Doripenem

Doripenem is part of the drug class:

• Carbapenems

You should not be treated with this medicine if you are allergic to doripenem, ertapenem (Invanz), imipenem (Primaxin), or meropenem (Merrem).

To make sure doripenem is safe for you, tell your doctor if you have:

• kidney disease;

• a history of stroke or seizure; or

• a history of allergy to penicillin antibiotics such as Amoxil, Augmentin, Bactocill, Bicillin L-A, Dycill, Dynapen, Moxatag, Omnipen, Principen, PC Pen VK, Pfizerpen, Ticar, Timentin, Unasyn, and others.

Doripenem is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether doripenem passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about doripenem, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about doripenem. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using doripenem.

Review Date: October 4, 2017

Increased Mortality in Ventilator-Associated Bacterial Pneumonia

In a clinical trial of patients with ventilator-associated bacterial pneumonia comparing Doripenem to imipenem, more subjects receiving Doripenem died 23% (31/135) compared to those receiving imipenem 16.7% (22/132) based on 28-day all-cause mortality in the intent-to-treat (ITT) population. Clinical response rates were also lower in the Doripenem arm. Doripenem is not approved for the treatment of ventilator-associated bacterial pneumonia.

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with Doripenem for Injection is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillin or other allergens. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross-reactivity among beta-lactam antibiotics has been clearly documented.

If an allergic reaction to Doripenem for Injection occurs, discontinue the drug. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment, as clinically indicated.

Seizures

Seizures have been reported during treatment with Doripenem (see section 6.2). In clinical trials, Doripenem-treated patients with pre-existing central nervous system (CNS) disorders (e.g. stroke or history of seizures), patients with compromised renal function and patients given doses greater than 500 mg every 8 hours appear to be at greater risk for developing seizures.

Interaction with Valproic Acid

Due to a drug interaction, patients with seizure disorders controlled with valproic acid or sodium valproate will be at an increased risk for breakthrough seizures when treated with Doripenem for Injection concomitantly. Reduction in serum valproic acid concentrations to below the therapeutic concentration range (50 to 100 mcg/mL) was observed by 12 hours after the initiation of Doripenem in healthy subjects co-administered both drugs. A similar drug interaction involving other carbapenem antibacterials and valproic acid has been described in published case reports. In some of these reports, increasing the dose of valproic acid or sodium valproate did not result in increased valproic acid serum concentrations. Alternative antibacterial therapies should be considered for patients receiving valproic acid or sodium valproate. If administration of Doripenem for Injection is necessary, supplemental anti-convulsant therapy should be considered. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains 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. [see Adverse Reactions (6.1)]

Development of Drug-Resistant Bacteria

Prescribing Doripenem for Injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Pneumonitis with Inhalational Use

When Doripenem for Injection has been used investigationally via inhalation, pneumonitis has occurred. Doripenem for Injection should not be administered by this route.

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

• Anaphylaxis and serious hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Seizures [see Warnings and Precautions (5.3)]
• Interaction with sodium valproate [see Warnings and Precautions (5.4) and Drug Interactions (7.1)]
• Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.5)]
• Development of drug-resistant bacteria [see Warnings and Precautions (5.6)]
• Pneumonitis with inhalational use [see Warnings and Precautions (5.7)]

Adverse Reactions from Clinical Trials

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

During clinical investigations, 1338 adult patients were treated with Doripenem for Injection (1076 patients received Doripenem 500 mg administered over 1 hour every 8 hours and 262 patients received Doripenem 500 mg administered over 4 hours every 8 hours); in some patients parenteral therapy was followed by a switch to an oral antimicrobial. [see Clinical Studies (14)]. The median age of patients treated with Doripenem for Injection was 54 years (range 18–90) in the comparative complicated urinary tract infections (cUTI) study, 46 years (range 18–94) in the pooled comparative complicated intra-abdominal infections (cIAI) studies, and 56 years (range 18-94) in the other Phase 3 trials. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63% and 75%) in the comparative cIAI and other Phase 3 trials, respectively. The patients treated with Doripenem for Injection were predominantly Caucasian (79%) in the five comparator-controlled Phase 3 studies.

The most common adverse drug reactions (≥ 5%) observed in the five Doripenem for Injection comparator-controlled Phase 3 clinical trials were anemia, headache, nausea, diarrhea, rash, phlebitis, and elevated hepatic enzymes. During clinical trials, adverse events led to discontinuation of Doripenem for Injection in 4.1% (55 of 1338) of patients compared to 4.3% (58 of 1325) of comparator-treated patients.

Adverse reactions due to Doripenem for Injection 500 mg every 8 hours that occurred at a rate ≥ 1 % are listed in Table 4. Hypersensitivity reactions related to intravenous study drug occurred at a rate of less than 1%.

