Prochlorperazine Edisylate

Class: Phenothiazines
Note: This monograph also contains information on Prochlorperazine, Prochlorperazine Maleate
VA Class: CN701
CAS Number: 58-38-8
Brands: Compazine, Compro

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section. For more information visit the FDA website at: , and .

Introduction

Phenothiazine; antipsychotic and antiemetic agent.^{a d e f}

Uses for Prochlorperazine Edisylate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Psychotic Disorders

Symptomatic management of psychotic disorders (i.e., schizophrenia).^{d e f}

Nonpsychotic Anxiety

Short-term management of nonpsychotic anxiety in patients with generalized anxiety disorder.^{d e f}

Not established whether prochlorperazine is useful for the management of other nonpsychotic conditions in which anxiety or manifestations that mimic anxiety are evident (e.g., physical illness, organic mental conditions, agitated depression, character pathologies).^{d e f}

Because of the risks of toxicity, use only as an alternative to other less toxic anxiolytic agents (e.g., benzodiazepines) in most patients.^{d e f}

Nausea and Vomiting

Management of severe nausea and vomiting of various etiologies (e.g., postoperative, acute migraine, toxins, radiation, or cytotoxic drugs).^{a b e f g}

Not effective in preventing vertigo or motion sickness, or for the management of emesis caused by the action of drugs on the nodose ganglion or locally on the GI tract.^{a b}

Use not recommended for the prevention and treatment of nausea and vomiting associated with pregnancy except in cases of severe nausea and vomiting so serious and intractable that pharmacologic intervention is required and the potential benefits justify the possible risks to the fetus.^{a b e f g} (See Fetal/Neonatal Morbidity under Cautions.)

Other Uses

Has not been shown to be effective for the management of behavioral complications in patients with mental retardation.^{d e f}

Prochlorperazine Edisylate Dosage and Administration

General

• 
  

  Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.^{d e f g}

  
  


• 
  

  Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued.^{d e f g} (See Tardive Dyskinesia under Cautions.)

  
  

Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Symptomatic relief of psychotic disorders may be seen in many patients during the first 2 days of therapy; however, optimum antipsychotic effect usually requires prolonged administration of the drug.^d

  
  


• 
  

  For prompt control of severe psychotic symptoms, administer IM; after symptoms are controlled, oral therapy should replace parenteral therapy at the same dosage level or higher.^d

  
  

Administration

Prochlorperazine edisylate is administered orally, by deep IM injection, by direct IV injection, or by IV infusion.^{a d f}

Prochlorperazine maleate is administered orally.^{a d e}

Prochlorperazine is administered rectally.^{a g}

Sub-Q administration is not recommended because of local irritation.^d

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

May be administered undiluted or diluted in isotonic solution.^{f g}

To minimize hypotension following IV administration, patient should remain in supine position under observation for ≥30 minutes.^{e f g} (See Hypotension under Cautions.)

Rate of Administration

Administer by IV infusion or by direct IV injection at a rate not exceeding 5 mg/minute.^{a f}

Do not administer as a rapid (“bolus”) injection.^{a f}

IM Administration

Administer by deep IM injection into the upper outer quadrant of the gluteus maximus.^{a b c d f}

If possible, avoid IM administration in geriatric patients who are thin or debilitated with reduced muscle mass (injections may be painful and absorption may be erratic or unpredictable).^b

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as prochlorperazine, prochlorperazine edisylate, or prochlorperazine maleate; dosage expressed in terms of prochlorperazine.^{a d}

Pediatric Patients

Children should receive the lowest possible effective dosage, and parents should be instructed not to exceed the prescribed dosage.^{d e f}

Use not recommended in children <2 years of age or those weighing <9 kg.^{d e}

Prescriptions for 2.5-mg pediatric suppositories should be written as “2 ½ mg” to avoid confusion with 25-mg adult suppositories.^c

