sunitinib is not recommended.^{35 36}

Report cases of microangiopathic hemolytic anemia associated with bevacizumab therapy to the manufacturer or FDA.^{35 36}

Other Warnings/Precautions

Neutropenia and Infection

Severe neutropenia, febrile neutropenia, and serious infection (including pneumonia, catheter infections, and wound infections), sometimes fatal, reported.¹

Immunogenicity

Potential for immunogenicity.¹ Incidence of antibody formation not established.¹

CHF

CHF reported; higher risk in patients also receiving or who had previously received anthracyclines.¹

Safety of continuation or resumption of bevacizumab in patients who develop cardiac dysfunction not studied.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether distributed into milk.¹ Discontinue nursing during treatment, taking into account the long half-life.¹ (See Half-life under Pharmacokinetics.)

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 3}

Geriatric Use

No difference in overall survival relative to younger adults observed in patients receiving bevacizumab and chemotherapy for metastatic colorectal cancer.^{1 a} However, possible increased risk of asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, MI, CHF, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, hyponatremia, nausea, vomiting, ileus, and fatigue.¹

Increased risk of proteinuria in patients ≥65 years of age receiving bevacizumab in combination with paclitaxel and carboplatin, compared with younger adults.¹ (See Proteinuria under Cautions.)

Insufficient experience in patients ≥65 years of age receiving bevacizumab in combination with paclitaxel for metastatic breast cancer to determine whether adverse effects differ from those in younger adults.¹

Possible increased incidence of arterial thromboembolic events, dyspepsia, GI hemorrhage, edema, epistaxis, increased cough, and voice alteration compared with younger adults.¹

Common Adverse Effects

Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, exfoliative dermatitis.^a

Interactions for Avastin

Specific Drugs

Drug	Interaction	Comments
Carboplatin	No effect on carboplatin exposure1
Interferon alfa	No effect on interferon alfa exposure.1 a
Irinotecan	No effect on pharmacokinetics of irinotecan or the active metabolite of irinotecan1 5 a
Paclitaxel	Possible decreased paclitaxel exposure after 4 treatment cycles of bevacizumab in combination with paclitaxel and carboplatin1
Sunitinib	Possible microangiopathic hemolytic anemia35 36 (see Microangiopathic Hemolytic Anemia under Cautions)	Use of bevacizumab in combination with sunitinib not recommended35 36

Avastin Pharmacokinetics

Absorption

Plasma Concentrations

Relationship between bevacizumab exposure and clinical outcome not studied.¹

Elimination

Metabolism

Metabolized by reticuloendothelial system.³

Elimination Route

Eliminated via reticuloendothelial system.³

Half-life

Approximately 20 days (range: 11–50 days).¹

Special Populations

Clearance varies by body weight, gender, and tumor burden.¹ Increased clearance observed in men and in patients with higher tumor burden; however, no evidence of reduced efficacy.¹

Stability

Storage

Parenteral

Injection Concentrate

2–8°C.¹ Do not freeze; protect from light.¹

Store diluted solution at 2–8°C for up to 8 hours.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities with PVC or polyolefin bags.¹

Solution Compatibility

Compatible
Sodium chloride 0.9%
Incompatible
Dextrose solutions

Actions

• 
  

  Antineoplastic agent;^{1 3 5} a recombinant humanized monoclonal IgG₁ antibody containing human framework regions and murine complementarity-determining regions.^{1 6}

  
  


• 
  

  Binds to human vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors (Flt-1, KDR) on the surface of endothelial cells.¹ This may result in inhibition of angiogenesis, thus reducing microvascular growth of tumors and inhibiting metastatic disease progression.^{1 2 3 5}

  
  

Advice to Patients

• 
  

  Importance of understanding potential risks associated with therapy, including severe hypertension, wound healing complications, and arterial thromboembolic events.^{1 a}

  
  


• 
  

  Importance of routine monitoring of BP; advise patients to inform clinician if BP is elevated.^a

  
  


• 
  

  Importance of immediately informing clinician if unusual bleeding, high fever, rigors, sudden worsening of neurological function, persistent or severe abdominal pain, severe constipation, or vomiting occurs.^a

