Dalfopristin and quinupristin

Dalfopristin and quinupristin is given as an injection through a needle placed into a vein. Your doctor, nurse, or other healthcare provider will give you this injection.

Dalfopristin and quinupristin is most often given in a hospital setting. The medicine must be given slowly through an IV infusion, and can take up to 1 hour or longer to complete.

Dalfopristin and quinupristin is usually given for at least 7 days, or longer for more severe infections.

Since this medicine is usually given in a hospital, it is not likely that you will miss a dose.

Applies to dalfopristin / quinupristin: intravenous powder for solution

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

Check with your doctor or nurse immediately if any of the following side effects occur while taking dalfopristin / quinupristin:

• Swelling, redness, or pain at the injection site

• Changes in skin color
• dry, red, hot, or irritated skin
• joint pain
• muscle pain
• pain
• redness, burning sensation, or pain under the skin usually in the injection site
• swelling of the foot or leg
• tenderness

• Agitation
• anxiety
• back, leg, or stomach pains
• black, tarry stools
• bleeding gums
• bloating or swelling of the face, arms, hands, lower legs, or feet
• blood in the urine
• bloody, black, or tarry stools
• blue lips, fingernails, or skin
• blurred vision
• bone pain
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• chest pain or discomfort
• chest pain, possibly moving to the left arm, neck, or shoulder
• chills
• coma
• confusion
• constipation
• convulsions or seizures
• cough or hoarseness
• darkened urine
• decreased urine output
• difficult, fast, or labored breathing
• difficult or painful urination
• difficulty with moving
• difficulty with swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drowsiness
• extremely shallow or slow breathing
• fainting
• fast, slow, irregular, pounding, or racing heartbeat or pulse
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck
• general body swelling
• general tiredness and weakness
• hallucinations
• headache
• high fever
• hives
• inability to speak
• increased thirst
• indigestion
• irritability
• itching
• light-colored stools
• loss of appetite
• loss of bladder control
• loss of consciousness
• loss of strength or energy
• lower back or side pain
• muscle pain or cramps
• muscle stiffness or weakness
• nausea or vomiting
• no blood pressure or pulse
• nosebleeds
• not breathing
• pain in the joints
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• problems with bleeding or clotting
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid weight gain
• redness, burning sensation, or pain in the vagina
• sensation of pins and needles
• severe bloody diarrhea
• severe or sudden headache
• shakiness in the legs, arms, hands, or feet
• shortness of breath
• skin rash
• skin rash with red patches
• slurred speech
• sore throat
• sores on the skin
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain
• stiff neck
• stopping of the heart
• sweating
• swelling of the face, ankles, or hands
• swollen glands
• temporary blindness
• tightness in the chest
• tingling of the hands or feet
• total body jerking
• trembling or shaking of the hands or feet
• troubled breathing
• unconsciousness
• unexplained bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss
• upper right abdominal or stomach pain
• vomiting
• vomiting of blood or material that looks like coffee grounds
• weakness in the arm or leg on one side of the body, sudden and severe
• wheezing
• worsening of the underlying disease
• yellowing of the eyes or skin

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

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

• Acid or sour stomach
• ankle, knee, or great toe joint pain
• belching
• cold sweats
• cool, pale skin
• cramps in the legs
• depression
• excessive muscle tone
• heartburn
• hives or welts
• increased hunger
• itching of the vagina or genital area
• joint stiffness or swelling
• lower back or side pain
• muscle tension or tightness
• nightmares
• pain during sexual intercourse
• redness of the skin
• shakiness
• sleeplessness
• stomach discomfort, upset, or pain
• sweating
• swelling or inflammation of the mouth
• thick, white vaginal discharge with no odor or with a mild odor
• trouble sleeping
• unable to sleep
• white patches in the mouth, tongue, or throat

Applies to dalfopristin / quinupristin: intravenous powder for injection

General

In all 5 comparative studies, patients discontinued therapy with dalfopristin-quinupristin as compared to comparator for the following reasons: venous adverse events (9.2% versus 2% comparator), rash (1% versus 0.5% comparator), nausea (0.9% versus 0.6% comparator), vomiting (0.5% versus 0.5% comparator), pain (0.5% versus 0% comparator), and pruritus (0.5% versus 0.3% comparator).

In the 2 comparative studies for complicated skin and skin structure infections (cSSSI), the side effect profile observed differed significantly from the profile observed in the other comparative studies. In these 2 comparative cSSSI studies, patients discontinued therapy with dalfopristin-quinupristin as compared to comparator for the following reasons: venous adverse events (12% versus 2% comparator), rash (2% versus 0.9% comparator), nausea (1.1% versus 0% comparator), vomiting (0.9% versus 0% comparator), pain (0.9% versus 0% comparator), and pruritus (0.9% versus 0.5% comparator). Venous adverse events were mainly observed in patients with peripheral infusions.

