Isentress 400 mg Film-coated Tablets

1. Name Of The Medicinal Product

ISENTRESS® 400 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 400 mg of raltegravir (as potassium).

Excipient: Each tablet contains 26.06 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Pink, oval tablet, marked with "227" on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients (see sections 4.4 and 5.1).

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection. ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1). The use of raltegravir in previously ART-naïve patients is based on a study in which it was co-administered with two NRTIs (see sections 4.4 and 5.1).

Posology

Adults

The recommended dosage of ISENTRESS is 400 mg administered twice daily with or without food. The effect of food on absorption of raltegravir is uncertain (see section 5.2). It is not recommended to chew, crush or split the tablets.

Elderly

There is limited information regarding the use of ISENTRESS in the elderly (see section 5.2). Therefore ISENTRESS should be used with caution in this population.

Children and adolescents

Safety and efficacy have not been established in patients below 16 years of age (see sections 5.1 and 5.2).

Renal impairment

No dosage adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Oral

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics of raltegravir (see sections 4.5 and 5.2).

Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance (see section 5.1).

In treatment-naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination anti-retroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

There are very limited data on the use of raltegravir in patients co-infected with HIV and hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination anti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.5).

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.8).

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS (see section 4.8).

ISENTRESS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro studies indicated that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely.

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam.

Effect of other agents on the pharmacokinetics of raltegravir

Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4). The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS.

Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required.

In healthy subjects, co-administration of ISENTRESS with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if unavoidable.

Table 1

Pharmacokinetic Interaction Data

Medicinal products by therapeutic area	Interaction (mechanism, if known)	Recommendations concerning co-administration
ANTI-RETROVIRAL
Protease inhibitors (PI)
atazanavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC ↑41% raltegravir C12hr ↑77% raltegravir Cmax ↑24% (UGT1A1 inhibition)	No dose adjustment required for ISENTRESS.
tipranavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz (raltegravir 400 mg Single Dose)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
etravirine (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction) etravirine AUC ↑ 10% etravirine C12hr ↑ 17% etravirine Cmax ↑ 4%	No dose adjustment required for ISENTRESS or etravirine.
Nucleoside/tide reverse transcriptase inhibitors
tenofovir (raltegravir 400 mg Twice Daily)	raltegravir AUC ↑49% raltegravir C12hr ↑3% raltegravir Cmax ↑64% (mechanism of interaction unknown) tenofovir AUC tenofovir C12hr tenofovir Cmax	No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.
CCR5 inhibitors
maraviroc (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (mechanism of interaction unknown) maraviroc AUC maraviroc C12hr maraviroc Cmax	No dose adjustment required for ISENTRESS or maraviroc.
ANTIMICROBIALS
Antimycobacterial
rifampicin (raltegravir 400 mg Single Dose)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	Rifampicin reduces plasma levels of ISENTRESS. If co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4).
SEDATIVE
midazolam (raltegravir 400 mg Twice Daily)	midazolam AUC midazolam Cmax↑3%	No dosage adjustment required for ISENTRESS or midazolam. These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.
ANTI-ULCER
omeprazole (raltegravir 400 mg Single Dose)	raltegravir AUC ↑ 212% raltegravir C12 hr↑ 46% raltegravir Cmax↑ 315%	Co-administration of proton pump inhibitors or other antiulcer medicinal products may increase plasma levels of raltegravir. Do not use ISENTRESS with medicinal products that increase gastric pH unless this is unavoidable.
HORMONAL CONTRACEPTIVES
Ethinyl Estradiol Norelgestromin (raltegravir 400 mg Twice Daily)	Ethinyl Estradiol AUC Ethinyl Estradiol Cmax↑ 1% Norelgestromin AUC ↑ 14% Norelgestromin Cmax↑ 29%	No dosage adjustment required for ISENTRESS or hormonal contraceptives (estrogen- and/or progesterone-based)
OPIOID ANALGESICS
methadone (raltegravir 400 mg Twice Daily)	methadone AUC ↔ methadone Cmax↔	No dose adjustment required for ISENTRESS or methadone.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of raltegravir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ISENTRESS should not be used during pregnancy.

Anti-retroviral Pregnancy Registry

To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Lactation

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.