  
  


• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed;¹ necessity for clinicians to advise women to avoid pregnancy during therapy and to use an effective method of contraception for ≥6 months after last dose of bevacizumab.³ Advise pregnant women of risk to the fetus and/or the potential risk for loss of the pregnancy.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).¹

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bevacizumab (Recombinant)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, concentrate, for IV infusion	25 mg/mL (100 and 400 mg)	Avastin	Genentech

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 01/2012. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avastin 100MG/4ML Solution (GENENTECH): 4/$645.96 or 12/$1,850.05

Avastin 400MG/16ML Solution (GENENTECH): 16/$2,525.85 or 48/$7,374.16

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2012, Selected Revisions December 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Genentech. Avastin (bevacizumab) prescribing information. South San Francisco, CA; 2008 Mar.

2. Kabbinavar F, Hurwitz HI, Fehrenbacher L et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003; 21:60-5. [IDIS 495428] [PubMed 12506171]

3. Genentech, South San Francisco, CA: Personal communication.

4. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335-42. [IDIS 516117] [PubMed 15175435]

5. Presta LG, Chen H, O’Connor SJ et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997; 57:4593-9. [PubMed 9377574]

6. Zondor SD, Medina PJ. Bevacizumab: An angiogenesis Inhibitor with efficacy in colorectal and other malignancies. Ann Pharmacother. 2004; 38:1258-64. [IDIS 528874] [PubMed 15187215]

7. Barron H. Dear healthcare provider regarding adverse arterial thromboembolic events associated with Avastin. South San Francisco, CA: Genentech; 2004 Jul.

8. Food and Drug Administration. Avastin (bevacizumab) injection [August 13, 2004: Genentech]. MedWatch drug labeling changes. Rockville, MD; August 2004. From FDA website.

9. Colon cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Aug 9.

10. Non-small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 May 1.

11. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small lung cancer. N Engl J Med 2006; 355:2542-50. [PubMed 17167137]

12. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003; 349:427-34. [IDIS 502305] [PubMed 12890841]

13. Rini BI, Halabi S, Rosenberg JE et al. CALGB 90206: A phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. Proc ASCO 2008 Genitourinary Cancers Symposium. 2008; Abstract 350.

14. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005; 23:792-9. [IDIS 532659] [PubMed 15681523]

15. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357:2666-76.

16. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Avastin (bevacizumab) [January 2005]. From FDA website.

17. Barron H. Dear healthcare provider letter regarding increased risk of arterial thromboembolic events associated with the use of Avastin in combination with chemotherapy. South San Francisco, CA: Genentech; 2005 Jan 5.

18. Hurwitz HI, Fehrenbacher L, Hainsworth JD et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005; 23:3502-8. [IDIS 536385] [PubMed 15908660]

19. Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005; 23:3697-705. [IDIS 540182] [PubMed 15738537]

20. Kabbinavar FF, Hambleton J, Mass RD et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005; 23:3706-12. [IDIS 540183] [PubMed 15867200]

21. Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007; 25:1539-44. [PubMed 17442997]

22. Chen HX, Mooney M, Boron M et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI treatment referral center trial TRC-0301. J Clin Oncol. 2006; 24:3354-60. [PubMed 16849749]

23. Picus J, Halabi S, Rini B et al. The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006. Proc ASCO. 2003; Abstract No. 1578.

24. Kelly W, protocol chair. Phase III randomized study of docetaxel and prednisone with versus without bevacizumab in patients with hormone-refractory metastatic adenocarcinoma of the prostate. Protocol ID: CALGB-90401. Last modified: 7/22/2006. National Cancer Institute: Clinical Trials (database).

25. Kindler H, protocol chair. Phase III randomized study of gemcitabine with versus without bevacizumab in patients with locally advanced or metastatic adenocarcinoma of the pancreas. Protocol ID: CALGB-80303. Last modified: 4/19/2006. National Cancer Institute: Clinical Trials (database).