In noncomparative studies, approximately one-third of patients discontinued therapy due to side effects; however, the discontinuation rate due to side effects possibly or probably related to dalfopristin-quinupristin was about 5%. The side effects leading to therapy discontinuation included increased total bilirubin (2.7%), increased conjugated bilirubin (2.3%), treatment-related arthralgia (2.3%), and treatment-related myalgia (1.8%). High baseline total and conjugated bilirubin levels were recorded in 46.5% and 59% of patients, respectively, prior to study entry.

In a study with 93 patients, 21.5% discontinued treatment due to side effects. The most common side effects were arthralgia, myalgia, nausea, and rash.[Ref]

Local

Local side effects have frequently included inflammation at the infusion site (all comparative studies: 42%; comparative cSSSI studies: 44.7%), pain at the infusion site (all comparative studies: 40%; comparative cSSSI studies: 38.2%), infusion site edema (all comparative studies: 17.3%; comparative cSSSI studies: 18%), and infusion site reaction (all comparative studies: 13.4%; comparative cSSSI studies: 11.6%).[Ref]

The manufacturer recommends flushing of the vein with 5% dextrose in water solution following each infusion of dalfopristin-quinupristin to minimize venous irritation. Consideration should be given to changing the infusion site in patients with moderate to severe venous irritation. Dalfopristin-quinupristin infusion (standard diluent volume of 250 mL) may also be further diluted (500 to 750 mL) in these patients. Venous adverse events occurred predominately in patients who had peripheral infusions; therefore, a peripherally inserted central catheter or a central venous catheter may be utilized in selected patients.[Ref]

Musculoskeletal

Some cases of arthralgia and myalgia noted improvement of symptoms with a reduction in dose frequency to every 12 hours. Resolution of symptoms has been reported following discontinuation of dalfopristin-quinupristin.

One trial with 93 patients reported an incidence of 10.8% and 8.6%, respectively, for arthralgia and myalgia.

Intravenous dalfopristin-quinupristin plus minocycline were associated with myalgia and arthralgia in 36% of neutropenic cancer patients (n=56).[Ref]

Musculoskeletal side effects have included arthralgia (up to 7.8%; severe: 3.3%), arthralgia and myalgia (up to 7.4%), myalgia (up to 5.1%; severe: 3.1%), elevated creatine phosphokinase (greater than 10 times ULN; 1.6%), and myasthenia (less than 1%). Bone pain and neck rigidity have been reported in less than 0.1% of patients.[Ref]

Gastrointestinal

Mild cases of pseudomembranous enterocolitis may respond to discontinuation of dalfopristin-quinupristin alone. Moderate to severe cases may require fluid replacement, electrolytes, protein supplementation, and antibiotics for treating C difficile.[Ref]

Gastrointestinal side effects have included nausea (all comparative studies: 4.6%; comparative cSSSI studies: 4%; noncomparative studies: up to 4.9%), vomiting (all comparative studies: 2.7%; comparative cSSSI studies: 3.7%), and diarrhea (2.7%). Abdominal pain, constipation, dyspepsia, oral moniliasis, pancreatitis, pseudomembranous enterocolitis, and stomatitis have been reported in less than 1% of patients. Gastrointestinal hemorrhage (less than 0.2%), mesenteric arterial occlusion (less than 0.1%), and Clostridium difficile associated diarrhea have been reported.[Ref]

Hepatic

Hepatic side effects have included increased conjugated bilirubin (greater than 5 times ULN; 3.1%), gamma-glutamyltransferase (greater than 10 times ULN; 1.9%), total bilirubin (greater than 5 times ULN; 0.9%), AST (greater than 10 times ULN; 0.9%), and ALT (greater than 10 times ULN; 0.4%). Irrespective of relationship to dalfopristin-quinupristin, increased total bilirubin (greater than 5 times ULN; 25%) and conjugated bilirubin (greater than 5 times ULN; 34.6%) were reported during noncomparative studies. Isolated hyperbilirubinemia (primarily conjugated bilirubin) can occur and is thought to be due to dalfopristin-quinupristin competing with bilirubin for excretion. Hepatitis and jaundice have been reported in less than 0.1% of patients.[Ref]

High baseline total and conjugated bilirubin levels were recorded in 46.5% and 59% of patients, respectively, prior to noncomparative study entry.[Ref]

Cardiovascular

Cardiovascular side effects have included thrombophlebitis (all comparative studies: 2.4%), thrombus or thrombophlebitis (comparative cSSSI studies: 1.7%), and hypotension (less than 0.2%). Palpitations, vasodilation, and phlebitis have been reported in less than 1% of patients. Arrhythmia, cerebral hemorrhage, cerebrovascular accident, heart arrest, pericardial effusion, pericarditis, supraventricular tachycardia, ventricular extrasystoles, and ventricular fibrillation have been reported in less than 0.1% of patients.[Ref]

Dermatologic

Dermatologic side effects have included rash (all comparative studies: 2.5%; comparative cSSSI studies: 3.1%), pruritus (1.5%), and skin ulcer (less than 0.1%). Maculopapular rash, sweating, and urticaria have been reported in less than 1% of patients.[Ref]