Psychotic Disorders

Oral or Rectal

Children 2–12 years of age: Initially, 2.5 mg 2 or 3 times daily.^{d e} Dosage may be increased according to patient’s therapeutic response and tolerance, but usually should not exceed 20 and 25 mg daily for children 2–5 and 6–12 years of age, respectively.^{d e}

Dosage for children <2 years of age or those weighing <9 kg not established.^{d e}

IM

Children <12 years of age: 0.13 mg/kg for prompt control of severe psychotic symptoms.^{d e} Generally, most pediatric patients respond after 1 dose, and oral therapy should replace parenteral therapy at the same dosage level or higher.^{d e}

Nausea and Vomiting

Oral or Rectal

Dosage for Treatment of Severe Nausea and Vomiting in Children ≥2 Years of Agece

Weight (kg)	Daily Dosage
≤9	Use not recommended
9.1–13.2	2.5 mg once or twice daily
13.6–17.7	2.5 mg 2 or 3 times daily
18.2–38.6	2.5 mg 3 times daily or 5 mg twice daily

Alternatively, in children ≥2 years of age and weighing >9 kg: 0.4 mg/kg or 10 mg/m² daily given in 3 or 4 divided doses.^a

Generally, it is not necessary to continue therapy for >24 hours.^{a c e}

IM

Children ≥2 years of age and weighing >9 kg: 0.13 mg/kg.^{a f} Generally, a single dose is sufficient to control nausea and vomiting in most patients.^{a f}

Adults

Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral

5 or 10 mg (as conventional tablets or oral solution) 3 or 4 times daily in office patients and outpatients with relatively mild symptomatology.^{d e}

Initially, 10 mg (as conventional tablets or oral solution) 3 or 4 times daily for hospitalized or well-supervised patients with moderate to severe symptomatology.^{d e} Gradually increase dosage every 2 or 3 days until symptoms are controlled or adverse effects become troublesome.^{d e} Although some patients exhibit optimum response with 50–75 mg daily, dosages up to 150 mg daily may be required in severely disturbed patients.^{d e}

IM

10–20 mg for prompt control in patients with severe symptomatology; may be necessary to repeat the initial dose every 1–4 hours to control symptoms in some patients.^{d f} Generally, not more than 3 or 4 doses are required.^{d f}

10–20 mg every 4–6 hours, if prolonged parenteral therapy is required.^{d f}

After the patient’s symptoms are controlled, oral therapy should replace parenteral therapy at the same dosage level or higher.^{d f}

Nonpsychotic Anxiety

Oral

5 mg (as conventional tablets or oral solution) 3 or 4 times daily for ≤12 weeks.^{d e}

Alternatively, a dosage of 15 mg (as extended-release capsules) once daily upon arising or 10 mg (as extended-release capsules) every 12 hours may be used.^{c d}

Nausea and Vomiting

Oral

Usually, 5 or 10 mg (as conventional tablets or oral solution) 3 or 4 times daily.^{a e}

Alternatively, 15 mg (as extended-release capsules) once daily upon arising or 10 mg (as extended-release capsules) every 12 hours may be used; some patients subsequently may require a dosage of 30 mg (using the appropriate number of 10- or 15-mg extended-release capsules) once daily in the morning.^{a c}

Dosages >40 mg daily should be used only in resistant cases.^{a c}

Rectal

25 mg twice daily.^g

IV

2.5–10 mg.^{a f}

For control of severe nausea and vomiting during surgery: 5–10 mg given 15–30 minutes before induction of anesthesia.^{a f} If necessary, repeat initial dose once before surgery.^{a f}

To control acute symptoms during or after surgery, usually 5–10 mg, repeated once, if necessary; single IV doses of the drug should not exceed 10 mg.^a

IM

Initially, 5–10 mg; if necessary, initial dose may be repeated every 3 or 4 hours, but total dosage should not exceed 40 mg daily.^{a f}

For control of severe nausea and vomiting during surgery: 5–10 mg given 1–2 hours before induction of anesthesia.^{a f} If necessary, dose may be repeated once, 30 minutes after the initial dose.^{a f}

