Sprix Nasal Spray

ketorolac tromethamine

Dosage Form: nasal spray
FULL PRESCRIBING INFORMATION

WARNING; LIMITATIONS OF USE, GASTROINTESTINAL, BLEEDING, CARDIOVASCULAR, and RENAL RISK

Limitations of Use

SPRIX (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug (NSAID), is indicated for short-term (up to 5 days in adults) management of moderate to moderately severe pain that requires analgesia at the opioid level. Do not exceed a total combined duration of use of SPRIX and other ketorolac formulations (IM/IV or oral) of 5 days [see Dosage and Administration, (2.1) and Warnings and Precautions (5.1)].

SPRIX is not indicated for use in pediatric patients and it is not indicated for minor or chronic painful conditions.

Gastrointestinal Risk

Ketorolac tromethamine, including SPRIX, can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, SPRIX is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events [see Contraindications (4), Warnings and Precautions (5.2)].

Bleeding Risk

Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding [see Contraindications (4), Warnings and Precautions (5.3)].

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.6)].

Sprix Nasal Spray is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)].

Renal Risk

SPRIX is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion [see Contraindications (4), Warnings and Precautions (5.4)].

Indications and Usage for Sprix Nasal Spray

SPRIX is indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level.

Sprix Nasal Spray Dosage and Administration

Limitations of Use

The total duration of use of SPRIX alone or sequentially with other formulations of ketorolac (IM/IV or oral) must not exceed 5 days because of the potential for increasing the frequency and severity of adverse reactions associated with the recommended doses [see Warnings and Precautions (5.1)]. Treat patients for the shortest duration possible, and do not exceed 5 days of therapy with SPRIX.

Do not use SPRIX concomitantly with other formulations of ketorolac or other NSAIDs [see Warnings and Precautions (5.1)].

SPRIX has not been shown to be safe and effective in pediatric patients 17 years of age and younger.

Adult Patients < 65 Years of Age

The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg (four doses).

Reduced Doses for Special Populations

For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the recommended dose is 15.75 mg SPRIX (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg (four doses) [see Warnings and Precautions (5.2, 5.4)].

Discard Used SPRIX Bottle after 24 Hours

Do not use any single SPRIX bottle for more than one day as it will not deliver the intended dose after 24 hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if the bottle still contains some liquid.

Dosage Forms and Strengths

Nasal spray: 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays.

Contraindications

• Known hypersensitivity to ketorolac tromethamine [see Warnings and Precautions (5.5, 5.7, 5.11)]


• Use in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding [see Warnings and Precautions (5.2)]


• Use in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs [see Warnings and Precautions (5.5, 5.7, 5.11)]


• Use as a prophylactic analgesic before any major surgery [see Warnings and Precautions (5.3)]


• Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.6)]


• Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion [see Warnings and Precautions (5.4,5.6)]


• Use in labor and delivery. Through its prostaglandin synthesis inhibitory effect, ketorolac may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.[see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.2)]


• Use in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates


• Use in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or those for whom hemostasis is critical [see Warnings and Precautions (5.3), Drug Interactions (7.1, 7.10)]


• Known hypersensitivity to aspirin or to other NSAIDs [see Warnings and Precautions (5.5, 5.7, 5.11)]


• Known hypersensitivity to ethylenediamine tetraacetic acid (EDTA) [see Description (11)]


• Concomitant use with probenecid [see Drug Interactions (7.4)]


• Concomitant use with pentoxifylline [see Drug Interactions (7.10)]

Warnings and Precautions

Limitations of Use

The total duration of use of SPRIX alone or sequentially with other forms of ketorolac is not to exceed 5 days. SPRIX must not be used concomitantly with other forms of ketorolac or other NSAIDs [see Dosage and Administration (2.1)].

Gastrointestinal (GI) Effects - Risk of Ulceration, Bleeding, and Perforation

SPRIX is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding [see Contraindications (4)]. Ketorolac tromethamine can cause serious GI adverse events including bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of GI complications increases with increasing dose of, and duration of treatment with, ketorolac. Even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of SPRIX until a serious GI adverse event is ruled out. For high risk patients, consider alternate therapies that do not involve NSAIDs. Use great care when giving SPRIX to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

Hematological Effects

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use caution with use of ketorolac tromethamine in patients who have coagulation disorders, and monitor these patients carefully. The effects of NSAIDs other than aspirin on platelet function are reversible. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, administer such concomitant therapy only with extreme caution. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low dose heparin (2500 to 5000 units q12h), warfarin and dextrans, has not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, carefully weigh the benefits against the risks and use such concomitant therapy in these patients only with extreme caution. Monitor patients receiving therapy that affects hemostasis closely.

In clinical trials, serious adverse events related to bleeding were more common in patients treated with SPRIX than placebo. In clinical trials and in postmarketing experience with ketorolac IV and IM dosing, postoperative hematomas and other signs of wound bleeding have been reported in association with peri-operative use. Therefore, use SPRIX with caution in the postoperative setting when hemostasis is critical.

Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Do not use SPRIX in patients for whom hemostasis is critical [see Contraindications (4), Drug Interactions (7.1, 7.2, 7.10)].

Renal Effects

Ketorolac and its metabolites are eliminated primarily by the kidneys. Patients with reduced creatinine clearance will have diminished clearance of the drug [see Clinical Pharmacology (12.4)]. SPRIX is contraindicated in patients with advanced renal impairment [see Contraindications (4)].

In patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and renal blood flow, which may precipitate overt renal decompensation. Decreased intravascular volume such as when oral intake is poor increases the risks of renal toxicity with NSAIDs. Therefore, patients treated with SPRIX should be adequately hydrated. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Use SPRIX with caution in patients with impaired renal function, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, and the elderly. Assess the risks and benefits prior to giving SPRIX to these patients, and follow these patients closely during SPRIX therapy. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury such as interstitial nephritis and nephrotic syndrome.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients with or without a history of allergic reactions to aspirin or NSAIDs and in patients without known prior exposure to ketorolac. SPRIX should be discontinued immediately in patients with allergic reactions. SPRIX should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4), Warnings and Precautions (5.11)]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Cardiovascular Effects

• Cardiovascular (CV) Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious CV thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID increases the risk of serious GI events. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7.2, 7.3, 7.7)].

• Hypertension

NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7.3)].

• Congestive Heart Failure and Edema

Fluid retention, edema, retention of NaCl, oliguria, and elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac. Therefore, only use SPRIX very cautiously in patients with cardiac decompensation or similar conditions.

Skin Reactions

NSAIDs, including ketorolac, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications (4)].

Pregnancy

Starting at 30 weeks gestation, SPRIX can cause fetal harm when administered to a pregnant woman due to an increased risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Hepatic Effects

Use SPRIX with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ketorolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported [see Warnings and Precautions (5.4, 5.6),Clinical Pharmacology (12.4)].

