Invirase

saquinavir mesylate

Dosage Form: tablet, film coated; capsules
FULL PRESCRIBING INFORMATION

Product identification in this document includes: Invirase in reference to saquinavir mesylate; saquinavir 200 mg soft gel capsule formulation1 in reference to saquinavir active base.

1

The term "saquinavir soft gel capsules" used in this label refers to the drug product formerly marketed as "Fortovase" (saquinavir 200 mg soft gel capsule formulation). This formulation has been withdrawn from the market.

Indications and Usage for Invirase

 Invirase in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults (over the age of 16 years).

 The following points should be considered when initiating therapy with Invirase:

–

  The twice daily administration of Invirase in combination with ritonavir is supported by safety data from the MaxCmin 1 study [see Adverse Reactions (6.1)] and pharmacokinetic data [see Clinical Pharmacology (12.3)].

–

 The efficacy of Invirase with ritonavir has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.

–

 The number of baseline primary protease inhibitor mutations affects the virologic response to Invirase/ritonavir.

Invirase Dosage and Administration

Invirase must be used in combination with ritonavir, because it significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.

Adults (Over the Age of 16 Years)

• Invirase 1000-mg twice daily (5 × 200-mg capsules or 2 × 500-mg tablets) in combination with ritonavir 100-mg twice daily.


• Ritonavir should be taken at the same time as Invirase.


• Invirase and ritonavir should be taken within 2 hours after a meal.

Concomitant Therapy: Invirase with Lopinavir/Ritonavir

When administered with lopinavir/ritonavir 400/100 mg twice daily, the appropriate dose of Invirase is 1000 mg twice daily (with no additional ritonavir).

Dosage Forms and Strengths

Capsules: 200 mg

Film-coated tablets: 500 mg

Contraindications

 QT interval prolongation and torsades de pointes have been reported rarely with Invirase/ritonavir use. Do not use in patients with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].

 Invirase is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block [see Warnings and Precautions (5.2)].

Invirase is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients including ritonavir.

Invirase when administered with ritonavir is contraindicated in patients with severe hepatic impairment.

Coadministration of Invirase/ritonavir is contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions. These drugs and potentially related adverse events are listed in Table 1.

Table 1 Drugs That Are Contraindicated With Invirase/Ritonavir

Drug Class	Drugs Within Class That Are Contraindicated With Invirase	Clinical Comment
Alpha 1-adrenoreceptor antagonist	Alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics	Amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine	Potential for serious and/or life-threatening cardiac arrhythmia.
Antidepressant	Trazodone	Increased trazodone concentrations can result in potentially life threatening cardiac arrhythmia.
Antimycobacterial Agents	Rifampin	Rifampin should not be administered in patients taking ritonavir-boosted Invirase part of an ART regimen due to the risk of severe hepatocellular toxicity.
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine	Potential for serious and life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent	Cisapride	Potential for serious and/or life threatening reactions such as cardiac arrhythmias.
HMG-CoA Reductase Inhibitors	Lovastatin, Simvastatin	Potential for myopathy including rhabdomyolysis.
Neuroleptics	Pimozide	Potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 Inhibitors	Sildenafil (Revatio®)[for treatment of pulmonary arterial hypertension]	Increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). A safe and effective dose has not been established when used with Invirase/ritonavir.
Sedative/Hypnotics	Triazolam, orally administered midazolam	Potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam and orally administered midazolam with Invirase/ritonavir may cause large increases in the concentration of these benzodiazepines.

Warnings and Precautions

Invirase must be used in combination with ritonavir. Please refer to the ritonavir full prescribing information for additional precautionary measures.

If a serious or severe toxicity occurs during treatment with Invirase, Invirase should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose Invirase may be considered. For antiretroviral agents used in combination with Invirase, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

Drug Interactions

The combination Invirase/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. See Table 1 for a listing of drugs that are contraindicated for use with Invirase/ritonavir due to potentially life-threatening adverse events or significant drug interactions [see Contraindications (4)]. See Table 3 for established and other potentially significant drug interactions [see Drug Interactions (7.3)].

 5.2 PR Interval Prolongation

 Saquinavir/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre-existing conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients [see Warnings and Precautions (5.3)].

 The impact on the PR interval of co-administration of saquinavir/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of saquinavir/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see Clinical Pharmacology (12.2)].

 5.3 QT Interval Prolongation

 Saquinavir/ritonavir causes dose-dependent QT prolongation. Torsades de pointes has been reported rarely post-marketing. Avoid saquinavir/ritonavir in patients with long QT syndrome. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating saquinavir/ritonavir and monitor these electrolytes periodically during therapy. Do not use in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval (see Tables 1 and 3) [see Clinical Pharmacology (12.2)].

 Patients initiating therapy with ritonavir-boosted Invirase:

 An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should not receive ritonavir-boosted Invirase. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 days of therapy; patients with a QT interval > 480 msec or prolongation over pre-treatment by > 20 msec should discontinue ritonavir-boosted Invirase.

 Patients requiring treatment with medications with the potential to increase the QT interval and concomitant ritonavir-boosted Invirase:

 Such combinations should only be used where no alternative therapy is available and the potential benefits outweigh the potential risks. An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval < 450 msec, an on-treatment ECG should be performed after 3-4 days of therapy. For patients demonstrating a subsequent increase in QT interval to > 480 msec or increase by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either ritonavir-boosted Invirase or the concomitant therapy or both.

 A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.

Diabetes Mellitus and Hyperglycemia

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease-inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease-inhibitor therapy and these events has not been established.

Hepatotoxicity

In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities, there have been reports of worsening liver disease.

Hemophilia

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients additional factor VIII was required. In the majority of reported cases treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Hyperlipidemia

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of Invirase with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.