To control acute symptoms during or after surgery: 5–10 mg, repeated once in 30 minutes, if necessary.^{a f}

Prescribing Limits

Pediatric Patients

Psychotic Disorders

Oral or Rectal

Maximum 10 mg daily for the first day.^d

Subsequently, maximum 20 and 25 mg daily for children 2–5 and 6–12 years of age, respectively.^{d e}

Nausea and Vomiting

Oral or Rectal

Maximum Dosage for Treatment of Severe Nausea and Vomiting in Children ≥2 Years of Agee

Weight (kg)	Maximum Daily Dosage
≤9	Use not recommended
9.1–13.2	Maximum 7.5 mg daily
13.6–17.7	Maximum 10 mg daily
18.2–38.6	Maximum 15 mg daily

Adults

Nonpsychotic Anxiety

Oral

Maximum 20 mg daily; do not administer for >12 weeks.^e

Nausea and Vomiting

Oral

Dosages >40 mg daily should be used only in resistant cases.^{a c}

IV

Maximum 10 mg as a single dose.^{a f} Maximum 40 mg daily (total daily dosage).^{a f}

IM

Maximum 40 mg daily (total daily dosage).^{a f}

Special Populations

Geriatric Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Generally, select dose at lower end of recommended range; increase dosage gradually and monitor closely.^{d e f g} (See Geriatric Use under Cautions.)

Debilitated or Emaciated Patients

Increase dosage gradually.^{d e f g}

Cautions for Prochlorperazine Edisylate

Contraindications

• 
  

  Comatose states or in the presence of large amounts of CNS depressants (e.g., alcohol, barbituates, opiates).^{d e f g} (See Specific Drugs and Laboratory Tests under Interactions.)

  
  


• 
  

  Pediatric surgery.^{d e f g}

  
  


• 
  

  Children <2 years of age or <9 kg.^{d e f g}

  
  


• 
  

  Children with conditions for which dosage has not been established.^{d e f g}

  
  


• 
  

  Known hypersensitivity to prochlorperazine or other phenothiazines.^{d e f g}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Shares the toxic potentials of other phenothiazines; observe the usual precautions of phenothiazine therapy.^{a d}

Extrapyramidal Reactions

Possible extrapyramidal reactions, especially in hospitalized psychiatric patients and in children.^{d e f g} Consider dosage reduction or discontinuance, depending on severity of symptoms.^{c e f g} An anticholinergic antiparkinsonian agent or diphenhydramine may be given to control persistent or severe reactions.^{b c}

Signs and symptoms may be similar to those accompanying certain disorders (e.g., encephalitis, Reye’s syndrome, encephalopathy, meningitis, tetanus); diagnosis of these disorders may be obscured or the disease-associated signs and symptoms may be incorrectly diagnosed as drug induced.^b

Tardive Dyskinesia

Possible persistent and potentially irreversible tardive dyskinesia, especially in geriatric patients receiving high dosages (especially females).^{b e f g} Use of higher dosages or longer periods of treatment may increase risk of developing the syndrome.^{b e f g}

Reserve long-term therapy for patients with a chronic disorder known to be responsive to antipsychotic agents and for which alternative, equally effective, but potentially less toxic therapy is not available or appropriate.^b

Periodically reassess the need for continued therapy in patients requiring chronic treatment.^{b e f g} Unless contraindicated, make periodic efforts to gradually reduce dosage and provide drug holidays and/or nondrug (e.g., behavioral) therapy in an attempt to discontinue antipsychotic drug therapy whenever clinically possible.^b

If signs and symptoms of tardive dyskinesia develop, consider discontinuance of the drug.^{e f g} Some patients may require treatment despite the presence of the syndrome.^{e f g}

Neuroleptic Malignant Syndrome

Potentially fatal neuroleptic malignant syndrome (NMS) characterized by hyperthermia, severe extrapyramidal dysfunction, varying levels of consciousness, altered mental status, and autonomic instability has been reported.^{b e f g}