Evaluate patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, for evidence of the development of a more severe hepatic reaction while on therapy with SPRIX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SPRIX.

Inflammation and Fever

The pharmacological activity of SPRIX in reducing inflammation and fever may diminish the utility of these diagnostic signs in detecting infections.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, do not administer SPRIX to patients with this form of aspirin sensitivity, and use with caution in patients with preexisting asthma [see Contraindications (4), Warnings and Precautions (5.5)].

Eye Exposure

Avoid contact of SPRIX with the eyes. If eye contact occurs, wash out the eye with water or saline, and consult a physician if irritation persists for more than an hour.

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling:

• Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)]


• Hemorrhage [see Boxed Warning and Warnings and Precautions (5.3)]


• Renal effects [see Boxed Warning and Warnings and Precautions (5.4)]


• Anaphylactoid reactions [see Warnings and Precautions (5.5)]


• Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.6)]


• Hypertension [see Warnings and Precautions (5.6)]


• Congestive heart failure and edema [see Warnings and Precautions (5.6)]


• Serious skin reactions [see Warnings and Precautions (5.7)]


• Hepatic effects [see Warnings and Precautions (5.9)]

The most frequently reported adverse reactions were related to local symptoms, i.e., nasal discomfort or irritation. These reactions were generally mild and transient in nature.

The most common drug-related adverse events leading to premature discontinuation were nasal discomfort or nasal pain (rhinalgia).

Experience from SPRIX Clinical Studies

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 practice.

The data described below reflect exposure to SPRIX in patients enrolled in placebo-controlled efficacy studies of acute pain following major surgery. The studies enrolled 828 patients (183 men, 645 women) ranging from 18 years to over 75 years of age.

The patients in the postoperative pain studies had undergone major abdominal, orthopedic, gynecologic, or other surgery; 455 patients received SPRIX (31.5 mg) three or four times a day for up to 5 days, and 245 patients received placebo. Most patients were receiving concomitant opioids, primarily PCA morphine.

Table 1. Post-operative Patients with Adverse Reactions Observed at a rate of 2% or more and at least twice the incidence of the placebo group.

	SPRIX (N=455)	Placebo (N= 245)
Nasal discomfort	15%	2%
Rhinalgia	13%	<1%
Lacrimation increased	5%	0%
Throat irritation	4%	<1%
Oliguria	3%	1%
Rash	3%	<1%
Bradycardia	2%	<1%
Urine output decreased	2%	<1%
ALT and/or AST increased	2%	1%
Hypertension	2%	1%
Rhinitis	2%	<1%

In controlled clinical trials in major surgery, primarily knee and hip replacements and abdominal hysterectomies, seven patients (N=455, 1.5%) treated with SPRIX experienced serious adverse events of bleeding (4 patients) or hematoma (3 patients) at the operative site versus one patient (N=245, 0.4%) treated with placebo (hematoma).  Six of the seven patients treated with SPRIX underwent a surgical procedure and/or blood transfusion and the placebo patient subsequently required a blood transfusion.

Adverse Reactions Reported in Clinical Trials with Other Dosage Forms of Ketorolac or Other NSAIDs

Adverse reaction rates increase with higher doses of ketorolac. It is necessary to remain alert for the severe complications of treatment with ketorolac, such as GI ulceration, bleeding, and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure. These complications can be serious in certain patients for whom ketorolac is indicated, especially when the drug is used inappropriately.

In patients taking ketorolac or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:

Gastrointestinal (GI) experiences including:

*Incidence greater than 10%
abdominal pain	constipation/diarrhea	dyspepsia
flatulence	GI fullness	GI ulcers (gastric/duodenal)
gross bleeding/perforation	heartburn	nausea*
stomatitis	vomiting
Other experiences:
abnormal renal function	anemia	dizziness
drowsiness	edema	elevated liver enzymes
headache*	hypertension	increased bleeding time
injection site pain	pruritus	purpura
rash	tinnitus	sweating

Additional adverse experiences reported occasionally (<1% in patients taking ketorolac or other NSAIDs in clinical trials) include:

Body as a Whole: fever, infection, sepsis

Cardiovascular System: congestive heart failure, palpitation, pallor, tachycardia, syncope

Digestive System: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding

Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia

Metabolic and Nutritional: weight change

Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise

Respiratory: asthma, dyspnea, pulmonary edema, rhinitis

Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss

Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention

Adverse Reactions from Postmarketing Experience with Other Dosage Forms of Ketorolac or Other NSAIDs

Other observed reactions (reported from postmarketing experience in patients taking ketorolac or other NSAIDs) are:

Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema, myalgia

Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis

Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis

Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)

Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion)

Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia

Nervous System: aseptic meningitis, convulsions, coma, psychosis

Respiratory: bronchospasm, respiratory depression, pneumonia

Special Senses: conjunctivitis

Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome

Drug Interactions

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Warfarin, Digoxin, Salicylate, and Heparin

The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding.

The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.

Aspirin

When ketorolac is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of SPRIX and aspirin is not generally recommended because of the potential of increased adverse effects [see Warnings and Precautions (5.2, 5.5, 5.11)].

Diuretics

Clinical studies, as well as postmarketing observations, have shown that ketorolac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with SPRIX, observe the patient closely for signs of renal failure [see Warnings and Precautions (5.4, 5.6)], as well as to assure diuretic efficacy.

Probenecid

Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL), and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of SPRIX and probenecid is contraindicated.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when SPRIX and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Use caution when SPRIX is administered concomitantly with methotrexate.

ACE Inhibitors/Angiotensin II Receptor Antagonists

Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. Consider this interaction in patients taking SPRIX concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists [see Warnings and Precautions (5.4, 5.6)].

Antiepileptic Drugs

Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).

Psychoactive Drugs

Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

Pentoxifylline

When ketorolac is administered concurrently with pentoxifylline, there is an increased tendency to bleeding. Therefore, concomitant use of SPRIX and Pentoxifylline is contraindicated [see Contraindications (4) and Warnings and Precautions (5.3)].

Nondepolarizing Muscle Relaxants

In postmarketing experience there have been reports of a possible interaction between ketorolac and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac with muscle relaxants has not been formally studied.

Selective Serotonin Reuptake Inhibitors (SSRIs)

There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Use caution when SPRIX is administered concomitantly with SSRIs.

Fluticasone

The rate and extent of absorption of ketorolac from SPRIX administration (31.5 mg dose) were assessed in subjects with allergic rhinitis before and after the administration of a single daily dose of 200 mcg (as 2 x 50 mcg in each nostril) of fluticasone propionate nasal spray for 7 consecutive days. There was no effect on the pharmacokinetic characteristics of SPRIX that can be considered clinically significant [see Clinical Pharmacology (12.4)].