4.7 Effects On Ability To Drive And Use Machines

No studies have been performed on the effects of ISENTRESS on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).

4.8 Undesirable Effects

The safety profile of ISENTRESS was based on the pooled safety data from two Phase III clinical studies in treatment-experienced patients and one Phase III clinical study in treatment-naïve patients; described below.

In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 244 patient-years in the group receiving placebo.

In treatment-naïve patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total follow-up was 480 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 463 patient-years in the group receiving efavirenz 600 mg at bedtime.

In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9 % in patients receiving ISENTRESS + OBT and 4.6 % in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 3.6 % in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 6.7 % in patients receiving efavirenz + emtricitabine (+) tenofovir.

Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with other ART) are listed below by System Organ Class. Any term that includes at least one serious adverse reaction is identified with a dagger (^†). Adverse reactions identified from post-marketing experience are included in italics.

Frequencies are defined as common (

System Organ Class	Frequency	Adverse reactions ISENTRESS (alone or in combination with other ART)
Infections and infestations	uncommon	genital herpes†, folliculitis, gastro-enteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps)	uncommon	skin papilloma
Blood and lymphatic system disorders	uncommon	anaemia†, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia
uncommon	thrombocytopenia‡‡
Immune system disorders	uncommon	immune reconstitution syndrome†, drug hypersensitivity, hypersensitivity
Metabolism and nutrition disorders	uncommon	anorexia, cachexia, decreased appetite, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia
Psychiatric disorders	common uncommon uncommon	abnormal dreams, insomnia mental disorder†, suicide attempt†, anxiety, confusional state, depressed mood, depression, major depression, middle insomnia, mood altered, nightmare, panic attack, sleep disorder suicidal ideation‡‡, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness) ‡‡
Nervous system disorders	common uncommon	dizziness, headache amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor
Eye disorders	uncommon	visual impairment
Ear and labyrinth disorders	common uncommon	vertigo tinnitus
Cardiac disorders	uncommon	palpitations, sinus bradycardia, ventricular extrasystoles
Vascular disorders	uncommon	hot flush, hypertension
Respiratory, thoracic and mediastinal disorders	uncommon	dysphonia, epistaxis, nasal congestion
Gastro-intestinal disorders	common uncommon	abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting gastritis†, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, dry mouth, constipation, dyspepsia, epigastric discomfort, erosive duodenitis, eructation, gastro-oesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrhage
Hepato-biliary disorders	uncommon	hepatitis†, hepatic steatosis
Skin and subcutaneous tissue disorders	common uncommon   uncommon	rash‡ acne, alopecia, dermatitis acneiforme, dry skin, erythema, facial wasting, hyperhidrosis, lipodystrophy acquired, lipohypertrophy, night sweats, prurigo, pruritus, pruritus generalised, rash macular, rash maculo-papular, rash pruritic, skin lesion, urticaria, xeroderma Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS) ‡‡
Musculoskeletal and connective tissue disorders	uncommon	arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis
Uncommon	rhabdomyolysis‡‡
Renal and urinary disorders	uncommon	renal failure†, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Reproductive system and breast disorders	uncommon	erectile dysfunction, gynaecomastia, menopausal symptoms
General disorders and administration site conditions	common uncommon	asthenia, fatigue, pyrexia chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, oedema peripheral, pain
Investigations	common uncommon	alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased, blood amylase increased, blood bilirubin increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, low density lipoprotein decreased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
Injury, poisoning and procedural complications	uncommon	accidental overdose†
† Includes at least one serious adverse reaction ‡ In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing ISENTRESS + darunavir compared to those containing ISENTRESS without darunavir or darunavir without ISENTRESS. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4). ‡‡ This adverse reaction was identified through post-marketing surveillance but not reported as drug-related in randomised controlled Phase III clinical trials (Protocols 018, 019, and 021). The frequency category of "uncommon" was defined per the Summary of Product Characteristics (SmPC) guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of subjects treated with ISENTRESS in the Phase III clinical program (n=743).