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs.^{b e f g} Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.^{b e f g}

Fetal/Neonatal Morbidity

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Safety of use during pregnancy not established.^{b e f g} Jaundice, prolonged extrapyramidal signs and symptoms, hyperreflexia, and hyporeflexia reported in some neonates born to women who received phenothiazines during pregnancy.^{b e f g} Generally, use during pregnancy only when the potential benefits justify the possible risks to the fetus.^{b e f g}

Sensitivity Reactions

Possible sensitivity reactions (e.g., cholestatic jaundice, blood dyscrasias, dermatoses, photosensitivity).^{e f g} Use generally not recommended in patients with bone marrow depression or those who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to a phenothiazine, unless potential benefits outweigh the possible risks.^{b e f g}

Contact dermatitis occurs rarely following skin contact with prochlorperazine edisylate oral solution or injection; use care to avoid skin contact with oral solution or injection.^{a b d f}

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

CNS Depression

May impair mental and/or physical abilities, especially during the first few days of therapy; use caution with activities requiring alertness (e.g., operating vehicles or machinery).^{b e f g}

Because of CNS depressant effects, use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).^b

Hypotension

Possible hypotension; large dosages and parenteral administration should be used with caution in patients with severe cardiovascular disorders.^{b e f g}

To minimize hypotension following IV administration, patient should remain in supine position under observation for ≥30 minutes.^{e f g}

If hypotension occurs, place patient in Trendelenburg’s position and, if required, administer norepinephrine or phenylephrine; epinephrine or dopamine should not be used.^{e f g} (See Specific Drugs and Laboratory Tests under Interactions.)

Prolactin Secretion

Increased serum prolactin concentrations; may be associated with galactorrhea, menstrual cycle changes (e.g., oligomenorrhea, amenorrhea), and gynecomastia.^{b e f g}

Since approximately one-third of human breast cancers are prolactin dependent, use with caution in patients with previously detected breast cancer.^{b e f g}

Mutagenicity

Chromosomal aberrations in spermatocytes and abnormal sperm have been demonstrated in rodents.^{b e f g}

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, mydriasis, constipation, nausea, adynamic ileus, atonic colon, urinary retention, decreased sweating, and impotence).^{b e f g}

Use with caution in patients with glaucoma or prostatic hypertrophy.^{b e f g}

Regulation of Body Temperature

Phenothiazines depress the hypothalamic mechanism for regulation of body temperature; possible hyperthermia and heat prostration or hypothermia when exposed to temperature extremes.^{b e f g}

Use with caution in patients exposed to extreme heat or cold.^{b e f g}

Surgery

Possible suppression of the cough reflex and aspiration of gastric contents.^{b e f g} Use caution in postoperative patients.^{b e f g}

Other Precautions

Antiemetic effects may mask signs of overdosage of other drugs (e.g., antineoplastic agents) or obscure the cause of vomiting in various disorders (e.g., intestinal obstruction, brain tumor, Reye’s syndrome).^{b e f g} (See Extrapyramidal Effects under Cautions.)

Use phenothiazines with caution in patients with hypocalcemia, since susceptibility to dystonic reactions may be increased.^b

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.^f

Lactation

Distributed into milk.^{e f g} Caution if used in nursing women.^{e f g}

Pediatric Use

Safety and efficacy not established in children <2 years of age or those weighing <9 kg.^{a d e f}

Avoid use in children and adolescents with suspected Reye’s syndrome, since the antiemetic and potential extrapyramidal effects produced by the drug may obscure the diagnosis of or be confused with CNS manifestations of this condition.^{a d e f} (See Extrapyramidal Reactions under Cautions.)