Lactose Intolerance

Each capsule contains lactose (anhydrous) 63.3 mg. This quantity should not induce specific symptoms of intolerance.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), facial wasting, peripheral wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. A causal relationship between protease-inhibitor therapy and these events has not been established and the long-term consequences are currently unknown.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Invirase. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Resistance/Cross-resistance

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued administration of Invirase therapy following loss of viral suppression may increase the likelihood of cross resistance to other protease inhibitors [see Clinical Pharmacology (12.4)].

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• PR Interval Prolongation [see Warnings and Precautions (5.2)]


• QT Interval Prolongation [see Warnings and Precautions (5.3)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The original Invirase safety database consisted of a total of 574 patients who received saquinavir 600 mg alone or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1 infected patients and 166 healthy subjects who received various combinations of either saquinavir (hard gel or soft-gel capsules) with ritonavir.

The recommended dose of Invirase is 1000 mg twice daily co-administered with ritonavir 100 mg twice daily, in combination with other antiretroviral agents. Table 2 lists grade 2, 3 and 4 adverse events that occurred in ≥2% of patients receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).

Table 2 Grade 2, 3 and 4 Adverse Events (All Causality*) Reported in ≥2% of Adult Patients in the MaxCmin 1 Study of Saquinavir Soft Gel Capsules in Combination with Ritonavir 1000/100 mg bid

Adverse Events	Saquinavir soft gel capsules 1000 mg plus Ritonavir 100 mg bid (48 weeks) N=148 n (%=n/N)
* Includes events with unknown relationship to study drug
Endocrine Disorders
Diabetes mellitus/hyperglycemia	4 (2.7)
Lipodystrophy	8 (5.4)
Gastrointestinal Disorders
Nausea	16 (10.8)
Vomiting	11 (7.4)
Diarrhea	12 (8.1)
Abdominal Pain	9 (6.1)
Constipation	3 (2.0)
General Disorders and Administration Site Conditions
Fatigue	9 (6.1)
Fever	5 (3.4)
Musculoskeletal Disorders
Back Pain	3 (2.0)
Respiratory Disorders
Pneumonia	8 (5.4)
Bronchitis	4 (2.7)
Influenza	4 (2.7)
Sinusitis	4 (2.7)
Dermatological Disorders
Rash	5 (3.4)
Pruritus	5 (3.4)
Dry lips/skin	3 (2.0)
Eczema	3 (2.0)

Limited experience is available from three studies investigating the pharmacokinetics of the Invirase 500 mg film-coated tablet compared to the Invirase 200 mg capsule in healthy volunteers (n=140). In two of these studies saquinavir was boosted with ritonavir; in the other study, saquinavir was administered as single drug. The Invirase tablet and the capsule formulations were similarly tolerated. The most common adverse events were gastrointestinal disorders (such as diarrhea). Similar bioavailability was demonstrated and no clinically significant differences in saquinavir exposures were seen. Thus, similar safety profiles are expected between the two Invirase formulations.

In a study investigating the drug-drug interaction of rifampin 600 mg/day daily and Invirase 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted Invirase) involving 28 healthy volunteers, 11 of 17 healthy volunteers (65%) exposed concomitantly to rifampin and ritonavir-boosted Invirase developed severe hepatocellular toxicity which presented as increased hepatic transaminases. In some subjects, transaminases increased up to >20-fold the upper limit of normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical symptoms abated and the increased hepatic transaminases normalized [see Contraindications (4)].

Additional Adverse Reactions Reported During Clinical Trials with Saquinavir

Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, thrombocytopenia

Cardiac disorders: heart murmur, syncope

Ear and labyrinth disorders: tinnitus

Eye disorders: visual impairment

Gastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructation, flatulence, gastritis, gastrointestinal hemorrhage, intestinal obstruction, mouth dry, mucosal ulceration, pancreatitis

General disorders and administration site conditions: anorexia, asthenia, chest pain, edema, lethargy, wasting syndrome, weight increased

Hepatobiliary disorders: chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertension

Immune system disorders: allergic reaction

Investigations: ALT increase, AST increase, blood creatine phosphokinase increased, increased alkaline phosphatase, GGT increase, raised amylase, raised LDH

Metabolism and nutrition disorders: increased or decreased appetite, dehydration, hypertriglyceridemia

Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, polyarthritis

Neoplasms benign, malignant and unspecified (incl cysts and polyps): acute myeloid leukemia, papillomatosis

Nervous system disorders: confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache, hypoaesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral neuropathy, somnolence, tremor

Psychiatric disorders: anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder, suicide attempt

Renal and urinary disorders: nephrolithiasis

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis bullous, drug eruption, erythema, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, sweating increased, urticaria

Vascular disorders: hypertension, hypotension, thrombophlebitis, peripheral vasoconstriction

Postmarketing Experience

Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with Invirase and saquinavir soft gel capsules alone or in combination with ritonavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Invirase exposure.

Drug Interactions

Drug interaction studies have been completed with both Invirase and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for Invirase/ritonavir. Because ritonavir is coadministered with Invirase, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.

Potential for Invirase to Affect Other Drugs

The combination Invirase/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. Drugs that are contraindicated specifically due to the observed or expected magnitude of interaction and potential for serious or life-threatening adverse events are listed in Table 1 [see Contraindications (4)]. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring (Table 3).

Potential for Other Drugs to Affect Invirase

The metabolism of saquinavir is mediated primarily by CYP3A. Additionally, saquinavir is a substrate for P-glycoprotein (P-gp). Therefore, drugs that affect CYP3A and/or P-gp may modify the pharmacokinetics of saquinavir. Coadministration with drugs that are potent inducers of CYP3A (e.g., phenobarbital, phenytoin, carbamazepine) may result in decreased plasma concentrations of saquinavir and reduced therapeutic effect.