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS in conjunction with other antiretroviral agents. The types and rates of specific cancers were those expected in a highly immunodeficient population. The risk of developing cancer in these studies was similar in the groups receiving ISENTRESS and in the groups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Patients co-infected with hepatitis B and/or hepatitis C virus

In Phase III studies, treatment-experienced patients (N = 114/699 or 16%; HBV=6 %, HCV=9 %, HBV+HCV=1%) and treatment-naïve patients (N = 34/563 or 6 %; HBV=4 %, HCV=2 %, HBV+HCV=0.2 %) with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enrol provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general the safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 11 %, 10 % and 9 % of all other subjects treated with ISENTRESS. In treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17 %, 28 % and 17 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 6 %, 6 % and 3 % of all other subjects treated with ISENTRESS.

4.9 Overdose

No specific information is available on the treatment of overdosage with ISENTRESS.

In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastro-intestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. It should be taken into account that raltegravir is presented for clinical use as the potassium salt. The extent to which ISENTRESS may be dialysable is unknown.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiviral for systemic use, Other Antivirals, ATC code: J05AX08.

Mechanism of action

Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.

Antiviral activity in vitro

Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC₉₅) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.

Resistance

Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Preliminary data indicate that there is potential for at least some degree of cross-resistance to occur between raltegravir and other integrase inhibitors.

Clinical experience

The evidence of efficacy of ISENTRESS is based on the analyses of 96-week data from two ongoing, randomised, double-blind, placebo-controlled trials, (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the analysis of 96-week data from an ongoing, randomised, double-blind, active-control trial, (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Efficacy

Treatment-experienced patients

BENCHMRK 1 and BENCHMRK 2 (ongoing multi-centre, randomised, double-blind, placebo-controlled trials) evaluate the safety and anti-retroviral activity of ISENTRESS 400 mg twice daily vs. placebo in a combination with optimised background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.

Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving ISENTRESS 400 mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.

Results 48-week and 96-week analyses

Durable outcomes (Week 48 and Week 96) for patients on the recommended dose ISENTRESS 400 mg twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2.

Table 2

Efficacy Outcome at Weeks 48 and 96

BENCHMRK 1 and 2 Pooled Parameter	48 Weeks	96 Weeks
ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)	ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)
Percent HIV-RNA < 400 copies/ml (95% CI)
All patients†	72 (68, 76)	37 (31, 44)	62 (57, 66)

Prochlorperazine Injection

Generic Name: prochlorperazine edisylate

Dosage Form: injection
Prochlorperazine Edisylate Injection, USP

Rx only

WARNING

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Prochlorperazine Edisylate Injection, USP is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS).

Prochlorperazine Injection Description

Prochlorperazine edisylate, 2-Chloro-10-[3-(4-methyl-1-piperazinyl)propyl] phenothiazine 1,2-ethanedisulfonate (1:1), has the following structural formula:

Prochlorperazine Edisylate Injection, an antiemetic and antipsychotic, is a sterile solution intended for intramuscular or intravenous administration.

Each mL contains prochlorperazine 5 mg as the edisylate, monobasic sodium phosphate monohydrate 5 mg, sodium tartrate dihydrate 12 mg, saccharin sodium 0.9 mg and benzyl alcohol 7.5 mg in Water for Injection. pH 4.2-6.2.

Prochlorperazine Injection - Clinical Pharmacology

Prochlorperazine is a propylpiperazine derivative of phenothiazine. Like other phenothiazines, it exerts an antiemetic effect through a depressant action on the chemoreceptor trigger zone. It also has a clinically useful antipsychotic effect. Following intramuscular administration of prochlorperazine edisylate, the drug has an onset of action within ten to twenty minutes and a duration of action of three to four hours.

Indications and Usage for Prochlorperazine Injection

To control severe nausea and vomiting. For the treatment of schizophrenia.

Prochlorperazine has not been shown effective in the management of behavioral complications in patients with mental retardation.

Contraindications

Do not use in patients with known hypersensitivity to phenothiazines.

Do not use in comatose states or in the presence of large amounts of central nervous system depressants (alcohol, barbiturates, narcotics, etc.).

Do not use in pediatric surgery.

Do not use in pediatric patients under 2 years of age or under 20 lbs. Do not use in children for conditions for which dosage has not been established.

Warnings

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Prochlorperazine Edisylate Injection, USP is not approved for the treatment of patients with dementia-related psychosis (see  BOXED WARNING).