Oxymetazoline

The rate and extent of absorption of ketorolac from SPRIX administration were assessed in subjects with allergic rhinitis before and 30 min after a single dose (3 sprays in each nostril) of oxymetazoline hydrochloride nasal spray. There was no effect on the pharmacokinetic characteristics of SPRIX that can be considered clinically significant [see Clinical Pharmacology (12.4)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects: Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

SPRIX can cause fetal harm when administered to a pregnant woman. Human data demonstrate that use of NSAIDs at or after 30 weeks gestation increases the risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus. There are no adequate, well-controlled studies in pregnant women. Prior to 30 weeks gestation, SPRIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.6 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg qid, based on area-under-the-plasma-concentration curve [AUC]) in rabbits and at 10 mg/kg (1.7 times the human AUC) in rats. These studies did not reveal evidence of teratogenicity or other adverse developmental outcomes. However, because animal dosing was limited by maternal toxicity, these studies do not adequately assess ketorolac's potential to cause adverse developmental outcomes in humans.

Labor and Delivery

The effects of SPRIX on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia and delayed parturition, and decreased pup survival.

Nursing Mothers

Ketorolac is excreted in human milk. Ten nursing mothers received 10 mg of oral ketorolac, four times a day, for two days. In four women, ketorolac was undetectable in milk (assay limit 5 ng/mL). In the remaining six women, ketorolac concentrations in milk ranged from 5.2 to 7.9 ng/mL. Based on these concentrations, the estimated maximum infant daily dose of ketorolac from breast milk is 1.185 mcg/kg/day. Exercise caution when administering SPRIX to a nursing woman.

Pediatric Use

The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established.

Geriatric Use (≥ 65 years of age)

Exercise caution when treating the elderly (65 years and older) with SPRIX. Carefully consider the potential benefits and risks of SPRIX and other treatment options before deciding to use SPRIX. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.4)]. After observing the response to initial therapy with SPRIX, then adjust the dose and frequency to suit an individual patient's needs.

Drug Abuse and Dependence

Ketorolac does not bind to opiate receptors. A study to evaluate the sedative and addictive potential of ketorolac in volunteers showed no withdrawal symptoms upon cessation of dosing with ketorolac 30 mg IM 4 times daily for 5 days. A single-dose clinical study of IM ketorolac showed no significant adverse effects on psychomotor measurements, including reaction time, computerized driving skills, ataxia, and sedation.

Overdosage

There has been no experience with overdosage of SPRIX. In controlled overdosage studies with IM ketorolac injection, daily doses of 360 mg given for five days (approximately 3 times the maximum daily dose of SPRIX) caused abdominal pain and peptic ulcers, which healed after discontinuation of dosing. Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction.

Symptoms and Signs

Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare.

Treatment

Manage patients using symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large oral overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Sprix Nasal Spray Description

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the structural formula is:

The molecular weight of ketorolac tromethamine is 376.41. Ketorolac tromethamine is highly water-soluble, allowing its formulation in an aqueous nasal spray product at pH 7.2.

SPRIX is available as an intranasal spray product containing the active ingredient (ketorolac tromethamine) and the excipients edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection.

Sprix Nasal Spray - Clinical Pharmacology

Mechanism of Action

SPRIX contains ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID).  Ketorolac is an analgesic that inhibits the enzyme cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced synthesis of prostaglandins, thromboxanes, and prostacyclin.    

Ketorolac does not bind to the opiate receptor subtypes (mu, kappa, delta), but a 30 mg dose of ketorolac tromethamine IM has demonstrated an overall analgesic effect between that obtained with morphine 6 mg and 12 mg. Ketorolac possesses no sedative or anxiolytic properties, and has no effect on gut motility.

Pharmacodynamics

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R-enantiomeric forms, with the S-form having analgesic activity. Ketorolac, the active component of SPRIX, has anti-inflammatory, analgesic, and anti-pyretic effects. Studies directly comparing the analgesic effects of SPRIX and opioids have not been conducted.

Pharmacokinetics

The half-lives of ketorolac by the IN and IM routes were similar. The bioavailability of ketorolac by the IN route of administration of a 31.5 mg dose was approximately 60% compared to IM administration. (See Table 2.)

Table 2: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration

Cmax = maximum plasma concentration; tmax = time of Cmax; AUC0-∞ = complete area under the concentration-time curve; T½ = half-life; SD = standard deviation. All values are means, except tmax, for which medians are reported.
Ketorolac Tromethamine	Cmax (SD) ng/mL	tmax (range) hours	AUC 0-∞ (SD) ng•h/mL	T½ (SD) hours
30 mg IM (1.0 mL of a 30 mg/mL solution)	2382.2 (432.7)	0.75 (0.25-1.03)	11152.8 (4260.1)	4.80 (1.18)
31.5 mg IN (SPRIX) (2 x 100 μL of a 15% w/w solution)	1805.8 (882.8)	0.75 (0.50-2.00)	7477.3 (3654.4)	5.24 (1.33)
15 mg IM (0.5 mL of a 30 mg/mL solution)	1163.4 (279.9)	0.75 (0.25-1.50)	5196.3 (2076.7)	5.00 (1.72)

Absorption: In a study in which SPRIX (31.5 mg) was administered to healthy volunteers four times daily for 5 days, the Cmax, tmax, and AUC values following the final dose were comparable to those obtained in the single-dose study. Accumulation of ketorolac has not been studied in special populations, geriatric, pediatric, renal failure or hepatic disease patients.

Distribution: Scintigraphic assessment of drug disposition of ketorolac following SPRIX intranasal dosing demonstrated that most of the ketorolac was deposited in the nasal cavity and pharynx, with less than 20% deposited in the esophagus and stomach, and zero or negligible deposition in the lungs (<0.5%).

The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations. Ketorolac tromethamine is excreted in human milk.

Metabolism: Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.

Excretion: The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac trom

Propoxacet-N

Generic Name: propoxyphene and acetaminophen (Oral route)

a-seet-a-MIN-oh-fen, proe-POX-i-feen NAP-si-late

Oral route(Tablet)

Accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol, has occurred, and may be fatal within the first hour. Many of the fatalities have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation. The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors leading to enhanced propoxyphene plasma levels; monitor patients closely and adjust dosages if necessary in patients receiving any CYP3A4 inhibitor concomitantly .

Commonly used brand name(s)

In the U.S.

• Balacet 325


• Darvocet A500


• Darvocet-N 100


• Darvocet-N 50


• Pronap-100


• Propoxacet-N


• Propoxacet-N 100

Available Dosage Forms:

• Tablet

Therapeutic Class: Opioid/Acetaminophen Combination

Chemical Class: Propoxyphene

Uses For Propoxacet-N

Propoxyphene and acetaminophen combination is used to relieve mild to moderate pain. Propoxyphene belongs to the group of medicines called narcotic analgesics (pain medicines). It acts on the central nervous system (CNS) to relieve pain.

Acetaminophen is used to relieve pain and reduce fever in patients. It does not become habit-forming when taken for a long time. But acetaminophen may cause other unwanted effects when taken in large doses, including liver damage.

When propoxyphene is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

Products containing propoxyphene were withdrawn from the U.S. market starting November 19, 2010.