Not recommended for use in children during surgery or in conditions for which pediatric dosage has not been established.^{a d e f}

Incidence of extrapyramidal reactions appears to be relatively high in children.^{d e f g} Children with acute illnesses (e.g., varicella-zoster [chickenpox] infections, CNS infections, measles, gastroenteritis) or dehydration appear to be at increased risk of such reactions (particularly dystonic reactions and akathisia); use only under close supervision in these patients.^{b c e f g}

Geriatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible increased incidence of adverse nervous system (e.g., tardive dyskinesia), anticholinergic, and cardiovascular (e.g., hypotension) effects compared with younger adults. (See Tardive Dyskinesia and also Anticholinergic Effects and also Hypotension, under Cautions.)^{b d e f g}

Generally, select dose at lower end of recommended range; increase dosage gradually and monitor closely.^{d e f g}

Hepatic Impairment

Use with caution.^b

Renal Impairment

Use with caution.^b

Common Adverse Effects

Drowsiness, dizziness, amenorrhea, blurred vision, skin reactions, hypotension.^{e f g}

Interactions for Prochlorperazine Edisylate

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Anticoagulants, oral	Potential decreased effect of oral anticoagulantse f g
Anticonvulsants (phenytoin)	Prochlorperazine may lower seizure thresholde f g Prochlorperazine may interfere with phenytoin metabolism and precipitate phenytoin toxicitye f g	Dosage adjustments of anticonvulsants may be necessarye f g
CNS depressants (e.g., alcohol, anesthetics, opiates)	May potentiate CNS depressione f g	Use with caution to avoid excessive sedation or CNS depressionb
Epinephrine or dopamine	Phenothiazines decrease these drugs’ vasopressor effectse f g	Do not use epinephrine or dopamine to treat phenothiazine-induced hypotension; concomitant use may cause further lowering of BPb e f g (see Hypotension under Cautions)
Guanethidine and related compounds	Potential for decreased effectiveness of guanethidine and related compoundse f g
Lithium	Possible acute encephalopathic syndrome, especially with high serum lithium concentrationsb c	Observe patients receiving combined therapy for evidence of adverse neurologic effects; discontinue treatment promptly if such signs or symptoms appearb c
Propranolol	Increased plasma concentrations of prochlorperazine and propranolole f g
Test for phenylketonuria (PKU)	Potential false positive test resultse f g
Thiazide diuretics	Potential for increased orthostatic hypotensione f g

Prochlorperazine Edisylate Pharmacokinetics

Absorption

Bioavailability

Phenothiazines are generally well absorbed from the GI tract and from parenteral sites.^b

Onset

Psychotic disorders: Symptomatic relief may be seen during the first 2 days of oral therapy; however, optimum antipsychotic effect usually requires prolonged administration.^d

Antiemetic effects: onset in 30–40 minutes (conventional tablet or extended-release capsule), 60 minutes (rectal suppository), or 10–20 minutes (IM administration).^a

Duration

Antiemetic effects: duration of 3–4 hours (conventional tablet, rectal suppository, or IM administration) or 10–12 hours (extended-release capsule).^a

Food

Extended-release capsule (Compazine Spansule): Food decreases rate of absorption and decreases peak plasma concentration by 23% and AUC by 13%.^c

Distribution

Extent

Phenothiazines are distributed into most body tissues and fluids, with high concentrations being distributed into the brain, lungs, liver, kidneys, and spleen.^b

Phenothiazines cross the placenta.^b Prochlorperazine is distributed into milk.^{e f g}

Plasma Protein Binding

Phenothiazines are highly bound to plasma proteins.^b

Elimination

Metabolism

Extensively metabolized, principally in the liver.^b

Elimination Route

Phenothiazines and their metabolites are excreted in urine and feces.^b

Stability

Storage

Rectal

Suppositories

15–30°C.^g Do not remove from wrapper until ready to use.^g

Oral

Tablets, Extended-release Capsules, and Oral Solution

15–30°C.^{c e} Protect from light.^{c e}

Parenteral

Injection

20–25°C; do not freeze.^f Protect from light.^f

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose–Ringer’s injection combinations
Dextrose–Ringer’s injection, lactated, combinations
Dextrose–saline combinations
Dextrose 2½, 5, or 10% in water
Fructose 10% in sodium chloride 0.9%
Fructose 10% in water
Invert sugar 5 and 10% in sodium chloride 0.9%
Invert sugar 5 and 10% in water
Ionosol products
Ringer’s injection
Ringer’s injection, lactated
Sodium chloride 0.45 or 0.9%
Sodium lactate (1/6) M