In a Phase 1 study of healthy subjects receiving Doripenem doses greater than the approved dose of 500 mg every 8 hours for 10 to 14 days, the incidence of rash was higher than that observed in subjects who received 500 mg every 8 hours. The rash resolved within 10 days after Doripenem administration was discontinued.

Postmarketing Experience

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

Hematologic: Leukopenia, Neutropenia, Thrombocytopenia

Immune System: Anaphylaxis

Nervous System: Seizure

Renal: Renal impairment/failure

Respiratory: Interstitial pneumonia

Skin: Toxic epidermal necrolysis, Stevens-Johnson Syndrome

Valproic Acid

Co-administration of Doripenem for Injection with valproic acid causes the serum concentrations of valproic acid to fall below the therapeutic range, increasing the risk for breakthrough seizures. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that Doripenem may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the plasma concentrations of valproic acid. This is consistent with case reports for other carbapenems, where serum concentrations of valproic acid were reduced upon co-administration with a carbapenem. If administration of Doripenem for Injection is necessary, supplemental anti-convulsant therapy should be considered. The pharmacokinetics of Doripenem were unaffected by the co-administration of valproic acid. [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]

Probenecid

Probenecid interferes with the active tubular secretion of Doripenem, resulting in increased plasma concentrations of Doripenem. [see Clinical Pharmacology (12.3)] Coadministration of probenecid with Doripenem for Injection is not recommended.

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 7th ed. CLSI Document M7-A7. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2006.
2. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – 9th ed. CLSI Document M2-A9. CLSI, Wayne, PA 19087, 2006.
3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 17th Informational Supplement. CLSI document M100-S17. CLSI, Wayne, PA 19087, 2007.
4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – 7th ed. CLSI document M11-A7. CLSI, Wayne, PA 19087, 2007.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Doribax: 250 mg (1 ea); 500 mg (1 ea)

Generic: 250 mg (1 ea); 500 mg (1 ea)

• Doribax

Reconstitute 250 mg and 500 mg vial with 10 mL of SWFI or NS; further dilute the 250 mg vial for infusion with 50 mL or 100 mL of NS or D5W. Further dilute the 500 mg vials for infusion with 100 mL of NS or D5W. Shake gently until clear. To prepare a 250 mg dose using a 500 mg vial, reconstitute the 500 mg vial and further dilute with 100 mL of NS or D5W as above: remove and discard 55 mL from the infusion bag (remaining solution contains 250 mg) Variations in color when reconstituted or diluted from colorless to slightly yellow do not affect product potency.

>10%:

Central nervous system: Headache (3% to 16%)

Gastrointestinal: Diarrhea (6% to 12%), nausea (4% to 12%)

1% to 10%:

Cardiovascular: Phlebitis (2% to 8%)

Dermatologic: Skin rash (1% to 6%; includes allergic/bullous dermatitis, erythema, macular/papular eruptions, urticaria, and erythema multiforme), pruritus (1% to 3%)

Gastrointestinal: Oral candidiasis (1% to 3%), Clostridium dificile associated diarrhea (≤1%)

Genitourinary: Vaginal infection (1% to 2%)

Hematologic & oncologic: Anemia (2% to 10%)

Hepatic: Increased serum transaminases (2% to 7%)

<1% (Limited to important or life-threatening): Anaphylaxis, interstitial pneumonitis, leukopenia, neutropenia, renal failure, renal insufficiency, seizure, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, and skin reactions have been reported in patients receiving beta-lactams.

• CNS effects: Carbapenems have been associated with CNS adverse effects, including confusional states; seizures with doripenem have been reported. Use caution with CNS disorders (eg, brain lesions, stroke, or history of seizures) and adjust dose in renal impairment to avoid drug accumulation, which may increase seizure risk. Patients receiving doses >500 mg every 8 hours may also be at increased risk of seizures.

• Superinfection: Use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in patients with moderate-to-severe renal dysfunction.

• Ventilator-associated pneumonia: Not approved for the treatment of pneumonia including hospital-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP). Demonstrated numerically lower cure rate (versus a comparator antibiotic) and increased mortality rate in patients with VAP in a Phase 3 study using a higher dose and fixed 7-day administration (Kollef 2012).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Administer via intravenous infusion only. Per manufacturer’s labeling, investigational experience of doripenem via inhalation resulted in pneumonitis.

Monitor for signs of anaphylaxis during first dose; periodic renal assessment

500 mg via IV infusion every 8 hours
Duration of therapy: 5 to 14 days

Comments:
-Therapy duration includes possible conversion to oral therapy, after at least 3 days of parenteral therapy and once clinical improvement occurs.

Use: As a single agent for the treatment of complicated intraabdominal infections due to Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, B fragilis, B thetaiotaomicron, B uniformis, B vulgatus, Streptococcus intermedius, S constellatus, and Peptostreptococcus micros

This drug is hemodialyzable; however, no dose adjustment guidelines have been reported.