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

Before Using Propoxacet-N

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of propoxyphene and acetaminophen combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of propoxyphene and acetaminophen combination in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving propoxyphene and acetaminophen combination.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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

• Naltrexone


• Rasagiline


• Selegiline

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.

• Adinazolam


• Alfentanil


• Alprazolam


• Amobarbital


• Anileridine


• Aprobarbital


• Bromazepam


• Brotizolam


• Buprenorphine


• Butabarbital


• Butalbital


• Butorphanol


• Carbamazepine


• Carisoprodol


• Chloral Hydrate


• Chlordiazepoxide


• Chlorzoxazone


• Clobazam


• Clonazepam


• Clorazepate


• Codeine


• Dantrolene


• Dezocine


• Diazepam


• Estazolam


• Ethchlorvynol


• Fentanyl


• Flunitrazepam


• Flurazepam


• Fospropofol


• Halazepam


• Hydrocodone


• Hydromorphone


• Ketazolam


• Levorphanol


• Lorazepam


• Lormetazepam


• Medazepam


• Meperidine


• Mephenesin


• Mephobarbital


• Meprobamate


• Metaxalone


• Methocarbamol


• Methohexital


• Midazolam


• Morphine


• Morphine Sulfate Liposome


• Nalbuphine


• Nitrazepam


• Nordazepam


• Opium


• Oxazepam


• Oxycodone


• Oxymorphone


• Pentazocine


• Pentobarbital


• Phenobarbital


• Prazepam


• Propoxyphene


• Quazepam


• Remifentanil


• Secobarbital


• Sodium Oxybate


• Sufentanil


• Tapentadol


• Temazepam


• Thiopental


• Triazolam

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.

• Acenocoumarol


• Carbamazepine


• Doxepin


• Isoniazid


• Metoprolol


• Phenytoin


• Propranolol


• Warfarin


• Zidovudine

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.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Cabbage

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:

• Alcohol abuse, or history of or


• Brain tumor, history of or


• Chronic obstructive pulmonary disease (COPD) or


• Cor pulmonale (serious heart condition) or


• Drug dependence, especially with narcotics, or history of or


• Gallbladder disease or gallstones or


• Head injuries, history of or


• Hypovolemia (low blood volume)—Use with caution. May increase risk for more serious side effects.

• Asthma, severe or


• Breathing problems, severe (e.g., hypoxia) or


• Paralytic ileus (intestine stops working and may be blocked) or


• Respiratory depression (very slow breathing) or


• Suicidal ideation (thoughts of hurting or killing oneself), history of—Should not be used in patients with these conditions.

• Hypotension (low blood pressure) or


• Pancreatitis (inflammation of the pancreas)—Use with caution. May make these conditions worse.

• Kidney disease or


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

Proper Use of propoxyphene and acetaminophen

This section provides information on the proper use of a number of products that contain propoxyphene and acetaminophen. It may not be specific to Propoxacet-N. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of this medicine is taken for a long time, it may become habit-forming (causing mental or physical dependence). Liver damage can occur if large amounts of acetaminophen are taken for a long time.

This combination medicine contains acetaminophen (Tylenol®). Carefully check the labels of all other medicines you are using, because they may also contain acetaminophen. It is not safe to use more than 4 grams (4,000 milligrams) of acetaminophen in one day (24 hours).

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

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 oral dosage form (tablets):
  
  • For mild to moderate pain:
    
    • Adults—One or two tablets every 4 hours as needed. Your doctor may adjust your dose if needed. However, the dose is usually not more than 6 to 12 tablets per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take 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. Do not double doses.

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.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Throw any unused medicine by mixing it with used coffee grounds or kitty litter and place it in a sealable bag, empty can, or container.

Precautions While Using Propoxacet-N

It is very important that your doctor check your progress while you are taking this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Talk to your doctor first before you stop taking this medicine and changing to another pain medicine.

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

This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Also, there may be a greater risk of liver damage if you drink three or more alcoholic beverages while you are taking acetaminophen. Do not drink alcoholic beverages, and check with your doctor before taking any of the medicines listed above while you are using this medicine.

This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.

This medicine may make you dizzy, drowsy, or lightheaded. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

If you have been using this medicine regularly for several weeks or longer, do not change your dose or suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.

Using this medicine while you are pregnant may cause serious unwanted effects in your newborn baby. Tell your doctor right away if you think you are pregnant or if you plan to become pregnant while using this medicine.

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

Propoxacet-N 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 immediately if any of the following side effects occur:

Rare

• Abdominal or stomach pain


• chills


• clay-colored stools


• dark urine


• dizziness


• fever


• headache


• itching


• loss of appetite


• nausea


• rash


• unpleasant breath odor


• unusual tiredness or weakness


• vomiting of blood


• yellow eyes or skin

Incidence not known

• Bloating


• bloody or black, tarry stools


• bloody or cloudy urine


• change in consciousness


• chest pain or discomfort


• confusion


• cough


• decreased urine output


• difficult or troubled breathing


• dilated neck veins


• drowsiness


• extreme fatigue


• fainting


• fast, slow, pounding, or irregular heartbeat or pulse


• fever with or without chills


• general feeling of discomfort or illness


• hives


• hoarseness


• irregular, fast, slow, or shallow breathing


• itching


• joint pain, stiffness, or swelling


• light-colored stools


• loss of consciousness


• low blood pressure or pulse


• muscle aches and pains


• muscle tremors


• pain or discomfort in the arms, jaw, back, or neck


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


• pale or blue lips, fingernails, or skin


• rapid, deep breathing


• redness of the skin


• restlessness


• right upper stomach pain and fullness


• runny nose


• severe stomach pain


• shakiness and unsteady walk


• shivering


• shortness of breath


• sore throat


• stomach cramps


• sudden decrease in the amount of urine


• sweating


• swelling of the eyelids, face, fingers, lips, hands, lower legs, or feet


• thoughts of suicide


• tightness in the chest


• trouble sleeping


• troubled breathing or swallowing


• unconsciousness


• unsteadiness, trembling, or other problems with muscle control or coordination


• very slow breathing


• very slow heartbeat


• vomiting of blood or material that looks like coffee grounds


• weight gain


• wheezing

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Agitation


• bluish color of the fingernails, lips, skin, palms, or nail beds


• convulsion


• coughing that sometimes produces a pink frothy sputum


• decreased awareness or responsiveness


• depression


• difficult, fast, or noisy breathing, sometimes with wheezing


• dilated pupils


• hostility


• increased sweating


• irritability


• lethargy


• muscle tremors


• muscle twitching


• pale skin


• pounding or rapid pulse


• rapid weight gain


• rapid, deep breathing


• severe sleepiness


• sleepiness or unusual drowsiness


• slow to respond


• slurred speech


• weight loss

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

More common

• Relaxed and calm feeling

Incidence not known

• Abnormal behavior


• blurred or loss of vision


• constipation


• diarrhea


• disturbed color perception


• double vision


• false or unusual sense of well-being


• halos around lights


• indigestion


• muscular pain, tenderness, wasting, or weakness


• night blindness


• nightmares or unusually vivid dreams


• overbright appearance of lights


• seeing, hearing, or feeling things that are not there


• swelling of the eye


• tunnel vision

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: Propoxacet-N 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 Propoxacet-N resources

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

Compare Propoxacet-N with other medications

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Carbidopa and Levodopa

Ingredient matches for Carbidopa and Levodopa

Carbidopa

Carbidopa is reported as an ingredient of Carbidopa and Levodopa in the following countries:

• United States

Levodopa

Levodopa is reported as an ingredient of Carbidopa and Levodopa in the following countries:

• United States

International Drug Name Search

Somavert

Dosage Form: injection
Somavert®

pegvisomant for injection

Rx only

Somavert Description

Somavert contains pegvisomant for injection, an analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist.