The extrapyramidal symptoms which can occur secondary to prochlorperazine may be confused with the central nervous system signs of an undiagnosed primary disease responsible for the vomiting, e.g., Reye’s syndrome or other encephalopathy. The use of prochlorperazine and other potential hepatotoxins should be avoided in children and adolescents whose signs and symptoms suggest Reye’s syndrome.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic drug treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on PRECAUTIONS and ADVERSE REACTIONS.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

General

An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and FBS) has occurred in a few patients treated with lithium plus an antipsychotic. In some instances, the syndrome was followed by irreversible brain damage. Because of a possible causal relationship between these events and the concomitant administration of lithium and antipsychotics, patients receiving such combined therapy should be monitored closely for early evidence of neurologic toxicity and treatment discontinued promptly if such signs appear. This encephalopathic syndrome may be similar to or the same as neuroleptic malignant syndrome (NMS).

Patients with bone marrow depression or who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) with a phenothiazine should not receive any phenothiazine, including prochlorperazine, unless in the judgment of the physician the potential benefits of treatment outweigh the possible hazards.

Prochlorperazine may impair mental and/or physical abilities, especially during the first few days of therapy. Therefore, caution patients about activities requiring alertness (e.g., operating vehicles or machinery).

Phenothiazines may intensify or prolong the action of central nervous system depressants (e.g., alcohol, anesthetics, narcotics).

Pregnancy

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Prochlorperazine Edisylate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Usage in Pregnancy

Safety for the use of prochlorperazine during pregnancy has not been established. Therefore, prochlorperazine is not recommended for use in pregnant patients except in cases of severe nausea and vomiting that are so serious and intractable that, in the judgment of the physician, drug intervention is required and potential benefits outweigh possible hazards.

There have been reported instances of prolonged jaundice, extrapyramidal signs, hyperreflexia or hyporeflexia in newborn infants whose mothers received phenothiazines.

Nursing Mothers

There is evidence that phenothiazines are excreted in the breast milk of nursing mothers. Caution should be exercised when prochlorperazine is administered to a nursing woman.

Precautions

Leukopenia, Neutropenia and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Prochlorperazine Edisylate Injection USP at the first sign of a decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Prochlorperazine Edisylate Injection USP and have their WBC followed until recovery.

Prochlorperazine’s antiemetic action may mask signs and symptoms of overdosage of other drugs and may obscure the diagnosis and treatment of other conditions such as intestinal obstruction, brain tumor and Reye’s syndrome (see WARNINGS).

When prochlorperazine is used with cancer chemotherapeutic drugs, vomiting as a sign of toxicity of these agents may be obscured by the antiemetic effect of prochlorperazine.

Because hypotension may occur, large doses and parenteral administration should be used cautiously in patients with impaired cardiovascular systems. To minimize the occurrence of hypotension after injection, keep patient lying down and observe for at least 1/2 hour. If hypotension occurs after parenteral dosing, place patient in head-low position with legs raised. If a vasoconstrictor is required, norepinephrine and phenylephrine are suitable. Other pressor agents, including epinephrine, should not be used because they may cause a paradoxical further lowering of blood pressure.

Aspiration of vomitus has occurred in a few postsurgical patients who have received prochlorperazine as an antiemetic. Although no causal relationship has been established, this possibility should be borne in mind during surgical aftercare.

Deep sleep, from which patients can be aroused, and coma have been reported, usually with overdosage.

Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.

Chromosomal aberrations in spermatocytes and abnormal sperm have been demonstrated in rodents tested with certain antipsychotics.

As with all drugs which exert an anticholinergic effect, and/or cause mydriasis, prochlorperazine should be used with caution in patients with glaucoma.

Because phenothiazines may interfere with thermoregulatory mechanisms, use with caution in persons who will be exposed to extreme heat.

Phenothiazines can diminish the effect of oral anticoagulants.

Phenothiazines can produce alpha-adrenergic blockade.

Thiazide diuretics may accentuate the orthostatic hypotension that may occur with phenothiazines.

Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concomitantly.

Concomitant administration of propranolol with phenothiazines results in increased plasma levels of both drugs.