Established and Other Potentially Significant Drug Interactions

Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving Invirase/ritonavir, additive effects on QT and/or PR interval prolongation may occur with certain members of the following drug classes: antiarrhythmics class IA or class III, neuroleptics, antidepressive agents, PDE5 inhibitors (when used for pulmonary arterial hypertension), antimicrobials, antihistaminics and others. This effect might lead to an increased risk of ventricular arrhythmias, notably torsades de pointes. Therefore, concurrent administration of these agents with Invirase/ritonavir is contraindicated [see Contraindications (4)].

Table 3 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or avoidance of the combination may be recommended depending on the interaction.

Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with Invirase/ritonavir

Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
* Invirase/ritonavir interaction has not been evaluated. † See Drug Interactions (7), Table 5 and Table 6 for magnitude of interactions.
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Delavirdine*	↑ Saquinavir Effect on delavirdine is not well established	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz†, nevirapine*	↓ Saquinavir ↔ Efavirenz	Appropriate doses of the combination of efavirenz or nevirapine and Invirase/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor: Atazanavir†	Invirase/ritonavir ↑ Saquinavir ↑ Ritonavir ↔ Atazanavir	Atazanavir in combination with Invirase/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with Invirase/ritonavir [see Warnings and Precautions (5.2)].
HIV-1 protease inhibitor: Indinavir*	↑ Saquinavir Effect on indinavir is not well established	Appropriate doses of the combination of indinavir and Invirase/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor: Lopinavir/ritonavir† (coformulated tablet)	↔ Saquinavir ↔ Lopinavir ↓ Ritonavir	Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with Invirase should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase [Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor: Tipranavir/ritonavir†	↓ Saquinavir	Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV-1 fusion inhibitor: Enfuvirtide†	Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide	No clinically significant interaction was noted from a study in 12 HIV-1 patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
HIV-1 CCR5 antagonist: Maraviroc	↑ maraviroc	Maraviroc dose should be 150 mg twice daily when coadministered with Invirase/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Ibutilide Sotalol		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Anticoagulant: Warfarin*	↑ Warfarin	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine*, phenobarbital*, phenytoin*	↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established	Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-gout: Colchicine	↑ Colchicine	Treatment of gout flares-coadministration of colchicine in patients on Invirase/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on Invirase/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Prophylaxis of gout-flares-co-administration of colchicine in patients on Invirase/ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with Invirase/ritonavir.
Anti-infective: Clarithromycin†	↑ Saquinavir ↑ Clarithromycin	Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Erythromycin Halofantrine Pentamidine		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Antifungal: Ketoconazole†, itraconazole*	↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole	When Invirase/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 3). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial: Rifabutin†	↔ Saquinavir ↑ Rifabutin ↔ Ritonavir	No dose adjustment of Invirase/ritonavir (1000/100 mg bid) is required if ritonavir-boosted Invirase is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure.
Benzodiazepines*: Alprazolam, clorazepate, diazepam, flurazepam	↑ Benzodiazepines	Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine*: Intravenously administered Midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, Invirase should not be given with orally administered midazolam [see Contraindications (4)]. If Invirase is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers*: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone*	↓ Saquinavir	Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations.
Digitalis Glycosides: Digoxin†	↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with Invirase/ritonavir.	Concomitant use of Invirase/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when Invirase/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with Invirase/ritonavir.
Endothelin receptor antagonists: Bosentan	↑ Bosentan	Coadministration of bosentan in patients on Invirase/ritonavir: In patients who have been receiving Invirase/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of Invirase/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of Invirase/ritonavir. After at least 10 days following the initiation of Invirase/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist: Salmeterol	↑ Salmeterol	Concurrent administration of salmeterol with Invirase/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone*	Invirase/ritonavir ↑ Fluticasone	Concomitant use of fluticasone propionate and Invirase/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and Invirase/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
HMG-CoA reductase inhibitors*: Atorvastatin, rosuvastatin	↑ Atorvastatin ↑ Rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir.
Immunosuppressants*: Cyclosporine, tacrolimus, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with Invirase/ritonavir.
Narcotic analgesic: Methadone†	↓ Methadone	Dosage of methadone may need to be increased when coadministered with Invirase/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Neuroleptics: Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives: Ethinyl estradiol*	↓ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and Invirase/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil†, vardenafil*, tadalafil*	↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with Invirase/ritonavir: Coadministration of ADCIRCA in patients on Invirase/ritonavir: In patients receiving Invirase/ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of Invirase/ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of Invirase/ritonavir. Stop ADCIRCA at least 24 hours prior to starting Invirase/ritonavir. After at least one week following the initiation of Invirase/ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir.
Tricyclic antidepressants*: Amitriptyline, imipramine	↑ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with Invirase/ritonavir.
Proton pump inhibitors: Omeprazole†	↑ Saquinavir	When Invirase/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with Invirase/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products: St. John's wort* (hypericum perforatum)	↓ Saquinavir	Coadministration may lead to loss of virologic response and possible resistance to Invirase or to the class of protease inhibitors.
Garlic Capsules*	↓ Saquinavir	Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Reproduction studies conducted with saquinavir have shown no embryotoxicity or teratogenicity in both rats and rabbits. Because of limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir. Clinical experience in pregnant women is limited. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including Invirase, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Invirase.

Pediatric Use

Safety and effectiveness of Invirase in HIV-1-infected pediatric patients younger than 16 years of age have not been established.

Geriatric Use

Clinical studies of Invirase did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from

Lamisil AT Topical

Generic Name: terbinafine (Topical route)

TER-bin-a-feen

Commonly used brand name(s)

In the U.S.

• Lamisil


• Lamisil AT

In Canada

• Lamisil Dermgel

Available Dosage Forms:

• Gel/Jelly


• Cream


• Solution


• Spray

Therapeutic Class: Antifungal

Chemical Class: Allylamine

Uses For Lamisil AT

Terbinafine is used to treat infections caused by a fungus. It works by killing the fungus or preventing its growth.