Hematologic

Hematologic side effects have included decreased hemoglobin (less than 8 g/dL; 2.6%), decreased platelets (less than 50,000/mm3; 0.6%), increased hematocrit (greater than 60%; 0.2%), increased platelets (greater than 1,000,000/mm3; 0.2%), and reversible reticulocytopenia. Coagulation disorder, hemolysis, hemolytic anemia, hypoplastic anemia, and pancytopenia have been reported in less than 0.1% of patients.[Ref]

Metabolic

Metabolic side effects have included increased lactate dehydrogenase (greater than 5 times ULN; 2.6%), blood glucose (greater than 22.2 mmol/L; 1.3%), alkaline phosphatase (greater than 5 times ULN; 0.3%), bicarbonates (greater than 40 mmol/L; 0.3%), and potassium (greater than 6 mmol/L; 0.3%), and decreased bicarbonates (less than 10 mmol/L; 0.5%), sodium (less than 120 mmol/L; 0.5%), carbon dioxide (less than 15 mmol/L; 0.2%), and blood glucose (less than 2.2 mmol/L; 0.1%). Gout has been reported in less than 1% of patients. Acidosis, hypoglycemia, hyponatremia, and hypovolemia have been reported in less than 0.1% of patients. Alkalosis, hyperkalemia, and hyperglycemia have also been reported.[Ref]

Nervous system

Nervous system side effects have included headache (1.6%). Confusion, dizziness, hypertonia, insomnia, leg cramps, and paresthesia have been reported in less than 1% of patients. Convulsion, dysautonomia, encephalopathy, grand mal convulsion, neuropathy, paraplegia, syncope, and tremor have been reported in less than 0.1% of patients.[Ref]

Other

Other side effects have included pain (all comparative studies: 1.5%; comparative cSSSI studies: 3.1%) and shock (less than 0.1%). Abdominal pain, worsening of underlying illness, chest pain, fever, peripheral edema, and infection have been reported in less than 1% of patients.[Ref]

Hypersensitivity

Hypersensitivity side effects have included allergic reaction (less than 1%) and anaphylactoid reaction (less than 0.1%). Angioedema and anaphylactic shock have been reported during postmarketing experience.[Ref]

Respiratory

Respiratory side effects have included dyspnea and pleural effusion in less than 1% of patients. Apnea, hypoventilation, hypoxia, and respiratory distress syndrome have been reported in less than 0.1%.[Ref]

Genitourinary

Genitourinary side effects have included hematuria and vaginitis in less than 1% of patients.[Ref]

Psychiatric

Psychiatric side effects have included anxiety in less than 1% of patients.

Renal

Renal side effects have included elevated BUN (35.5 mmol/L or greater; 0.3%) and creatinine (440 mcmol/L or greater; 0.1%).[Ref]

Some side effects of dalfopristin / quinupristin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Complicated: 7.5 mg/kg IV every 12 hours, infused over 1 hour

Clostridium difficile associated diarrhea (CDAD) has been reported with almost all antibiotics and may potentially be life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea following dalfopristin-quinupristin therapy. Mild cases generally improve with discontinuation of the drug, while severe cases may require supportive therapy and treatment with an antimicrobial agent effective against C difficile. Hypertoxin producing strains of C difficile cause increased morbidity and mortality; these infections can be resistant to antimicrobial treatment and may necessitate colectomy.

Dalfopristin-quinupristin is a major inhibitor of CYP450 3A4. If concurrently administered drugs are substrates of this isoenzyme and have narrow therapeutic windows, their levels should be monitored, and substrates that prolong the QTc interval should be avoided.

Dalfopristin-quinupristin should not be administered as a bolus due to the potential for increased toxicity. It should be infused over 60 minutes. There are no data on the safety of other infusion durations. Animal toxicity was higher with bolus administration compared to slow infusion.

To minimize venous irritation, a peripheral infusion should be followed by a flush with 5% dextrose in water. Saline and heparin are incompatible and should not be used for dilution or flushing. If moderate to severe venous irritation occurs with peripheral infusions of 250 mL, increasing the infusion volume to 500 mL or 750 mL, changing the infusion site, or infusing via a PICC line or central venous catheter should be considered.

Cases of arthralgia and myalgia, some severe, have been reported in with dalfopristin-quinupristin. Some patients showed improvement after reducing the dose frequency to every 12 hours. Symptoms resolved after treatment was discontinued in those patients available for follow-up.

Use of antibiotics may result in superinfections of nonsusceptible organisms. Appropriate measures should be taken if superinfection occurs during therapy.

To reduce the risk of development of drug-resistant organisms, antibiotics should only be used to treat or prevent proven or suspected infections caused by bacteria.

Safety and efficacy have not been established in pediatric patients less than 16 years of age.

The dosage is expressed in terms of combined "mg" of dalfopristin plus quinupristin.

The minimum recommended treatment duration for complicated skin and skin structure infections is 7 days.

There are no data on the excretion of dalfopristin-quinupristin into human milk. It is excreted into rat milk. The manufacturer recommends caution when administering dalfopristin-quinupristin to nursing women.