Pegvisomant is a protein of recombinant DNA origin containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bound (predominantly 4 to 6 PEG/protein molecule). The molecular weight of the protein of pegvisomant is 21,998 Daltons. The molecular weight of the PEG portion of pegvisomant is approximately 5000 Daltons. The predominant molecular weights of pegvisomant are thus approximately 42,000, 47,000, and 52,000 Daltons. The schematic shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Biological potency is determined using a cell proliferation bioassay.

Stippled residues indicate PEG attachment sites (Phe1, Lys38, Lys41, Lys70, Lys115, Lys120, Lys140, Lys145, Lys158)

Somavert is supplied as a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution with 1 mL of Sterile Water for Injection, USP. Somavert is available in single-dose sterile vials containing 10, 15, or 20 mg of pegvisomant protein (approximately 10, 15, and 20 U activity, respectively). Vials containing 10, 15, and 20 mg of pegvisomant protein correspond to approximately 21, 32, and 43 mg pegvisomant, respectively. Each vial also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium phosphate monobasic monohydrate.

Somavert is supplied in packages that include a vial containing diluent. Sterile Water for Injection, USP, is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, and is supplied in single-dose containers to be used as a diluent.

Somavert - Clinical Pharmacology

Mechanism of Action

Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction.

Inhibition of GH action results in decreased serum concentrations of insulin-like growth factor-I (IGF-I), as well as other GH-responsive serum proteins, including IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS).

Pharmacokinetics

Absorption

Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose.

Distribution

The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (Cmax, AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively.

Metabolism and Elimination

The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life of approximately 6 days following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans.

Drug-Drug Interactions

In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known (see PRECAUTIONS, Drug Interactions).

Special Populations

Renal

No pharmacokinetic studies have been conducted in patients with renal insufficiency.

Hepatic

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency.

Geriatric

No pharmacokinetic studies have been conducted in elderly subjects.

Pediatric

No pharmacokinetic studies have been conducted in pediatric subjects.

Gender

No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis.

Race

The effect of race on the pharmacokinetics of pegvisomant has not been studied.

Clinical Studies

One hundred twelve patients with acromegaly previously treated with surgery, radiation therapy, and/or medical therapies participated in a 12-week, randomized, double-blind, multi-center study comparing placebo and Somavert. Following withdrawal from previous medical therapy, the 80 patients randomized to treatment with Somavert received a subcutaneous (SC) loading dose, followed by 10, 15, or 20 mg/day SC. The three groups that received Somavert showed dose-dependent reductions in serum levels of IGF-I, free IGF-I, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1 and Table 1).

Figure 1. Effects of Somavert on Serum Markers

(Mean ± Standard Error)

After 12 weeks of treatment, serum IGF-I levels were normalized in 10%, 39%, 75%, and 82% of subjects treated with placebo, 10, 15, or 20 mg/day of Somavert, respectively (Figure 2).

Figure 2. Percent of Patients Whose IGF-I Levels Normalized at Week 12

Table 2 shows the effect of treatment with Somavert on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on both the total and individual scores for signs and symptoms of acromegaly. Each individual score (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7.

Table 1. Mean Percent Change from Baseline in IGF-I at Week 12 for Intent-to-Treat Population

	Somavert			Placebo n=31
	10 mg/day n=26	15 mg/day n=26	20 mg/day n=28
* P<0.01
Mean percent change from baseline in IGF-I (SD)	-27 (28)	-48 (26)	-63 (21)	-4.0 (17)
Somavert minus Placebo (95% CI for treatment difference)	-23* (-35, -11)	-44* (-56, -33)	-59* (-68, -49)

Table 2. Mean Change from Baseline (SD) at Week 12 for Ring Size and Signs and Symptoms of Acromegaly

	Somavert			Placebo n=30
	10 mg/day n=26	15 mg/day n=24–25	20 mg/day n=26–27
Ring size	-0.8 (1.6)	-1.9 (2.0)	-2.5 (3.3)	-0.1 (2.3)
Total score for signs and symptoms of acromegaly	-2.5 (4.3)	-4.4 (5.9)	-4.7 (4.7)	1.3 (6.0)
Soft-tissue swelling	-0.7 (1.6)	-1.2 (2.3)	-1.3 (1.3)	0.3 (2.3)
Arthralgia	-0.3 (1.8)	-0.5 (2.5)	-0.4 (2.1)	0.1 (1.8)
Headache	-0.4 (1.6)	-0.3 (1.4)	-0.3 (2.0)	0.1 (1.7)
Perspiration	-0.6 (1.6)	-1.1 (1.3)	-1.7 (1.6)	0.1 (1.7)
Fatigue	-0.5 (1.4)	-1.3 (1.7)	-1.0 (1.6)	0.7 (0.5)

Ring size at week 12 was smaller (improved) in the groups treated with 15 or 20 mg of Somavert, compared with placebo. The mean total score for signs and symptoms at week 12 was lower (improved) in each of the groups treated with Somavert, compared with the group treated with placebo.

Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant (see PRECAUTIONS, Drug/Laboratory Test Interactions), rise within two weeks of beginning treatment with Somavert. The largest GH response was seen in patients treated with doses of Somavert greater than 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-I levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of Somavert followed by a fixed daily dose, this rise in GH was inversely proportional to the fall in IGF-I and generally stabilized by week 2. Serum GH concentrations also remained stable in patients treated with Somavert for up to 18 months.

Figure 3. Percent Change in Serum GH and IGF-I Concentrations

Another cohort of 38 patients with acromegaly was treated with Somavert in a long-term, open-label, dose-titration study and received at least 12 consecutive months of daily dosing with Somavert (mean = 55 weeks). The mean (± standard deviation) IGF-I concentration at baseline in this cohort was 917 (± 356) ng/mL after withdrawal from previous medical therapy, falling to 268 (± 134) ng/mL at the end of treatment with Somavert. Thirty-five of the 38 patients (92%) achieved a normal (age-adjusted) IGF-I concentration. After the first visit at which a normal IGF-I concentration was observed, IGF-I levels remained within the normal range at 92% of all subsequent visits over a mean duration of one year.