Terbinafine is applied to the skin to treat:

• ringworm of the body (tinea corporis);


• ringworm of the foot (interdigital and plantar tinea pedis; athlete's foot);


• ringworm of the groin (tinea cruris; jock itch);


• tinea versicolor (sometimes called “sun fungus”); and


• yeast infections of the skin (cutaneous candidiasis).

This medicine is available both over-the-counter (OTC) and with your doctor's prescription.

Before Using Lamisil AT

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

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of terbinafine in children under the age of 12 with use in other age groups.

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. Although there is no specific information comparing use of terbinafine in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

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

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while 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 taking 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 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.

• Clozapine

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.

• Cyclosporine


• Metoprolol


• Nortriptyline


• 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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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:

• Fungus infection of the nails—condition may decrease the effect of terbinafine when this medicine is used to treat a type of ringworm of the foot (plantar tinea pedis)

Proper Use of terbinafine

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

Apply enough terbinafine cream to cover the affected and surrounding skin areas and rub in gently.

Apply enough terbinafine solution to wet and cover the affected and surrounding skin areas. Allow it to dry.

Keep this medicine away from the eyes, nose, mouth, and other mucous membranes. The solution may be especially irritating to the eyes.

Terbinafine spray solution contains alcohol and should not be applied to the face.

Do not apply an occlusive dressing (airtight covering, such as a tight bandage or plastic kitchen wrap) over this medicine unless you have been directed to do so by your doctor.

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 form (cream):
  
  • For cutaneous candidiasis:
    
    • Adults—Use one or two times a day for seven to fourteen days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For tinea corporis or tinea cruris:
    
    • Adults and children 12 years of age and older—Use one or two times a day for seven to twenty-eight days.
    
    
    • Infants and children younger than 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For tinea pedis (interdigital):
    
    • Adults and children 12 years of age and older—Use two times a day for seven to twenty-eight days.
    
    
    • Infants and children younger than 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For tinea pedis (plantar):
    
    • Adults and children 12 years of age and older—Use two times a day for fourteen days.
    
    
    • Infants and children younger than 12 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For tinea versicolor:
    
    • Adults—Use one or two times a day for fourteen days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  


• For topical dosage form (spray solution):
  
  • For tinea corporis or tinea cruris:
    
    • Adults—Use once a day for seven days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For tinea pedis or tinea versicolor:
    
    • Adults—Use two times a day for seven days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

To help clear up your infection completely, it is very important that you keep using terbinafine for the full time of treatment , even if your symptoms begin to clear up after a few days. Since fungus infections may be very slow to clear up, you may have to continue using this medicine every day for several weeks or more. If you stop using this medicine too soon, your symptoms may return. Do not miss any doses .

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 Lamisil AT

Discontinue using this medicine and check with your doctor if increased irritation or possible sensitization (redness, itching, burning, blistering, swelling, or oozing) occurs while using the medication.

If your skin problem does not improve within 4 to 7 weeks, or if it becomes worse, check with your doctor.

To help clear up your infection completely and to help make sure it does not return, good health habits are also needed. The following measures will help reduce chafing and irritation and will also help keep the area cool and dry.

• For patients using terbinafine for ringworm of the body:
  
  • Carefully dry yourself after bathing.
  
  
  • Avoid too much heat and humidity if possible. Try to keep moisture from building up on affected areas of the body.
  
  
  • Wear well-ventilated, loose-fitting clothing.
  
  
  • Use a bland, absorbent powder (for example, talcum powder) once or twice a day. Be sure to use the powder after terbinafine cream or solution has been applied and has disappeared into the skin.
  
  


• For patients using terbinafine for ringworm of the groin:
  
  • Avoid wearing underwear that is tight-fitting or made from synthetic (man-made) materials (for example, rayon or nylon). Instead, wear loose-fitting, cotton underwear.
  
  
  • Use a bland, absorbent powder (for example, talcum powder) on the skin. It is best to use the powder between the times you use terbinafine.
  
  


• For patients using terbinafine for ringworm of the foot:
  
  • Carefully dry the feet, especially between the toes, after bathing.
  
  
  • Avoid wearing socks made from wool or synthetic materials (for example, rayon or nylon). Instead, wear clean, cotton socks and change them daily or more often if the feet sweat a lot.
  
  
  • Wear sandals or well-ventilated shoes (for example, shoes with holes).
  
  
  • Use a bland, absorbent powder (for example, talcum powder) between the toes, on the feet, and in socks and shoes once or twice a day. It is best to use the powder between the times you use terbinafine.
  
  

If you have any questions about these measures, check with your health care professional.

Lamisil AT 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 as soon as possible if any of the following side effects occur:

Rare

• Dryness


• redness


• itching


• burning


• peeling


• rash


• stinging


• tingling


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

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: Lamisil AT 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 Lamisil AT Topical resources

• Lamisil AT Topical Side Effects (in more detail)
• Lamisil AT Topical Use in Pregnancy & Breastfeeding
• Lamisil AT Topical Support Group
• 4 Reviews for Lamisil AT Topical - Add your own review/rating

Compare Lamisil AT Topical with other medications

• Tinea Corporis
• Tinea Cruris
• Tinea Pedis

Haemate P 500 and 1000 IU

CSL Behring

HAEMATE P 500 and 1000 IU

Powder and solvent for solution for injection or infusion

Read all of this leaflet carefully before you start using this medicine.

Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or your haemophilia nurse. This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects become serious or you notice any others not listed below, please tell your doctor or haemophilia nurse.

In This Leaflet:

1. What Haemate P is and what it is used for

2. Before you use Haemate P

3. How to use Haemate P

4. Possible side effects

5. Storing Haemate P

6. Further information

What Haemate P Is And What It Is Used For

Haemate P is a product made from human plasma (this is the liquid part of the blood). It is used to prevent or stop the bleeding caused by a lack of factor VIII (haemophilia A) or von Willebrand factor (von Willebrand disease) in your blood. Both these factors are needed for the formation of blood clots which help bleeding to stop.