Drug Compatibility

Admixture CompatibilityHID

Compatible
Amikacin sulfate
Ascorbic acid injection
Dexamethasone sodium phosphate
Dimenhydrinate
Erythromycin lactobionate
Ethacrynate sodium
Lidocaine HCl
Nafcillin sodium
Penicillin G posassium
Sodium bicarbonate
Vitamin B complex with C
Incompatible
Aminophylline
Chloramphenicol sodium succinate
Chlorothiazide sodium
Furosemide
Hydrocortisone sodium succinate
Thiopental sodium
Variable
Calcium gluconate

Y-Site CompatibilityHID

Compatible
Amsacrine
Calcium gluconate
Cisplatin
Cladribine
Cyclophosphamide
Cytarabine
Dexmedetomidine HCl
Docetaxel
Doxorubicin HCl
Doxorubicin HCl liposome injection
Fluconazole
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium succinate
Linezolid
Melphalan HCl
Methotrexate sodium
Ondansetron HCl
Oxaliplatin
Paclitaxel
Potassium chloride
Propofol
Remifentanil HCl
Sargramostim
Sufentanil citrate
Teniposide
Thiotepa
Topotecan HCl
Vinorelbine tartrate
Vitamin B complex with C
Incompatible
Aldesleukin
Allopurinol sodium
Amifostine
Amphotericin B cholesteryl sulfate complex
Aztreonam
Bivalirudin
Cefepime HCl
Etoposide phosphate
Fenoldopam mesylate
Filgrastim
Fludarabine phosphate
Foscarnet sodium
Gallium nitrate
Gemcitabine HCl
Lansoprazole
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium

ActionsActions

• 
  

  Exhibits weak anticholinergic effects, moderate sedative effects, strong extrapyramidal effects, and strong antiemetic effects.^a

  
  


• 
  

  May antagonize dopamine-mediated neurotransmission at the synapses and may block postsynaptic dopamine receptor sites; however, precise mechanism(s) of action have not been determined.^b

  
  


• 
  

  Exerts an antiemetic effect by directly affecting the medullary chemoreceptor trigger zone (CTZ), apparently by blocking dopamine receptors in the CTZ.^{a e g} Inhibits apomorphine-induced vomiting.^a

  
  


• 
  

  Also has peripheral and/or central antagonistic activity against α-adrenergic, serotonergic, histaminic H₁, and muscarinic receptors.^b

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.^{e f g}

  
  


• 
  

  Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.^b

  
  


• 
  

  Importance of reporting signs or symptoms of hypersensitivity reactions (e.g., sore throat, other signs of infection).^{b c}

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).^{e f g}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{e f g}

  
  


• 
  

  Importance of advising patients of other important precautionary information.^{e f g} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Prochlorperazine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Rectal	Suppositories	2.5 mg	Compazine	GlaxoSmithKline
		5 mg	Compazine	GlaxoSmithKline
		25 mg*	Compazine

Tussamag

Tussamag may be available in the countries listed below.

Ingredient matches for Tussamag

Ibuprofen

Ibuprofen is reported as an ingredient of Tussamag in the following countries:

• Germany

International Drug Name Search

Aventyl Hydrochloride

Aventyl Hydrochloride is a brand name of nortriptyline, approved by the FDA in the following formulation(s):

AVENTYL HYDROCHLORIDE (nortriptyline hydrochloride - solution; oral)

• 
  Manufacturer: RANBAXY
  
  Approved Prior to Jan 1, 1982
  
  Strength(s): EQ 10MG BASE/5ML ^[RLD][AA]

Has a generic version of Aventyl Hydrochloride been approved?