Indications and Usage for Somavert

Somavert is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum IGF-I levels.

Contraindications

Somavert is contraindicated in patients with a history of hypersensitivity to any of its components.

Precautions

General

Tumor Growth

Tumors that secrete growth hormone (GH) may expand and cause serious complications. Therefore, all patients with these tumors, including those who are receiving Somavert, should be carefully monitored with periodic imaging scans of the sella turcica. During clinical studies of Somavert, two patients manifested progressive tumor growth. Both patients had, at baseline, large globular tumors impinging on the optic chiasm, which had been relatively resistant to previous anti-acromegalic therapies. Overall, mean tumor size was unchanged during the course of treatment with Somavert in the clinical studies.

Glucose Metabolism

GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may increase in some patients treated with Somavert. Although none of the acromegalic patients with diabetes mellitus who were treated with Somavert during the clinical studies had clinically relevant hypoglycemia, these patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary.

GH Deficiency

A state of functional GH deficiency may result from administration of Somavert, despite the presence of elevated serum GH levels. Therefore, during treatment with Somavert, patients should be carefully observed for the clinical signs and symptoms of a GH-deficient state, and serum IGF-I concentrations should be monitored and maintained within the age-adjusted normal range (by adjustment of the dose of Somavert).

Liver Tests (LTs)

Elevations of serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 10 times the upper limit of normal (ULN) were reported in two patients (0.8%) exposed to Somavert during pre-marketing clinical studies. One patient was rechallenged with Somavert, and the recurrence of elevated transaminase levels suggested a probable causal relationship between administration of the drug and the elevation in liver enzymes. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown etiology. In both patients, the transaminase elevations normalized after discontinuation of the drug.

During the pre-marketing clinical studies, the incidence of elevations in ALT greater than 3 times but less than or equal to 10 times the ULN in patients treated with Somavert and placebo were 1.2% and 2.1%, respectively.

Elevations in ALT and AST levels were not associated with increased levels of serum total bilirubin (TBIL) and alkaline phosphatase (ALP), with the exception of two patients with minimal associated increases in ALP levels (i.e., less than 3 times ULN). The transaminase elevations did not appear to be related to the dose of Somavert administered, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors.

Baseline serum ALT, AST, TBIL, and ALP levels should be obtained prior to initiating therapy with Somavert. Table 3 lists recommendations regarding initiation of treatment with Somavert, based on the results of these liver tests (LTs).

Table 3. Initiation of Treatment with Somavert Based on Results of Liver Tests

Baseline LT Levels	Recommendations
Normal	May treat with Somavert. Monitor LTs at monthly intervals during the first 6 months of treatment, quarterly for the next 6 months, and then biannually for the next year.
Elevated, but less than or equal to 3 times ULN	May treat with Somavert; however, monitor LTs monthly for at least one year after initiation of therapy and then biannually for the next year.
Greater than 3 times ULN	Do not treat with Somavert until a comprehensive workup establishes the cause of the patient's liver dysfunction. Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs. Based on the workup, consider initiation of therapy with Somavert. If the decision is to treat, LTs and clinical symptoms should be monitored very closely.

If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving Somavert, the following patient management is recommended (Table 4).

Table 4. Continuation of Treatment with Somavert Based on Results of Liver Tests

LT Levels and Clinical Signs/Symptoms	Recommendations
Greater than or equal to 3 but less than 5 times ULN (without signs/symptoms of hepatitis or other liver injury, or increase in serum TBIL)	May continue therapy with Somavert. However, monitor LTs weekly to determine if further increases occur (see below). In addition, perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present.
At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury)	Discontinue Somavert immediately. Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal. If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious reinitiation of therapy with Somavert, with frequent LT monitoring.
Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability)	Immediately perform a comprehensive hepatic workup. If liver injury is confirmed, the drug should be discontinued.

Lipohypertrophy

Lipohypertrophy has been reported in <5% of patients following pegvisomant administration.

Information for Patients

Patients and any other persons who may administer Somavert should be carefully instructed by a health care professional on how to properly reconstitute and inject the product (see enclosed instructions).

Patients should be informed about the need for serial monitoring of LTs, and told to immediately discontinue therapy and contact their physician if they become jaundiced. In addition, patients should be made aware that serial IGF-I levels will need to be obtained to allow their physician to properly adjust the dose of Somavert.

Laboratory Tests

Liver Tests

Recommendations for monitoring LTs are stated above (see PRECAUTIONS, Liver Tests [LTs]).

IGF-I Levels

Treatment with Somavert should be evaluated by monitoring serum IGF-I concentrations four to six weeks after therapy is initiated or any dose adjustments are made and at least every six months after IGF-I levels have normalized. The goals of treatment should be to maintain a patient's serum IGF-I concentration within the age-adjusted normal range and to control the signs and symptoms of acromegaly.

GH Levels

Pegvisomant interferes with the measurement of serum GH concentrations by commercially available GH assays (see Drug/Laboratory Test Interactions). Furthermore, even when accurately determined, GH levels usually increase during therapy with Somavert. Therefore, treatment with Somavert should not be adjusted based on serum GH concentrations.

Drug Interactions

Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with Somavert.

In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known.

Drug/Laboratory Test Interactions

Pegvisomant has significant structural similarity to GH, which causes it to cross-react in commercially available GH assays. Because serum concentrations of pegvisomant at therapeutically effective doses are generally 100 to 1000 times higher than endogenous serum GH levels seen in patients with acromegaly, commercially available GH assays will overestimate true GH levels. Treatment with Somavert should therefore not be monitored or adjusted based on serum GH concentrations reported from these assays. Instead, monitoring and dose adjustments should only be based on serum IGF-I levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8 and 20 mg/kg (about 2, 10 and 25-fold a single 20mg dose in humans on an AUC basis). Long term treatment with pegvisomant at 8 and 20 mg/kg caused an increase in malignant fibrous histiocytoma at injection sites in males. Injection site tumors were not seen in female rats at the same doses. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections.

Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration).

Pegvisomant was found to have no effect on fertility or reproductive performance of female rabbits at subcutaneous doses up to 10 mg/kg/day (10-fold the recommended human dose on a body surface area basis).

Pregnancy

Pregnancy Category B

Early embryonic development and teratology studies were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day. There was no evidence of teratogenic effects associated with pegvisomant treatment during organogenesis. At the 10-mg/kg/day dose (10 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, Somavert should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when Somavert is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Somavert in pediatric patients have not been established.

Geriatric Use

Clinical studies of Somavert did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

Laboratory Changes

Elevations of serum concentrations of ALT and AST greater than ten times the ULN were reported in two subjects (0.8%) exposed to Somavert in pre-approval clinical studies (see PRECAUTIONS, Liver Tests [LTs]).