Before You Use Haemate P

Do not use Haemate P

• If you are allergic to any of the ingredients. If you are unsure about this, ask your doctor (see section 6).

Take special care with Haemate P

• If you experience any signs of an allergic reaction to Haemate P (for example a rash, tight chest, wheezing or feeling dizzy), stop injecting the product immediately and contact your doctor.


• You should visit your doctor or haemophilia treatment centre regularly to ensure that your dose is correct. The doctor may wish to carry out some tests to make sure that you are getting the right amount.


• If your bleeding is not being controlled with Haemate P, tell your doctor immediately. You may have developed an inhibitor (an antibody which can cancel out the effects of factor VIII) and your doctor may wish to carry out more tests to confirm this.


• If you have von Willebrand’s Disease, you may be at risk of developing blood clots (thrombosis), particularly if you have known risk factors.


• Hepatitis A and B vaccination should be a consideration for patients who receive regular / repeated treatment of human plasma-derived products.

Taking or using other medicines

There are no medicines that are known to react with Haemate P. However, if you are taking another medicine and are concerned, please ask your doctor or haemophilia nurse.

Pregnancy and breast-feeding

If you are pregnant or planning a family soon, or if you are breast-feeding, ask your doctor for advice before using this product.

Driving and using machines

Haemate P does not affect your ability to drive or use machines.

Important information about some of the ingredients of Haemate P

Haemate P contains up to 70 mg sodium per 1000 IU. Please take this into account if you are on a sodium (salt) controlled diet as you may need to cut down on the salt in your diet.

Important safety information related to infections

When medicines are made from human blood, steps are taken to stop infections (e.g. HIV and Hepatitis) being passed on to the patient. This includes:

• Careful selection of the blood donors


• Testing of each donation for signs of infection


• Steps in the manufacture which can kill or remove viruses

However, there is still a small chance of an infection being passed on to the patient. This may include a new virus or infection. Therefore, every time Haemate P is used, it is important to note the name and batch number of the medicine (found on the carton).

How To Use Haemate P

The amount of factor VIII or von Willebrand factor you need will depend on several factors, such as your weight, the severity of your condition, the site and severity of bleeding or the need to prevent bleeding during an operation or investigation. Haemate P is given by injection or infusion into a vein. If you have been prescribed Haemate P to use at home, your doctor or haemophilia centre nurse will make sure that you are shown how to inject it and how much to use.

If you are in any doubt about injecting Haemate P, go back to your doctor or haemophilia centre for more advice and training before attempting to treat yourself.

Follow the directions given to you by your doctor or haemophilia nurse. You can also use the directions below as a guide.

Directions for preparing and administering Haemate P

Wash your hands thoroughly using soap and warm water.

If necessary, warm the Haemate P powder vial and the liquid (Water for Injections) vial to room or body temperature without opening either vial. You can do this by leaving the vials to stand at room temperature for about an hour or, if you need them quickly by holding them in your hands for a few minutes.

DO NOT expose the vials to direct heat or stand the vials on a radiator. The vials must not be heated above body temperature (37º C).

Carefully remove the protective caps from the vials and clean the exposed rubber stoppers with the alcohol swab provided. Allow the vials to dry before opening the Mix2Vial package, then follow the instructions given below.

1. Open the Mix2Vial package by peeling away the lid. Do not remove the Mix2Vial from the blister package.

2. Place the water vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the blue adaptor end straight down through the water vial stopper.

3. Carefully remove the blister package from the Mix2Vial set by holding at the rim and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set as well.

4. With the Haemate P vial firmly on an even surface, turn the water vial with the Mix2Vial set attached upside down and push the spike of the transparent adaptor end straight down through the Haemate P vial stopper.

The water will automatically flow into the Haemate P vial.

5. With one hand, grasp the Haemate P-side of the Mix2Vial set and with the other hand, grasp the waterside and unscrew the set carefully into two pieces (to avoid excessive foam build-up when dissolving the powder). Discard the water vial with the blue Mix2Vial adaptor attached.

Do not worry if there are a few flakes or particles left in the water as this can happen sometimes. They will be removed by the filter when you draw the liquid into the syringe.

6. Gently swirl the Haemate P vial with the transparent adaptor attached until the powder is fully dissolved. Do not shake.

7. Draw air into an empty, sterile syringe. While the Haemate P vial is upright, connect the syringe to the Mix2Vial´s Luer Lock fitting and inject air into the Haemate P vial.

Once you have made up the solution, it should be used immediately. If this is not possible it should be used up within 8 hours.

Withdrawal and application

8. Keep the syringe plunger pressed in, turn the system upside down and draw the required amount of liquid into the syringe by pulling the plunger back slowly.

9. Once the liquid has all been transferred into the syringe, hold onto the barrel of the syringe firmly while keeping the syringe plunger facing down and disconnect the transparent Mix2Vial adaptor set from the syringe.

If there are any particles in the liquid in the syringe, or it is cloudy, do not inject it as this could block your blood vessels.

10. Attach a suitable injection needle (or the slow injection kit) to the syringe and get rid of all trapped air by turning the needle upwards and tapping the syringe gently so that any air bubbles rise, then push the barrel of the syringe up gently until the liquid begins to come out of the end of the needle. Once the product has been transferred into a syringe, it should be used immediately.

11. Apply a tourniquet as you have been shown and find a suitable vein, clean the skin surface with an alcohol swab and insert the needle or slow injection kit into the vein. Make sure that no blood enters the syringe.

12. Remove the tourniquet and inject the solution slowly into the vein, keeping the needle in place all the time. The solution should be injected at a maximum rate of 4ml per minute.

13. If more than one vial of Haemate P is needed, leave the syringe attached to the slow injection kit. Prepare a new vial as directed in steps 1 - 9, fill a new syringe, remove the old syringe from the slow injection kit and repeat steps 10 13.