26. Burger R, Fleming G, protocol chairs. Phase III randomized study of carboplatin and paclitaxel versus carboplatin, paclitaxel, and concurrent bevacizumab with versus without extended bevacizumab in patients with stage III or IV ovarian epithelial or primary peritoneal cancer. Protocol ID: GOG-0218. Last modified: 10/10/2008. National Cancer Institute: Clinical Trials (database).

27. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: non-small cell lung cancer. Version 2.2006.

28. Allegra C, protocol chair. Phase III randomized study of adjuvant chemotherapy comprising fluorouracil, leucovorin calcium, and oxaliplatin with versus without bevacizumab in patients with resected stage II or III adenocarcinoma of the colon. Protocol ID: NSABP-C-08. Last modified: 6/20/2008. National Cancer Institute: Clinical Trials (database).

29. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006; 354:980-1. [PubMed 16510760]

30. Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006; 354:981-2.

31. Barron H. Reversible posterior leukoencephalopathy syndrome and bevacizumab. Manufacturer reply. N Engl J Med. 2006; 354:982.

32. Barron H. Dear healthcare provider letter regarding reversible posterior leukoencephalopathy syndrome in patients receiving bevacizumab (Avastin). South San Francisco, CA: Genentech; 2006 Sep.

33. Cruzan S (US Food and Drug Administration). FDA approves new combination therapy for lung cancer. Rockville, MD; 2006 Oct 12. Press release P06-166.

34. Steinbrook R. The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006; 355:1409-12. [PubMed 17021315]

35. Food and Drug Administration. Safety Alert: Avastin (bevacizumab) [July 14 2008]. From FDA web site .

36. Barron H. Dear healthcare provider letter: Important drug warning: microangiopathic hemolytic anemia (MAHA) in patients treated with Avastin (bevacizumab) and sunitinib malate. South San Francisco, CA: Genentech; 2008 Jul.

37. Eremina V, Jefferson JA, Kowalewska J et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358:1129-36. [PubMed 18337603]

38. Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008; 26:2013-9. [PubMed 18421054]

39. Miles D, Chan A, Romieu G et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. Proc ASCO. 2008; Abstract LBA1011.

40. Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007; 370:2103-11.

41. Martin DF, Fine SL, protocol chairs. Comparison of age-related macular degeneration treatments trials: Lucentis-Avastin Trial (CATT). Last updated: 3/4/2008. National Eye Institute: Clinical Studies (database).

42. Scappaticci FA, Skillings JR, Holden SN et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007; 99:1232-9. [PubMed 17686822]

43. Reidy DL, Chung KY, Timoney JP et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol. 2007; 25:2691-5. [PubMed 17602073]

44. Genentech. Avastin (bevacizumab) prescribing information. South San Francisco, CA; 2008 Mar.

58. Food and Drug Administration. FDA drug safety communication: Avastin (bevacizumab): Process for removal of breast cancer indication begun. Rockville, MD; 2010 Dec 16. From FDA website.

59. Food and Drug Administration. Memorandum to the file BLA 125085 Avastin (bevacizumab): Regulatory decision to withdraw Avastin (bevacizumab) first-line metastatic breast cancer indication. Rockville, MD; 2010 Dec 15. From FDA website.

60. Woodcock J. Dear breast cancer community letter. Silver Spring, MD: Food and Drug Administration; 2010 Dec 16. From FDA website.

61. Food and Drug Administration. Avastin (bevacizumab) information. Rockville, MD; 2011 Jun 29. From FDA website.

64. Genentech. Avastin (bevacizumab) prescribing information. South San Francisco, CA; 2011 Feb.

a. Genentech. Avastin (bevacizumab) prescribing information. South San Francisco, CA; 2009 Jul.

d. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol. 2004; 22:2184-91. [PubMed 15169807]

e. Genentech. Avastin dosing and administration in the first-line treatment of NSCLC. From Genentech website. Accessed 2007 Feb 7.

f. Genentech. Pivotal NSCLC trial overview. From Genentech website. Accessed 2007 Feb 7.

g. Barron H. Dear healthcare provider letter: important drug warning regarding Avastin (bevacizumab). South San Francisco, CA: Genentech, Inc; 2007 Apr. From FDA website.

h. Food and Drug Administration. Avastin (bevacizumab) [April 21, 2007: Genentech]. Medwatch alert. Rockville, MD; April 2007. From FDA website.