Phenothiazines may lower the convulsive threshold; dosage adjustments of anticonvulsants may be necessary. Potentiation of anticonvulsant effects does not occur. However, it has been reported that phenothiazines may interfere with the metabolism of phenytoin and thus precipitate phenytoin toxicity.

The presence of phenothiazines may produce false-positive phenylketonuria (PKU) test results.

Long-Term Therapy

Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

To lessen the likelihood of adverse reactions related to cumulative drug effect, patients with a history of long-term therapy with prochlorperazine and/or other antipsychotics should be evaluated periodically to decide whether the maintenance dosage could be lowered or drug therapy discontinued.

Children with acute illnesses (e.g., chickenpox, CNS infections, measles, gastroenteritis) or dehydration seem to be much more susceptible to neuromuscular reactions, particularly dystonias, than are adults. In such patients, the drug should be used only under close supervision.

Drugs which lower the seizure threshold, including phenothiazine derivatives, should not be used with metrizamide. As with other phenothiazine derivatives, prochlorperazine should be discontinued at least 48 hours before myelography, should not be resumed for at least 24 hours postprocedure, and should not be used for the control of nausea and vomiting occurring either prior to myelography with metrizamide or postprocedure.

Adverse Reactions

Drowsiness, dizziness, amenorrhea, blurred vision, skin reactions and hypotension may occur. Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs (see WARNINGS).

Cholestatic jaundice has occurred. If fever with grippe-like symptoms occurs, appropriate liver studies should be conducted. If tests indicate an abnormality, stop treatment. There have been a few observations of fatty changes in the livers of patients who have died while receiving the drug. No causal relationship has been established.

Leukopenia and agranulocytosis have occurred.Warn patients to report the sudden appearance of sore throat or other signs of infection. If white blood cell and differential counts indicate leukocyte depression, stop treatment and start antibiotic and other suitable therapy.

Neuromuscular (Extrapyramidal) Reactions

These symptoms are seen in a significant number of hospitalized mental patients. They may be characterized by motor restlessness, be of the dystonic type, or they may resemble parkinsonism.

Depending on the severity of symptoms, dosage should be reduced or discontinued. If therapy is reinstituted, it should be at a lower dosage. Should these symptoms occur in children or pregnant patients, the drug should be stopped and not reinstituted. In most cases barbiturates by suitable route of administration will suffice, or injectable diphenhydramine may be useful.

In more severe cases, the administration of an antiparkinsonism agent, except levodopa, usually produces rapid reversal of symptoms. Suitable supportive measures such as maintaining a clear airway and adequate hydration should be employed.

Motor Restlessness

Symptoms may include agitation or jitteriness and sometimes insomnia. These symptoms often disappear spontaneously. At times these symptoms may be similar to the original neurotic or psychotic symptoms. Dosage should not be increased until these side effects have subsided.

If these symptoms become too troublesome, they can usually be controlled by a reduction of dosage or change of drug. Treatment with antiparkinsonian agents, benzodiazepines or propranolol may be helpful.

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Pseudoparkinsonism

Symptoms may include mask-like facies, drooling, tremors, pillrolling motion, cogwheel rigidity, and shuffling gait. Reassurance and sedation are important. In most cases, these symptoms are readily controlled when an antiparkinsonism agent is administered concomitantly. Antiparkinsonism agents should be used only when required. Generally, therapy of a few weeks to two or three months will suffice. After this time, patients should be evaluated to determine their need for continued treatment. (Note: Levodopa has not been found effective in pseudoparkinsonism.) Occasionally, it is necessary to lower the dosage of prochlorperazine or to discontinue the drug.

Tardive Dyskinesia

As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. The syndrome can also develop, although much less frequently, after relatively brief treatment periods at low doses. This syndrome appears in all age groups. Although its prevalence appears to be highest among elderly patients, especially elderly women, it is impossible to rely upon prevalence estimates to predict at the inception of antipsychotic treatment which patients are likely to develop the syndrome. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities. In rare instances, these involuntary movements of the extremities are the only manifestations of tardive dyskinesia. A variant of tardive dyskinesia, tardive dystonia, has also been described.

There is no known effective treatment for tardive dyskinesia; antiparkinsonism agents do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment or increase the dosage of the agent or switch to a different antipsychotic agent, the syndrome may be masked.