14. If no further vials are needed, remove the needle or slow injection kit plus syringe, hold a sterile swab over the injection site for about 2 minutes with the arm stretched out and supported, then apply a small plaster.

Any unused solution should be left in the vial or syringe. Dispose of all vials, needles, syringes and swabs in a ‘Sharps box’ or as you have been told. Do not throw them away with your household rubbish.

If you use more Haemate P than you should

No symptoms of overdose with Haemate P have been reported. However, if you accidentally inject a large overdose, then you should tell your doctor or haemophilia centre immediately.

In some circumstances, you may be a risk of a thrombosis (blood clot). Symptoms of a thrombosis are listed in the side effects section.

If you forget to use Haemate P

Inject your normal dose as soon as you remember and then continue as instructed by your doctor or haemophilia nurse.

Possible Side Effects

Like all medicines, Haemate P can cause side effects, although not everybody gets them.

Rare side effects (affect less than 1 in 1,000 people):

• Fever

Very rare side effects (affect less than 1 in 10,000 people):

• Chills, flushing, redness, swelling


• Burning and stinging around the injection/infusion site


• Itching, tingling, rash


• Headache, dizziness, feeling sick or actually being sick


• Tight chest, wheezing, faster heartbeat


• Feeling restless or feeling tired

If your side effects are severe, this could be a sign of allergic shock (anaphylaxis), so stop your injection immediately and contact your doctor.

If you inject too much Haemate P, you may be at risk of a thrombosis (blood clot) where you do not want one, especially if you have von Willebrand disease. You may also be at risk if you have a family history of thrombosis or if you have ever had a thrombosis. Symptoms of a thrombosis include:

• Unusual pain or swelling in your legs


• Sudden sharp pain in your chest


• Sudden difficulty breathing


• An unusual, severe or long-lasting headache


• Dizziness or fainting

If you have any of these symptoms, stop your injection immediately and contact your doctor.

If you notice that your Haemate P is less effective than usual, contact your doctor or haemophilia centre immediately.

Storing Haemate P

Do not store above 25 ºC. Do not freeze.

Keep the vials in the outer carton, in order to protect from light.

Keep out of the reach and sight of children.

Do not use Haemate P after the expiry date on the carton. Please ask your doctor or haemophilia nurse how to dispose of the medicine properly.

Further Information

What Haemate P contains

The active substances are:

• 500 or 1000 International Units (IU) human plasma coagulation factor VIII and 1200 or 2400 IU von Willebrand factor.

Other ingredients are:

• glycine


• human albumin


• sodium citrate


• sodium chloride


• traces of sodium hydroxide or hydrochloric acid may also be present (used for pH adjustment).

Bottles of product and liquid will appear partly empty but this is normal and does not mean that there is the wrong amount of powder or solution.

Marketing Authorisation Holder and Manufacturer

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

This leaflet was last approved on: 07/2010

For further information contact

CSL Behring UK Limited

Hayworth House

Market Place

Haywards Heath

West Sussex

RH16 1DB

UK

Telephone number:01444 447 405

This leaflet was last approved on: 07/2010

Merrem

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Merrem

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Merrem I.V. and other antibacterial drugs, Merrem I.V. should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Merrem I.V. is useful as presumptive therapy in the indicated condition (e.g., intra-abdominal infections) prior to the identification of the causative organisms because of its broad spectrum of bactericidal activity.

Skin and Skin Structure Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)

Merrem I.V. is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to Staphylococcus aureus (β-lactamase- and non-β-lactamase-producing, methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

Intra-abdominal Infections (Adult Patients and Pediatric Patients ≥ 3 Months only)

Merrem I.V. is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

Bacterial Meningitis (Pediatric Patients ≥ 3 Months only)

Merrem I.V. is indicated as a single agent therapy for the treatment of bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (β-lactamase- and non-β-lactamase-producing isolates), and Neisseria meningitidis.

‡ The efficacy of meropenem as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established.

Merrem I.V. has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

For information regarding use in pediatric patients (3 months of age and older) [see Indications and Usage (1.1), (1.2) or (1.3); Dosage and Administration (2.3), and Adverse Reactions (6.1)].

Merrem Dosage and Administration

Adult Patients

The recommended dose of Merrem I.V. is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. Merrem I.V. should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Use in Adult Patients with Renal Impairment

Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.)

When only serum creatinine is available, the following formula (Cockcroft and Gault equation)5 may be used to estimate creatinine clearance.

Males: Creatinine Clearance (mL/min) =

Weight (kg) x (140 - age)__

72 x serum creatinine (mg/dL)

Females: 0.85 x above value

Recommended Merrem I.V. Dosage Schedule for Adult Patients With Renal Impairment

Creatinine Clearance (mL/min)	Dose (dependent on type of infection)	Dosing Interval
> 50	Recommended dose (500 mg cSSSI and 1g Intra-abdominal)	Every 8 hours
>25-50	Recommended dose	Every 12 hours
10-25	One-half recommended dose	Every 12 hours
<10	One-half recommended dose	Every 24 hours

There is inadequate information regarding the use of Merrem I.V. in patients on hemodialysis or peritoneal dialysis.

Use in Pediatric Patients (≥ 3 Months only)

For pediatric patients from 3 months of age and older, the Merrem I.V. dose is 10, 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered Merrem I.V. at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 g every 8 hours for intra-abdominal infections and 2 g every 8 hours for meningitis. Merrem I.V. should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Recommended Merrem I.V. Dosage Schedule for Pediatric Patients With Normal Renal Function

Type of Infection	Dose (mg/kg)	Up to a Maximum Dose	Dosing Interval
Complicated skin and skin structure	10	500 mg	Every 8 hours
Intra-abdominal	20	1 g	Every 8 hours
Meningitis	40	2 g	Every 8 hours

There is no experience in pediatric patients with renal impairment.

Preparation of Solution

For Intravenous Bolus Administration

Constitute injection vials (500 mg and 1 g) with sterile Water for Injection. (See table below.) Shake to dissolve and let stand until clear.