Epsom Salts BP (Boots Company plc)

1. Name Of The Medicinal Product

Epsom Salts B.P.

2. Qualitative And Quantitative Composition

Magnesium sulphate Ph Eur 100%w/w

3. Pharmaceutical Form

Crystalline powder

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of occasional constipation.

For oral administration.

4.2 Posology And Method Of Administration

Adults and children over 12 years: One to two teaspoonfuls.

Children 5 to 12 years: Half to one teaspoonful.

Children under 5 years: Not recommended.

To be taken, preferably before breakfast, either with a cup of tea or in half to one tumbler of water.

There is no need for dosage reduction in the elderly.

4.3 Contraindications

Should not be taken where there is severe abdominal pain, nausea or vomiting or for prolonged periods.

4.4 Special Warnings And Precautions For Use

Use of magnesium sulphate is inadvisable in patients with renal impairment. Laxatives should not be taken where there is severe abdominal pain or used regularly for prolonged periods, except on medical advice.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

The safety of Epsom Salts during pregnancy and lactation

has not been established, it is therefore best avoided during the first trimester of pregnancy and during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Ingestion of magnesium salts may cause gastro-intestinal irritation, colic and watery diarrhoea. Prolonged use may result in hypermagnesaemia, particularly in patients with renal impairment, symptoms of which include nausea and vomiting.

4.9 Overdose

Overdosage may lead to hypermagnesaemia, symptoms of which may include, flushing, thirst, hypotension, drowsiness, hyporeflexia, respiratory depression, cardiac arrhythmias, coma and cardiac arrest.

Emergency treatment should include intravenous injection of calcium gluconate, fluid replacement and if necessary, dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Magnesium sulphate is a saline purgative. In dilute solution it produces an osmotic reduction in the water absorbed from the intestine with the result that the intestinal contents distend the bowel and stimulate peristalsis.

5.2 Pharmacokinetic Properties

Magnesium sulphate is absorbed from the gastrointestinal tract. In plasma 25-30% of magnesium is protein bound. Magnesium salts are excreted mainly in the urine, over 90% of filtered magnesium being reabsorbed. Small amounts are excreted in breast milk, faeces and saliva. Magnesium sulphate also crosses the placenta.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

A cardboard carton with a paper/polythene liner.

Pack sizes: 200g and 500g.

A cardboard jcarton containing a metallised PET laminate bag.

Pack sizes: 200g and 500g.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL0014/5552R

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation: 30 March 1984

Date of Last Renewal: 17 October 1994

10. Date Of Revision Of The Text

October 1999

Metrolotion Topical

Generic Name: metronidazole (Topical route)

met-roe-NYE-da-zole

Commonly used brand name(s)

In the U.S.

• Metrocream


• Metrogel


• Metrolotion


• Noritate


• Rozex


• Vitazol

Available Dosage Forms:

• Cream


• Lotion


• Gel/Jelly


• Emulsion

Therapeutic Class: Antiacne Antibacterial

Chemical Class: Nitroimidazole

Uses For Metrolotion

Topical metronidazole is applied to the skin in adults to help control rosacea , also known as acne rosacea and “adult acne.” This medicine helps to reduce the redness of the skin and the number of pimples, usually found on the face, in patients with rosacea.

Topical metronidazole is available only with your doctor's prescription.

Before Using Metrolotion

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

Rosacea is usually considered an adult disease. Therefore, topical metronidazole is not generally used in children.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of topical metronidazole in the elderly with use in other age groups.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

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:

• Blood disease or a history of blood disease—Metronidazole may make the condition worse

Proper Use of metronidazole

This section provides information on the proper use of a number of products that contain metronidazole. It may not be specific to Metrolotion. Please read with care.

Do not use this medicine in or near the eyes. Watering of the eyes may occur when the medicine is used too close to the eyes.

If this medicine does get into your eyes, wash them out immediately, but carefully, with large amounts of cool tap water. If your eyes still burn or are painful, check with your doctor.