It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome, and if the medication is stopped at that time, the syndrome may not develop.

Contact Dermatitis

Avoid getting the injection solution on hands or clothing because of the possibility of contact dermatitis.

Adverse Reactions Reported with Prochlorperazine or Other Phenothiazine Derivatives

Adverse reactions with different phenothiazines vary in type, frequency, and the mechanism of occurrence, i.e., some are dose-related, while others involve individual patient sensitivity.

Some adverse reactions may be more likely to occur, or occur with greater intensity, in patients with special medical problems, e.g., patients with mitral insufficiency or pheochromocytoma have experienced severe hypotension following recommended doses of certain phenothiazines.

Not all of the following adverse reactions have been observed with every phenothiazine derivative but they have been reported with one or more and should be borne in mind when drugs of this class are administered: extrapyramidal symptoms (opisthotonos, oculogyric crisis, hyperreflexia, dystonias, akathisia, dyskinesia, parkinsonism), some of which have lasted months and even years, particularly in elderly patients with previous brain damage; grand mal and petit mal convulsions, particularly in patients with EEG abnormalities or history of such disorders; altered cerebrospinal fluid proteins; cerebral edema; intensification and prolongation of the action of central nervous system depressants (opiates, analgesics, antihistamines, barbiturates, alcohol), atropine, heat, organophosphorus insecticides; autonomic reactions (dryness of mouth, nasal congestion, headache, nausea, constipation, obstipation, adynamic ileus, ejaculatory disorders/impotence, priapism, atonic colon, urinary retention, miosis and mydriasis); reactivation of psychotic processes, catatonic-like states; hypotension (sometimes fatal); cardiac arrest; blood dyscrasias (pancytopenia, thrombocytopenic purpura, leukopenia, agranulocytosis, eosinophilia, hemolytic anemia, aplastic anemia); liver damage (jaundice, biliary stasis); endocrine disturbances (hyperglycemia, hypoglycemia, glycosuria, lactation, galactorrhea, gynecomastia, menstrual irregularities, false-positive pregnancy tests); skin disorders (photosensitivity, itching, erythema, urticaria, eczema up to exfoliative dermatitis); other allergic reactions (asthma, laryngeal edema, angioneurotic edema, anaphylactoid reactions); peripheral edema; reversed epinephrine effect; hyperpyrexia; mild fever after large IM doses; increased appetite; increased weight; a systemic lupus erythematosus-like syndrome; pigmentary retinopathy; with prolonged administration of substantial doses, skin pigmentation, epithelial keratopathy, and lenticular and corneal deposits.

EKG changes—particularly nonspecific, usually reversible Q- and T-wave distortions—have been observed in some patients receiving phenothiazines.

Although phenothiazines cause neither psychic nor physical dependence, sudden discontinuation in long-term psychiatric patients may cause temporary symptoms, e.g., nausea and vomiting, dizziness, tremulousness.

NOTE: There have been occasional reports of sudden death in patients receiving phenothiazines. In some cases, the cause appeared to be cardiac arrest or asphyxia due to failure of the cough reflex.

Overdosage

(See also ADVERSE REACTIONS.)

Symptoms

Primarily involvement of the extrapyramidal mechanism producing some of the dystonic reactions described above. Symptoms of central nervous system depression to the point of somnolence or coma. Agitation and restlessness may also occur. Other possible manifestations include convulsions, EKG changes and cardiac arrhythmias, fever, and autonomic reactions such as hypotension, dry mouth and ileus.

Treatment

It is important to determine other medications taken by the patient since multiple drug therapy is common in overdosage situations. Treatment is essentially symptomatic and supportive. Keep patient under observation and maintain an open airway, since involvement of the extrapyramidal mechanism may produce dysphagia and respiratory difficulty in severe overdosage.

Extrapyramidal symptoms may be treated with antiparkinsonism drugs, barbiturates, or diphenhydramine. See prescribing information for these products. Care should be taken to avoid increasing respiratory depression.

If administration of a stimulant is desirable, amphetamine, dextroamphetamine, or caffeine and sodium benzoate is recommended. Stimulants that may cause convulsions (e.g., picrotoxin or pentylenetetrazol) should be avoided.