Vial Size	Amount of Diluent Added (mL)	Approximate Withdrawable Volume (mL)	Approximate Average Concentration (mg/mL)
500 mg	10	10	50
1 g	20	20	50

For Infusion

Infusion vials (500 mg and 1 g) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an I.V. container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)].

WARNING: Do not use flexible container in series connections.

Compatibility

Compatibility of Merrem I.V. with other drugs has not been established. Merrem I.V. should not be mixed with or physically added to solutions containing other drugs.

Stability and Storage

Freshly prepared solutions of Merrem I.V. should be used whenever possible. However, constituted solutions of Merrem I.V. maintain satisfactory potency at controlled room temperature 15-25ºC (59-77°F) or under refrigeration at 4°C (39°F) as described below. Solutions of intravenous Merrem I.V. should not be frozen.

Intravenous Bolus Administration

Merrem I.V. injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of Merrem I.V.) may be stored for up to 2 hours at controlled room temperature 15-25°C (59-77°F) or for up to 12 hours at 4°C (39°F).

Intravenous Infusion Administration

Stability in Infusion Vials: Merrem I.V. infusion vials constituted with Sodium Chloride Injection 0.9% (Merrem I.V. concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25°C (59- 77°F) or for up to 18 hours at 4°C (39°F). Infusion vials of Merrem I.V. constituted with Dextrose Injection 5% (Merrem I.V. concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 1 hour at controlled room temperature 15-25°C (59-77°F) or for up to 8 hours at 4°C (39°F).

Stability in Plastic I.V. Bags: Solutions prepared for infusion (Merrem I.V. concentrations ranging from 1 to 20 mg/mL) may be stored in plastic intravenous bags with diluents as shown below:

* NORMOSOL is a registered trademark of Hospira Inc.
	Number of Hours Stable at Controlled Room Temperature 15-25°C (59-77°F)	Number of Hours Stable at 4°C (39°F)
Sodium Chloride Injection 0.9%	4	24
Dextrose Injection 5.0%	1	4
Dextrose Injection 10.0%	1	2
Dextrose and Sodium Chloride Injection 5.0%/0.9%	1	2
Dextrose and Sodium Chloride Injection 5.0%/0.2%	1	4
Potassium Chloride in Dextrose Injection 0.15%/5.0%	1	6
Sodium Bicarbonate in Dextrose Injection 0.02%/5.0%	1	6
Dextrose Injection 5.0% in Normosol®-M*	1	8
Dextrose Injection 5.0% in Ringers Lactate Injection	1	4
Dextrose and Sodium Chloride Injection 2.5%/0.45%	3	12
Mannitol Injection 2.5%	2	16
Ringers Injection	4	24
Ringers Lactate Injection	4	12
Sodium Lactate Injection 1/6 N	2	24
Sodium Bicarbonate Injection 5.0%	1	4

Stability in Baxter Minibag Plus: Solutions of Merrem I.V. (Merrem I.V. concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Sodium Chloride Injection 0.9% may be stored for up to 4 hours at controlled room temperatures 15-25°C (59-77°F) or for up to 24 hours at 4°C (39°F). Solutions of Merrem I.V. (Merrem I.V. concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Dextrose Injection 5.0% may be stored up to 1 hour at controlled room temperatures 15-25°C (59-77°F) or for up to 6 hours at 4°C (39°F).

Stability in Plastic Syringes, Tubing and Intravenous Infusion Sets: Solutions of Merrem I.V. (Merrem I.V. concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride Injection 0.9% (for up to 4 hours) or in Dextrose Injection 5.0% (for up to 2 hours) at controlled room temperatures 15-25°C (59-77°F) are stable in plastic tubing and volume control devices of common intravenous infusion sets.

Solutions of Merrem I.V. (Merrem I.V. concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride Injection 0.9% (for up to 48 hours) or in Dextrose Injection 5% (for up to 6 hours) are stable at 4ºC (39ºF) in plastic syringes.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage Forms and Strengths

Single use clear glass vials containing 500 mg or 1 g (as the trihydrate blend with anhydrous sodium carbonate for constitution) of sterile meropenem powder.

Contraindications

Merrem I.V. is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to β-lactams.

Warnings and Precautions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with Merrem I.V., careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to Merrem I.V. occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management, including intubation. Other therapy may also be administered as indicated.

Seizure Potential

Seizures and other adverse CNS experiences have been reported during treatment with Merrem I.V. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.2)].

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or reduced renal function [see Dosage and Administration (2.2)].

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Anti-convulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anti-convulsant therapy if not already instituted, and the dosage of Merrem I.V. re-examined to determine whether it should be decreased or the antibiotic discontinued.

Interaction with Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Merrem I.V. is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.2)].

Clostridium difficile–Associated Diarrhea

Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Merrem I.V., and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing Merrem I.V. in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Overgrowth of Nonsusceptible Organisms

As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

Laboratory Tests

While Merrem I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Patients with Renal Impairment

In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use In Specific Populations (8.5) and (8.6), andClinical Pharmacology (12.3)].

Dialysis

There is inadequate information regarding the use of Merrem I.V. in patients on hemodialysis or peritoneal dialysis.

Adverse Reactions

The following are discussed in greater detail in other sections of labeling:

• 
  

  Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

  
  


• 
  

  Seizure Potential [see Warnings and Precautions (5.2)]

  
  


• 
  

  Interaction with Valproic Acid [see Warnings and Precautions (5.3)]

  
  


• 
  

  Clostridium difficile – Associated Diarrhea [see Warnings and Precautions (5.4)]

  
  


• 
  

  Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5)]

  
  


• 
  

  Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.6)]

  
  


• 
  

  Laboratory Tests [see Warnings and Precautions (5.7)]

  
  


• 
  

  Patients with Renal Impairment [see Warnings and Precautions (5.8)]

  
  


• 
  

  Dialysis [see Warnings and Precautions (5.9)]

  
  

Adverse Reactions from Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients:

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Merrem I.V. (500 mg or 1000 mg every 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Merrem I.V.