Before applying this medicine, thoroughly wash the affected area(s) with a mild, nonirritating cleanser, rinse well, and gently pat dry.

To use:

• After washing the affected area(s), apply this medicine with your fingertips.


• Apply and rub in a thin film of medicine, using enough to cover the affected area(s) lightly. You should apply the medicine to the whole area usually affected by rosacea, not just to the pimples themselves .


• Wash the medicine off your hands.

To help keep your rosacea under control, keep using this medicine for the full time of treatment. You may have to continue using this medicine every day for 9 weeks or longer. Do not miss any doses.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For topical dosage forms (cream, gel, and lotion):
  
  • For rosacea:
    
    • Adults—Apply to the affected area(s) of skin two times a day, morning and evening, for nine weeks.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Metrolotion

If your rosacea does not improve within 3 weeks, or if it becomes worse, check with your doctor. However, treatment of rosacea may take up to 9 weeks or longer before you see full improvement.

Stinging or burning of the skin may be expected after this medicine is applied. These effects may last up to a few minutes or more. If irritation continues, check with your doctor. You may have to use the medicine less often or stop using it altogether. Follow your doctor's directions.

You may continue to use cosmetics (make-up) while you are using this medicine for rosacea. However, it is best to use only “oil-free” cosmetics. Also, it is best not to use cosmetics too heavily or too often. They may make your rosacea worse. If you have any questions about this, check with your doctor.

Metrolotion 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.

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

• Dry skin


• redness or other signs of skin irritation not present before use of this medicine


• stinging or burning of the skin


• watering of eyes

Rare

• Metallic taste in the mouth


• nausea


• tingling or numbness of arms, legs, hands, or feet

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: Metrolotion Topical 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 Metrolotion Topical resources

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

Compare Metrolotion Topical with other medications

• Perioral Dermatitis
• Rosacea

Heparin antagonists

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

See also

Medical conditions associated with heparin antagonists:

• Heparin Overdose

Drug List:

Protamine-Sulfate

High Blood Pressure (Hypertension) Medications

Definition of High Blood Pressure:

Hypertension means high blood pressure. This generally means:

• systolic blood pressure is consistently over 140 (systolic is the "top" number of your blood pressure measurement, which represents the pressure generated when the heart beats)


• diastolic blood pressure is consistently over 90 (diastolic is the "bottom" number of your blood pressure measurement, which represents the pressure in the vessels when the heart is at rest)

Either or both of these numbers may be too high.

Pre-hypertension is when your systolic blood pressure is between 120 and 139 or your diastolic blood pressure is between 80 and 89 on multiple readings. If you have pre-hypertension, you are likely to develop high blood pressure at some point. Therefore, your doctor will recommend lifestyle changes to bring your blood pressure down to normal range.

Drugs associated with High Blood Pressure

The following drugs and medications are in some way related to, or used in the treatment of High Blood Pressure. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

See sub-topics

Topics under High Blood Pressure

• Hypertensive Emergency (13 drugs)

• Hypertensive Heart Disease (0 drugs in 2 topics)

• Pseudotumor Cerebri (34 drugs in 4 topics)

Learn more about High Blood Pressure (Hypertension)

Micromedex Care Notes:

• Chronic Hypertension

Medical Encyclopedia:

• Drug-induced hypertension
• Essential hypertension
• High blood pressure
• Hypertension
• Renovascular hypertension

Harvard Health Guide:

• Symptoms and treatment for High Blood Pressure (Hypertension)

Drug List:

Accupril

Accuretic

Aceon

Adalat-Cc-Sustained-Release-Tablets

Afeditab-Cr

Aldactazide

Aldactone

Aldoclor-150

Aldoclor-250

Aldomet

Aldoril

Aldoril-15

Aldoril-25

Aldoril-D30

Aldoril-D50

Altace

Amlobenz

Amturnide

Apresazide

Apresoline

Aquatensen

Aquazide-H

Atacand

Atacand-Hct

Avalide

Avapro

Azor

Benicar

Benicar-Hct

Blocadren

Bystolic

Caduet

Calan

Calan-Sr-Controlled-Release-Tablets

Capoten

Capozide

Capozide-25-15

Capozide-25-25

Capozide-50-15

Capozide-50-25

Cardene

Cardene-Iv

Cardene-Sr-Sustained-Release-Capsules

Cardizem

Cardizem-Cd-24-Hour-Sustained-Release-Beads-Capsules

Cardizem-La-24-Hour-Extended-Release-Beads-Tablets

Cardura

Cartia-Xt-24-Hour-Sustained-Release-Beads-Capsules

Cartrol

Catapres

Catapres-Tts-Patches

Cleviprex

Clorpres

Coreg

Coreg-Cr-Extended-Release-Capsules

Corgard

Corzide

Corzide-40-5

Corzide-80-5

Covera-Hs-Sustained-Release-Tablets-Controlled-Onset

Cozaar

Demadex

Demi-Regroton

Dilacor-Xr-24-Hour-Sustained-Release-Capsules

Dilt-Xr-24-Hour-Sustained-Release-Capsules

Diltia-Xt-24-Hour-Sustained-Release-Capsules

Diltiazem-Hydrochloride-Cd

Diltiazem-Hydrochloride-Sr

Diltiazem-Hydrochloride-Xr

Diltiazem-Hydrochloride-Xt

Diltzac

Diovan

Diovan-Hct

Diupres-250

Diupres-500

Diuretic-Ap-Es

Diuril

Diuril-Sodium

Dyazide

Dynacirc

Dynacirc-Cr-Extended-Release-Tablets

Edarbi

Enduron

Enduronyl

Esidrix

Esimil

Exforge

Exforge-Hct

Hydra-Zide

Hydrap-Es

Hydrodiuril

Hydropres-25

Hydropres-50

Hydroserpine

Hylorel

Hytrin

Hyzaar

Inderal

Inderal-La-Sustained-Release-Capsules

Inderide

Innopran-Xl-Sustained-Release-Bead-Capsules

Inspra

Inversine

Ismelin

Isoptin

Isoptin-Sr-Controlled-Release-Tablets

Jenloga

Kerlone

Lasix

Levatol

Lexxel

Loniten

Lopressor

Lopressor-Hct

Lotensin

Lotensin-Hct

Lotrel

Lozol

Matzim-La

Mavik

Maxzide

Maxzide-25

Metoprolol-Succinate-Er

Micardis

Micardis-Hct

Microzide

Midamor

Minipress

Minitran-Patch

Minizide

Moduretic

Moduretic-5-50

Monopril

Monopril-Hct

Mykrox

Naturetin

Nexiclon-Xr

Nifediac-Cc

Nifedical-Xl

Nitrek-Transdermal

Nitro-Td-Patch-A-Transdermal

Nitro-Bid-Ointment

Nitro-Dur-Patch

Nitro-Time-Controlled-Release-Capsules

Nitrocot

Nitrogard

Nitrol-Appli-Kit-Topical

Nitrolingual-Pumpspray-Spray

Nitromist

Nitroquick

Nitrostat

Normodyne

Norvasc

Plendil

Prinivil

Prinzide

Procardia-Xl-Sustained-Release-Tablets

Quinaretic

Regroton

Renese

Renese-R

Saluron

Sectral

Ser-Ap-Es

Serpazide

Sular-Extended-Release-Tablets

Tarka

Taztia-Xt-24-Hour-Extended-Release-Beads-Capsules

Teczem

Tekamlo

Tekturna

Tekturna-Hct

Tenex

Tenoretic

Tenoretic-100

Tenoretic-50

Tenormin

Teveten

Teveten-Hct

Thalitone

Tiazac

Timolide

Timolide-10-25

Toprol

Trandate

Transderm-Nitro

Tri-Hydroserpine

Tribenzor

Twynsta

Uni-Serp

Uniretic

Univasc

Valturna

Vaseretic

Vaseretic-10-25

Vaseretic-5-12-5

Vasotec

Verelan-Sustained-Release-Pellet-Filled-Capsules

Verelan-Pm-Sustained-Release-Capsules-Controlled-Onset

Visken

Wytensin

Zaroxolyn

Zebeta

Zestoretic

Zestril

Ziac

Balantidium coli Medications

Definition of Balantidium coli: A very large parasitic ciliate species, usually 50 to 80 um in length, reaching up to 200 um in pigs, found in the caecum or large intestine, swimming actively in the lumen; usually harmless in man but may invade and ulcerate the intestinal wall, producing a colitis resembling amoebic dysentery.