General

Nine acromegalic patients (9.6%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations (see PRECAUTIONS, Liver Tests [LTs]), one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain. The majority of reported adverse events were of mild to moderate intensity and limited duration. Most adverse events did not appear to be dose dependent. Table 5 shows the incidence of treatment-emergent adverse events that were reported in at least two patients treated with Somavert and at frequencies greater than placebo during the 12-week, placebo-controlled study.

Table 5. Number of Patients (%) with Acromegaly Reporting Adverse Events in a 12-week Placebo-controlled Study with Somavert*

Event	Somavert			Placebo n=32
	10 mg/day n=26	15 mg/day n=26	20 mg/day n=28
* Table includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with Somavert than in patients treated with placebo. † The 6 events coded as "infection" in the group treated with Somavert 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1).The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1).
Body as a whole
Infection†	6 (23%)	0	0	2 (6%)
Pain	2 (8%)	1 (4%)	4 (14%)	2 (6%)
Injection site reaction	2 (8%)	1 (4%)	3 (11%)	0
Accidental injury	2 (8%)	1 (4%)	0	1 (3%)
Back pain	2 (8%)	0	1 (4%)	1 (3%)
Flu syndrome	1 (4%)	3 (12%)	2 (7%)	0
Chest pain	1 (4%)	2 (8%)	0	0
Digestive
Abnormal liver function tests	3 (12%)	1 (4%)	1 (4%)	1 (3%)
Diarrhea	1 (4%)	0	4 (14%)	1 (3%)
Nausea	0	2 (8%)	4 (14%)	1 (3%)
Nervous
Dizziness	2 (8%)	1 (4%)	1 (4%)	2 (6%)
Paresthesia	0	0	2 (7%)	2 (6%)
Metabolic and nutritional disorders
Peripheral edema	2 (8%)	0	1 (4%)	0
Cardiovascular
Hypertension	0	2 (8%)	0	0
Respiratory
Sinusitis	2 (8%)	0	1 (4%)	1 (3%)

Immunogenicity

In pre-marketing clinical studies, approximately 17% of the patients developed low titer, non-neutralizing anti-GH antibodies. Although the presence of these antibodies did not appear to impact the efficacy of Somavert, the long-term clinical significance of these antibodies is not known. No assay for anti-pegvisomant antibodies is commercially available for patients receiving Somavert.

Post-Marketing Experience

Lipohypertrophy has been reported in <5% of patients following pegvisomant administration.

Asymptomatic, transient elevations in transaminases up to 15 times ULN have been observed in <2% of patients in the post-marketing experience. These reports were not associated with an increase in bilirubin, and there were no clinical consequences for these patients. Transaminase elevations normalized with time, most often after suspending treatment (Somavert should be used in accordance with the information presented in Table 4 with respect to liver test abnormalities).

Overdosage

In one reported incident of acute overdose with Somavert during pre-marketing clinical studies, a patient self-administered 80 mg/day for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities.

In cases of overdose, administration of Somavert should be discontinued and not resumed until IGF-I levels return to within or above the normal range.

Drug Abuse and Dependence

Available data do not demonstrate drug-abuse potential or psychological dependence with Somavert. Radiolabeled pegvisomant does not cross the blood-brain barrier in rats.

Somavert Dosage and Administration

A loading dose of 40 mg of Somavert should be administered subcutaneously under physician supervision. The patient should then be instructed to begin daily subcutaneous injections of 10 mg of Somavert. Serum IGF-I concentrations should be measured every four to six weeks, at which time the dosage of Somavert should be adjusted in 5-mg increments if IGF-I levels are still elevated (or 5-mg decrements if IGF-I levels have decreased below the normal range).While the goals of therapy are to achieve (and then maintain) serum IGF-I concentrations within the age-adjusted normal range and to alleviate the signs and symptoms of acromegaly, titration of dosing should be based on IGF-I levels. It is unknown whether patients who remain symptomatic while achieving normalized IGF-I levels would benefit from increased dosing with Somavert.

The maximum daily maintenance dose should not exceed 30 mg.

Somavert is supplied as a lyophilized powder. Each vial of Somavert should be reconstituted with 1 mL of the diluent provided in the package (Sterile Water for Injection, USP). Instructions regarding reconstitution and administration are included in the package of Somavert and should be closely followed. To prepare the solution, withdraw 1 mL of Sterile Water for Injection, USP and inject it into the vial of Somavert, aiming the stream of liquid against the glass wall. Hold the vial between the palms of both hands and gently roll it to dissolve the powder. DO NOT SHAKE THE VIAL, as this may cause denaturation of pegvisomant. Discard the diluent vial containing the remaining water for injection. After reconstitution, each vial of Somavert contains 10, 15, or 20 mg of pegvisomant protein in one mL of solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear after reconstitution. If the solution is cloudy, do not inject it. Only one dose should be administered from each vial. Somavert should be administered within six hours after reconstitution.

Pegvisomant may be given in the thigh, buttocks, upper arm, or abdomen; the site of SC injections should be rotated daily to help prevent lipohypertrophy.

How is Somavert Supplied

Somavert is available in single-dose, sterile glass vials in the following strengths:

10 mg (as protein) vial          NDC 0009-5176-01

15 mg (as protein) vial          NDC 0009-5178-01

20 mg (as protein) vial          NDC 0009-5180-01

Each package of Somavert also includes a single-dose vial containing Sterile Water for Injection, USP.

Storage

Prior to reconstitution, Somavert should be stored in a refrigerator at 2 to 8°C (36 to 46°F). Protect from freezing.

After reconstitution, Somavert should be administered within six hours. Only one dose should be administered from each vial.

Manufactured by Pfizer Ireland Pharmaceuticals

Dublin, Ireland

LAB-0196-12.0

August 2010

Somavert®

pegvisomant for injection

PATIENT INFORMATION

Somavert (SOM-ah-vert) (pegvisomant for injection)

Read the patient information that comes with Somavert before you start using it and each time you get a refill, because new information may have been added. The information in this leaflet does not take the place of talking to your doctor about your medical condition or your treatment. If there is anything you do not understand in the instructions, or cannot do, call the toll-free number listed at the end of this leaflet.

What is Somavert?

Somavert is a medicine used to treat patients who have acromegaly. Acromegaly is a disease caused by the body making too much growth hormone.

Who should not use Somavert?

Do not use Somavert if you are allergic to Somavert or any of its ingredients. The active ingredient is pegvisomant, which includes polyethylene glycol. The inactive ingredients are glycine, mannitol, sodium phosphate dibasic anhydrous, and sodium phosphate monobasic monohydrate.

Somavert has not been studied in children.

Tell your doctor if you:

• are pregnant or plan to become pregnant. We do not know if Somavert can harm your unborn baby. You and your doctor will have to decide if Somavert is right for you.


• are breast-feeding. We do not know if Somavert passes into your milk or if it can harm your baby.


• have diabetes.