If hypotension occurs, the standard measures for managing circulatory shock should be initiated. If it is desirable to administer a vasoconstrictor, norepinephrine or phenylephrine are most suitable. Other pressor agents, including epinephrine, are not recommended, because phenothiazine derivatives may reverse the usual elevating action of these agents and cause a further lowering of blood pressure.

Limited experience indicates that phenothiazines are not dialyzable.

Prochlorperazine Injection Dosage and Administration

NOTE ON INJECTION: For intramuscular administration, inject deeply into the upper, outer quadrant of the buttock.

Subcutaneous administration is not advisable because of local irritation.

Stability

This solution should be protected from light. Slight yellowish discoloration will not alter potency. If markedly discolored, solution should be discarded.

Compatibility

It is recommended that Prochlorperazine Edisylate Injection not be mixed with other agents in the syringe.

Adults

(For children’s dosage and administration, see below.) Dosage should be increased more gradually in debilitated or emaciated patients.

Elderly Patients

In general, dosages in the lower range are sufficient for most elderly patients. Since they appear to be more susceptible to hypotension and neuromuscular reactions, such patients should be observed closely. Dosage should be tailored to the individual, response carefully monitored, and dosage adjusted accordingly. Dosage should be increased more gradually in elderly patients.

To Control Severe Nausea and Vomiting

Adjust dosage to the response of the individual. Begin with lowest recommended dosage.

IM Dosage

Initially 5 mg to 10 mg (1 to 2 mL) injected deeply into the upper, outer quadrant of the buttock. If necessary, repeat every 3 or 4 hours. Total IM dosage should not exceed 40 mg per day.

IV Dosage

2.5 mg to 10 mg (0.5 to 2 mL) by slow IV injection or infusion at a rate not to exceed 5 mg per minute. Prochlorperazine Edisylate Injection may be administered either undiluted or diluted in isotonic solution. A single dose of the drug should not exceed 10 mg; total IV dosage should not exceed 40 mg per day. When administered IV, do not use bolus injection. Hypotension is a possibility if the drug is given by IV injection or infusion.

Subcutaneous administration is not advisable because of local irritation.

Adult Surgery (for severe nausea and vomiting)

Total parenteral dosage should not exceed 40 mg per day. Hypotension is a possibility if the drug is given by IV injection or infusion.

IM Dosage

5 mg to 10 mg (1 to 2 mL) 1 to 2 hours before induction of anesthesia (repeat once in 30 minutes, if necessary), or to control acute symptoms during and after surgery (repeat once if necessary).

IV Dosage

5 mg to 10 mg (1 to 2 mL) as a slow IV injection or infusion 15 to 30 minutes before induction of anesthesia, or to control acute symptoms during or after surgery. Repeat once if necessary. Prochlorperazine may be administered either undiluted or diluted in isotonic solution, but a single dose of the drug should not exceed 10 mg. The rate of administration should not exceed 5 mg per minute. When administered IV, do not use bolus injection.

In Adult Psychiatric Disorders

Adjust dosage to the response of the individual and according to the severity of the condition. Begin with the lowest recommended dose. Although response ordinarily is seen within a day or two, longer treatment is usually required before maximal improvement is seen.

IM Dosage

For immediate control of adult schizophrenic patients with severe symptomatology, inject an initial dose of 10 mg to 20 mg (2 to 4 mL) deeply into the upper, outer quadrant of the buttock. Many patients respond shortly after the first injection. If necessary, however, repeat the initial dose every 2 to 4 hours (or, in resistant cases, every hour) to gain control of the patient. More than 3 or 4 doses are seldom necessary. After control is achieved, switch patient to an oral form of the drug at the same dosage level or higher. If, in rare cases, parenteral therapy is needed for a prolonged period, give 10 mg to 20 mg (2 to 4 mL) every 4 to 6 hours. Pain and irritation at the site of injection have seldom occurred.

Subcutaneous administration is not advisable because of local irritation.

Children

DO NOT USE IN PEDIATRIC SURGERY

Children seem more prone to develop extrapyramidal reactions, even on moderate doses. Therefore, use lowest effective dosage. Tell parents not to exceed prescribed dosage, since the possibility of adverse reactions increases as dosage rises.