Drugs associated with Balantidium coli

The following drugs and medications are in some way related to, or used in the treatment of Balantidium coli. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Drug List:

Diquinol

Yodoxin

Methotrexate Tablets BP 10mg

1. Name Of The Medicinal Product

Methotrexate Tablets B.P. 10 mg.

2. Qualitative And Quantitative Composition

Active Constituent

Methotrexate Ph EUR 10.0 mg.

There is no overage included in the formulation.

3. Pharmaceutical Form

Tablet for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia and in the control of severe recalcitrant psoriasis which is not responsive to other forms of therapy.

4.2 Posology And Method Of Administration

ADULTS AND CHILDREN

Antineoplastic Chemotherapy

Methotrexate is active orally and parenterally. Methotrexate Injection B.P. may be given by the intramuscular, intravenous, intra-arterial or intrathecal routes. Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15-30mg daily for a 5-day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.

The effectiveness of therapy can be evaluated by 24 hour quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.

Hydatidiform mole may precede or be followed by choriocarcinoma, and Methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.

Breast Carcinoma

Prolonged cyclic combination with Cyclophosphamide, Methotrexate and Fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40mg/m² intravenously on the first and eighth days.

Leukaemia

Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.

Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral Methotrexate 3.3mg/m² daily, and Prednisolone 40-60mg/m² daily for 4-6 weeks has been used. After a remission is attained, Methotrexate in a maintenance dosage of 20-30mg/m² orally or by I.M. injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5mg/kg has been administered I.V. every 14 days.

Meningeal Leukaemia

Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.

Passage of Methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. Methotrexate is administered by intrathecal injection in doses of 200-500 microgram/kg body weight. The administration is at intervals of 2 to 5 days and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Alternatively, Methotrexate 12mg/m² can be given once weekly for 2 weeks, and then once monthly. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.

Lymphomas

In Burkitt's Tumour, stages 1-2, Methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25mg per day orally for 4 to 8 days. In stage 3, Methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with Methotrexate given in doses of 0.625mg to 2.5mg/kg daily. Hodgkin's Disease responds poorly to Methotrexate and to most types of chemotherapy.

Mycosis Fungoides

Therapy with Methotrexate appears to produce clinical remissions in one half of the cases treated. Recommended dosage is usually 2.5 to 10mg daily by mouth for weeks or months and dosage should be adjusted according to the patient's response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50mg once weekly or 25mg twice weekly.

Psoriasis Chemotherapy

Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, I.M. or I.V. doses of 10-25mg per week, adjusted according to the patient's response. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10mg.

An alternative dosage schedule consists of 2.5 to 5mg of Methotrexate administered orally at 12 hour intervals for 3 doses each week or at 8-hour intervals for 4 doses each week; weekly dosages should not exceed 30mg.

A daily oral dosage schedule of 2 to 5mg administered orally for 5 days followed by a rest period of at least 2 days may also be used. The daily dose should not exceed 6.25mg.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting Methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of Methotrexate may permit the return to conventional topical therapy which should be encouraged.

4.3 Contraindications

Significantly impaired renal function.

Significantly impaired hepatic function

Pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.

Methotrexate is contraindicated in pregnancy.

Due to the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contra-indicated in women taking methotrexate.

Patients with a known allergic hypersensitivity to methotrexate should not receive methotrexate.

4.4 Special Warnings And Precautions For Use

WARNINGS

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

Deaths have been reported with the use of Methotrexate in the treatment of psoriasis.

In the treatment of psoriasis, Methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

1. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, methotrexate dosing should be suspended for at least 2 weeks.Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.

3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive Methotrexate.

4. Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 — 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625mg tablets every three hours) or acetazolamide (500mg orally four times a day) is recommended as a preventative measure . Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

6. Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of Methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

7. Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of Methotrexate should be taken into account when immune responses of patients are important or essential.

8. Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

9. Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

12. A chest X-ray is recommended prior to initiation of methotrexate therapy.

13. If acute methotrexate toxicity occurs, patients may require folinic acid.

4.3 Contraindications

Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

Carcinogenesis, mutagenesis, and impairment of fertility:

Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes, embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see 'Warnings').

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of Methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving Methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Liver biopsy may be considered after cumulative doses> 1.5g have been given, if hepatic impairment is suspected.

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to Methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Since it is reported that Methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

In all instances where the use of Methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently.

Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed.

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

Methotrexate-induced stomatitis and other toxic effects may be increased by the use of nitrous oxide.

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

4.6 Pregnancy And Lactation

Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving Methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women. Women of childbearing potential should not receive Methotrexate until pregnancy is excluded. For the management of psoriasis or rheumatoid arthritis, Methotrexate therapy in women should be started immediately following a menstrual period and appropriate measures should be taken in men or women to avoid conception during and for at least 6 months following cessation of Methotrexate therapy.

Both men and women receiving Methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during Methotrexate therapy. In cancer chemotherapy, Methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving Methotrexate.

Methotrexate is distributed into breast milk. Because of the potential for serious adverse reactions to Methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin:

Stevens-Johnson syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Blood:

Bone marrow depression, leukopenia, thrombocytopenia, anaemia, hypogammaglobulinaemia, haemorrhage from various sites, septicaemia.

Alimentary System:

Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Hepatic:

Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System:

Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.

Pulmonary System:

Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Central Nervous System:

Headaches, drowsiness, blurred vision, aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of Methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Adverse reactions following intrathecal methotrexate

are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

4.9 Overdose

Calcium Folinate (Calcium Leucovorin) is a potent agent for neutralizing the immediate toxic effects of Methotrexate on the haematopoietic system. Where large doses or overdoses are given, Calcium Folinate may be administered by intravenous infusion in doses up to 75mg within 12 hours, followed by 12mg intramuscularly every 6 hours for 4 doses. Where average doses of Methotrexate appear to have an adverse effect 6-12mg of Calcium Folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of Calcium Folinate should be equal to or higher than, the offending dose of Methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.

Other supporting therapy such as blood transfusion and renal dialysis may be required. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methotrexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by Methotrexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of Methotrexate. It also inhibits antibody synthesis.

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.

5.2 Pharmacokinetic Properties

In doses of 0.1mg (of Methotrexate) per kg, Methotrexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. Peak serum concentrations are achieved within 0.5 - 2 hours following I.V. / I.M. or intra-arterial administration. Serum concentrations following oral administration of Methotrexate may be slightly lower than those following I.V. injection.

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

In one study, Methotrexate had a serum half-life of 2-4 hours following I.M. administration. Following oral doses of 0.06mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037mg/kg were given.

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If Methotrexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress Methotrexate clearance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Other Constituents

Maize Starch	Ph EUR 27.6mg
Lactose	Ph EUR 38.5mg
Pre gelatinized Starch (Prejel PA5)	Ph EUR 2.5mg
Polysorbate 80	Ph EUR 0.2mg
Microcrystalline Cellulose (AVICEL 101)	Ph EUR 18.2mg
Magnesium Stearate	Ph EUR 3.0mg

There is no overage included in the formulation.

6.2 Incompatibilities

Immediate precipitation or turbidity results when combined with certain concentrations of

Droperidol, Heparin Sodium, Metoclopramide Hydrochloride, Ranitidine Hydrochloride in

Syringe.

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

There are no specific storage requirements.

6.5 Nature And Contents Of Container

White polyethylene bottle with high density polyethylene screw closure containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Faulding Pharmaceuticals Plc

Queensway

Royal Leamington Spa

Warwickshire, CV31 3RW

8. Marketing Authorisation Number(S)

PL 04515/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

9^th September 1985/24^th June 1996

10. Date Of Revision Of The Text

4^th July 2001