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Merrem I.V.

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with Merrem I.V. were as follows:

Inflammation at the injection site	2.4%
Injection site reaction	0.9%
Phlebitis/thrombophlebitis	0.8%
Pain at the injection site	0.4%
Edema at the injection site	0.2%

Systemic Adverse Reactions

Systemic adverse reactions that were reported irrespective of the relationship to Merrem I.V. occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%).

Additional systemic adverse reactions that were reported irrespective of relationship to therapy with Merrem I.V. and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%.

Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain

Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope

Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction

Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia

Metabolic/Nutritional: peripheral edema, hypoxia

Nervous System: insomnia, agitation/delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.2)]

Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema

Skin and Appendages: urticaria, sweating, skin ulcer

Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence

Adverse Laboratory Changes

Adverse laboratory changes that were reported irrespective of relationship to Merrem I.V. and occurring in greater than 0.2% of the patients were as follows:

Hepatic: increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin

Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia

Renal: increased creatinine and increased BUN

NOTE: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to Merrem I.V., increased in patients with moderately severe renal impairment (creatinine clearance >10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)].

Urinalysis: presence of red blood cells

Complicated Skin and Skin Structure Infections

In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in >5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of >1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.

Pediatric Patients

Clinical Adverse Reactions

Merrem I.V. was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitis. See next section.) at dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Merrem I.V. and their rates of occurrence as follows:

Diarrhea		3.5%
Rash		1.6%
Nausea and Vomiting		0.8%

Merrem I.V. was studied in 321 pediatric patients (> 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Merrem I.V. and their rates of occurrence as follows:

Diarrhea	4.7%
Rash (mostly diaper area moniliasis)	3.1%
Oral Moniliasis	1.9%
Glossitis	1.0%

In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the Merrem I.V. treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm.

Adverse Laboratory Changes

Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.

There is no experience in pediatric patients with renal impairment.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Merrem I.V. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Hematologic - agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Skin-toxic epidermal necrolysis, Stevens-Johnson Syndrome, angioedema, and erythema multiforme.

Drug Interactions

Probenecid

Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with meropenem is not recommended.

Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of Merrem I.V. is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B. Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Merrem I.V. is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Merrem I.V. have been established for pediatric patients ≥ 3 months of age. Use of Merrem I.V. in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. Use of Merrem I.V. in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of Merrem I.V. in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)].

Geriatric Use

Of the total number of subjects in clinical studies of Merrem I.V., approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

A pharmacokinetic study with Merrem I.V. in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)].

Patients with Renal Impairment

Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), and Clinical Pharmacology (12.3)].

Overdosage

In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Intentional overdosing of Merrem I.V. is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 g given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

Merrem Description

Merrem® I.V. (meropenem for injection) is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. It is (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6- [(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is:

Merrem I.V. is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When constituted as instructed, each 1 g Merrem I.V. vial will deliver 1 g of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg Merrem I.V. vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [see Dosage and Administration (2.4)].

Merrem - Clinical Pharmacology

Mechanism of Action

Meropenem is an antibacterial drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

Plasma Concentrations

At the end of a 30-minute intravenous infusion of a single dose of Merrem I.V. in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Merrem I.V. in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 g dose.

Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.

No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of meropenem is approximately 2%.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Merrem I.V., the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below.

Table 1. Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

* at 1 hour unless otherwise noted † obtained from blister fluid ‡ in pediatric patients of age 5 months to 8 years § in pediatric patients of age 1 month to 15 years
Tissue	I.V. Dose (g)	Number of Samples	Mean [μg/mL or mcg/(g)]*	Range [μg/mL or mcg/(g)]
Endometrium	0.5	7	4.2	1.7–10.2
Myometrium	0.5	15	3.8	0.4–8.1
Ovary	0.5	8	2.8	0.8–4.8
Cervix	0.5	2	7.0	5.4–8.5
Fallopian tube	0.5	9	1.7	0.3-3.4
Skin	0.5	22	3.3	0.5–12.6
Interstitial fluid†	0.5	9	5.5	3.2-8.6
Skin	1.0	10	5.3	1.3–16.7
Interstitial fluid†	1.0	5	26.3	20.9–37.4
Colon	1.0	2	2.6	2.5–2.7
Bile	1.0	7	14.6 (3 h)	4.0–25.7
Gall bladder	1.0	1	—	3.9
Peritoneal fluid	1.0	9	30.2	7.4–54.6
Lung	1.0	2	4.8 (2 h)	1.4–8.2
Bronchial mucosa	1.0	7	4.5	1.3–11.1
Muscle	1.0	2	6.1 (2 h)	5.3–6.9
Fascia	1.0	9	8.8	1.5–20
Heart valves	1.0	7	9.7	6.4–12.1
Myocardium	1.0	10	15.5	5.2–25.5
CSF (inflamed)	20 mg/kg‡ 40 mg/kg§	8 5	1.1 (2 h) 3.3 (3 h)	0.2-2.8 0.9-6.5
CSF (uninflamed)	1.0	4	0.2 (2 h)	0.1–0.3

Metabolism

There is one metabolite of meropenem that is microbiologically inactive.

Excretion

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Specific Populations

Renal Impairment

Pharmacokinetic studies with Merrem I.V. in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2) and Use In Specific Populations (8.6)].

Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)].

Hepatic Impairment

A pharmacokinetic study with Merrem I.V. in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Geriatric Patients

A pharmacokinetic study with Merrem I.V. in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients

The pharmacokinetics of meropenem in pediatric patients 2 years of age or older are essentially similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years. The pharmacokinetics are linear over the dose range from 10 to 40 mg/kg.

Drug Interactions

Probenecid competes with meropenem