• have or had liver problems.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Be sure to tell your doctor if you use:

• insulin or other medicines (oral hypoglycemic medicines) for diabetes. The doses of these medicines may need to be changed if you use Somavert.


• narcotic painkillers (opioid medicines). Your dose of Somavert may need to be changed if you use any of these medicines.

How should I use Somavert?

• Read the detailed "Instructions for Use" at the end of this leaflet before using Somavert.


• Somavert is given once a day as an injection under the skin (subcutaneous).


• Your first dose, called a loading dose, will be given to you by your health care professional.


• Your health care professional will teach you or your caregiver how to inject Somavert.


• If you forget to give yourself an injection of Somavert, skip that dose. Get back on your schedule the next day. Do not inject a double dose to make up for a forgotten injection.


• If there is anything you do not understand in the instructions, or cannot do, call your health care professional or the toll-free number listed at the end of this leaflet.

What are the possible side effects of Somavert?

Some patients who have used Somavert have developed liver problems. Stop Somavert right away and call your doctor if you get any of the following symptoms:

• your skin or the white part of your eyes turns yellow (jaundice).


• your urine turns dark.


• your bowel movements (stools) turn light in color.


• you do not feel like eating for several days.


• you feel sick to your stomach (nausea).


• you have unexplained tiredness.


• you have pain in the stomach area (abdomen).

Your doctor may do blood tests before and during your treatment with Somavert to check that your liver is working correctly and to see how you are responding to Somavert. Your dose of Somavert may be changed based on these test results.

The most common side effects with Somavert are pain, infection, reaction at the site of injection, flu symptoms, nausea, and diarrhea. These are not all of the possible side effects of Somavert. For more information, ask your doctor or pharmacist.

INSTRUCTIONS FOR USE

Your health care professional shoud teach you how to mix and inject Somavert.

Somavert is packaged in dry powdered form. Before you use Somavert, it must first be mixed with a liquid called a diluent. The diluent is in the same packaging with the medicine. It is called Sterile Water for Injection, USP. Use only this diluent for mixing Somavert. Do not use any other liquid to mix the medicine.

Use only one dose from each vial (small bottle) of Somavert.

Storage

Before you mix the powder and the liquid, store the package of Somavert in a refrigerator (36 to 46°F). Do not freeze.

After mixing the powder and liquid, you may keep the mixed medicine at room temperature inside the vial or the syringe, but you must inject the mixed Somavert within 6 hours. If you have not used the mixed medicine within 6 hours, throw it away.

Getting Started

Remove 1 package of Somavert from the refrigerator. Let it warm up to room temperature for about 10 minutes while you get ready to prepare your injection.

1. Wash your hands with soap and warm water. Dry your hands well.
   
   
   


2. Gather the necessary supplies:
   
   • The package of Somavert that is now at room temperature, which contains 1 vial of powder (Somavert) and 1 vial of liquid (diluent called Sterile Water for Injection, USP)
   
   
   • One 1-cc syringe, with a 18- to 21-gauge, 1-inch or longer needle (this will be the "diluent syringe")
   
   
   • One 1-cc insulin syringe, with a 27- to 30-gauge, 1/2-inch needle that is permanently attached to the syringe (this is the syringe you will use for the injection)
   
   
   • Alcohol or antiseptic swabs
   
   
   • Proper container for throwing away used needles.
   
   
   
   
   
   Mixing Somavert


3. Remove the protective plastic caps from the tops of both vials (medicine and diluent). Do not touch the rubber vial stoppers. The stoppers are clean. If the stoppers are touched by anything, you must clean them with an antiseptic or alcohol swab before use.
   
   
   Carefully remove the cap from the syringe with the larger needle and set the cap aside. This is the diluent syringe.
   
   
   


4. Pull the plunger of the diluent syringe out to the 1-cc mark. With one hand, firmly hold the vial of diluent. With the other hand, push the needle of the diluent syringe straight through the center of the rubber stopper and deep into the vial. Gently push the plunger in until the air is injected into the vial.
   
   
   


5. Firmly hold the diluent vial and syringe together, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe together upside down. Bring them to eye level.
   
   
   


6. Slide one hand carefully down the diluent vial so that with your thumb and forefinger you can firmly hold the neck of the vial, and with your other fingers you can hold the upper part of the syringe. With the other hand, slowly pull the syringe plunger out to slightly past the 1-cc mark.
   
   
   Check the syringe for air bubbles. If you see bubbles, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger in to push only the air bubbles back into the vial. Recheck that 1 cc of diluent remains in the syringe. Then, pull the needle out of the vial. The vial should still have a lot of diluent in it. Do not use the leftover diluent.
   
   
   


7. Push the needle of the diluent syringe straight through the stopper of the vial of Somavert (the one with the powder). Tilt the syringe to the side and gently push the plunger in to inject the diluent down the inner side of the vial of Somavert. Be sure the diluent does not fall directly on the powder, but flows down the inside wall of the vial. When the syringe is empty, pull the needle out from the vial. Throw away the diluent vial with the leftover liquid in it, and the diluent syringe and needle as directed by your health care professional. To help prevent accidental injury, recap the needle only if taught to do so by your health care professional, and in the way you were told to do so by your health care professional.
   
   
   


8. Hold the vial of Somavert upright between your hands and gently roll it to dissolve the powder. Do not shake the vial. Shaking may destroy the medicine. The medicine mixture should be clear after the powder is dissolved. Do not inject the mixture if it looks cloudy or hazy, slightly colored, or if solid particles are visible. Tell your pharmacist and ask for a replacement vial. Do not throw the vial away because the pharmacist may ask that you return it. Inject Somavert within 6 hours of mixing it. If you wait more than 6 hours, you must throw away the mixture without injecting it.
   
   
   
   
   Preparing the Injection


9. Clean the rubber stopper of the vial of Somavert with an antiseptic or alcohol swab. Carefully remove the cap from the insulin syringe (the one with the permanently attached needle) and set the cap aside. Pull the syringe plunger out to the 1-cc mark. With one hand, firmly hold the vial. With the other hand, push the needle straight through the center of the rubber stopper and deep into the vial. Gently push the plunger in until the air is injected into the vial.
   
   
   Firmly hold the vial and syringe together, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe together upside down. Bring them to eye level.
   
   
   


10. As before, slide one hand carefully down the vial so that with your thumb and forefinger you can firmly hold the neck of the vial, and with your other fingers you can hold the upper part of the syringe. With the other hand, slowly pull the syringe plunger out to withdraw the full contents of the vial (1 cc). To keep the needle tip within the mixture, you may have to pull the needle out of the stopper slowly as you draw out the liquid.
    
    
    Check the syringe for air bubbles. If you see bubbles, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger in to push only the air bubbles back into the vial. Recheck that 1 cc of the mixture remains in the syringe. Then pull the needle out of the vial.
    
    
    Recap the needle as directed by your health care professional to help prevent accidental injury while preparing the site for injection.
    
    
    
    
    Giving the Injection
    
    Sub