Occasionally the patient may react to the drug with signs of restlessness and excitement; if this occurs, do not administer additional doses. Take particular precaution in administering the drug to children with acute illnesses or dehydration (see under PRECAUTIONS and Dystonia).

Severe Nausea and Vomiting in Children

Prochlorperazine should not be used in pediatric patients under 20 pounds in weight or two years of age. It should not be used in conditions for which children’s dosages have not been established. Dosage and frequency of administration should be adjusted according to the severity of the symptoms and the response of the patient. The duration of activity following intramuscular administration may last up to 12 hours. Subsequent doses may be given by the same route if necessary.

IM Dosage

Calculate each dose on the basis of 0.06 mg of the drug per lb of body weight; give by deep IM injection. Control is usually obtained with one dose.

Children with Schizophrenia

IM Dosage

For ages under 12, calculate each dose on the basis of 0.06 mg of prochlorperazine per lb of body weight; give by deep IM injection. Control is usually obtained with one dose. After control is achieved, switch the patient to an oral form of the drug at the same dosage level or higher.

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

How is Prochlorperazine Injection Supplied

Prochlorperazine Edisylate Injection, USP 5 mg/mL

2 mL (10 mg) DOSETTE vials packaged in 25s (NDC 0641-0491-25)

Storage

PROTECT FROM LIGHT. Store in the box until ready to use. Discard if markedly discolored.

Store at 20˚-25˚C (68˚-77˚F), excursions permitted to 15˚-30˚C (59˚-86˚F) [see USP Controlled Room Temperature].

Baxter and Dosette are trademarks of Baxter International Inc.

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

Revised September 2010

MLT00100,E

PRINCIPAL DISPLAY PANEL - PACKAGE LABELING

Container Label

NDC 0641-0491-21

Prochlorperazine

Edisylate Injection, USP

10 mg/2 mL

Rx only

(5 mg/mL)

2 mL DOSETTE Vial

FOR DEEP IM

OR IV USE ONLY

 NOT FOR SC USE

PROTECT FROM LIGHT

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

(01)00306410491217

462-304-01

Lot:

Exp.:

Carton Label

LOT

EXP.

LIGHT SENSITIVE: Keep covered in carton until

time of use. To open—Cut seal along dotted line.

NDC 0641-0491-25

Prochlorperazine

Edisylate Injection, USP

10 mg/2 mL

Rx only

(5 mg/mL)

25 x 2 mL DOSETTE Vials

FOR DEEP IM OR IV USE ONLY

NOT FOR SUBCUTANEOUS USE

PROTECT FROM LIGHT: Keep covered in

carton until time of use. Discard contents

if markedly discolored.

Each mL contains prochlorperazine 5 mg

as the edisylate, monobasic sodium

phosphate monohydrate 5 mg, sodium

tartrate dihydrate 12 mg, saccharin

sodium 0.9 mg and benzyl alcohol 7.5 mg

in Water for Injection. pH 4.2-6.2.

USUAL DOSAGE: See package in-

sert for complete prescribing infor-

mation for children and adults.

DO NOT USE IN PEDIATRIC SURGERY.

Store at 20°-25°C (68°-77°F)

[see USP Controlled Room

Temperature].

Baxter logo

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

462-305-00

(01)00306410491255

PROCHLORPERAZINE EDISYLATE  prochlorperazine edisylate  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0641-0491 Route of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength prochlorperazine edisylate (prochlorperazine) prochlorperazine edisylate 5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE 5 mg  in 1 mL SODIUM TARTRATE 12 mg  in 1 mL SACCHARIN SODIUM .9 mg  in 1 mL benzyl alcohol 7.5 mg  in 1 mL water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0641-0491-25 25 VIAL In 1 PACKAGE contains a VIAL (0641-0491-21) 1 0641-0491-21 2 mL In 1 VIAL This package is contained within the PACKAGE (0641-0491-25)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA089903	01/14/2011

Labeler - Baxter Healthcare Corporation (005083209)

Establishment
Name	Address	ID/FEI	Operations
Baxter Healthcare Corporation		946499746	MANUFACTURE

Revised: 01/2011Baxter Healthcare Corporation

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