Yes. The following products are equivalent to Aventyl Hydrochloride:

nortriptyline hydrochloride solution; oral

• 
  Manufacturer: PHARM ASSOC
  
  Approval date: August 28, 2000
  
  Strength(s): EQ 10MG BASE/5ML ^[AA]


• 
  Manufacturer: TARO
  
  Approval date: June 20, 2006
  
  Strength(s): EQ 10MG BASE/5ML ^[AA]

Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Aventyl Hydrochloride. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.

See also: About generic drugs.

Related Patents

There are no current U.S. patents associated with Aventyl Hydrochloride.

See also...

• Aventyl Consumer Information (Wolters Kluwer)
• Aventyl Advanced Consumer Information (Micromedex)
• Nortriptyline Consumer Information (Drugs.com)
• Nortriptyline Consumer Information (Wolters Kluwer)
• Nortriptyline Solution Consumer Information (Wolters Kluwer)
• Nortriptyline Consumer Information (Cerner Multum)
• Nortriptyline Advanced Consumer Information (Micromedex)
• Nortriptyline Hydrochloride AHFS DI Monographs (ASHP)

Thelin (Sitaxentan) 100mg film-coated tablets

1. Name Of The Medicinal Product

Thelin

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 100 mg sitaxentan sodium.

Excipients:

Also contains 166.3mg of lactose monohydrate.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet

Capsule shaped yellow-to-orange film-coated tablets, debossed with T

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of patients with pulmonary arterial hypertension (PAH) classified as WHO functional class III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and in pulmonary hypertension associated with connective tissue disease.

4.2 Posology And Method Of Administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Thelin is to be taken orally as a dose of 100 mg once daily. It may be taken with or without food and without regard to the time of day.

In the case of clinical deterioration despite Thelin treatment for at least 12 weeks, alternative therapies should be considered. However, a number of patients who showed no response by week 12 of treatment with Thelin responded favourably by week 24, so an additional 12 weeks of treatment may be considered.

Higher doses did not confer additional benefit sufficient to offset the increased risk of adverse reactions, particularly liver injury (see section 4.4).

Discontinuation of treatment

There is limited experience with abrupt discontinuation of sitaxentan sodium. No evidence for acute rebound has been observed.

Dosage in hepatic impairment:

Studies in patients with pre-existing liver impairment have not been conducted. Thelin is contraindicated in patients with elevated liver aminotransferases prior to initiation of treatment (> 3 x Upper Limit of Normal (ULN)) or with elevated direct bilirubin > 2 x ULN prior to initiation of treatment (see section 4.3).

Dosage in renal impairment:

No dose adjustment is required in patients with renal impairment.

Use in children and adolescents (< 18 years).

Thelin is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

Elderly patients:

No dosage adjustment is needed in patients over the age of 65 years.

Use in patients using other medicines:

The efficacy and safety of Thelin co-administration with other treatments for PAH (eg, epoprostenol, sildenafil, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

4.3 Contraindications

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

Mild to severe hepatic impairment (Child-Pugh Class A-C).

Elevated aminotransferases prior to initiation of treatment (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 x ULN).

Elevated direct bilirubin > 2 x ULN prior to initiation of treatment.

Concomitant administration with ciclosporin A (see section 4.5).

Lactation (see section 4.6).

4.4 Special Warnings And Precautions For Use

The efficacy of Thelin as monotherapy has not been established in patients with NYHA/WHO functional class IV PAH. Transfer to a therapy that is recommended at the severe stage of the disease (eg, epoprostenol) should be considered if the clinical condition deteriorates (see section 4.2).

Liver function:

Liver function abnormalities have been associated with PAH. Endothelin receptor antagonists, as a class, have been associated with liver function abnormalities.

Elevations of AST and/or ALT associated with Thelin occur both early and late in treatment, usually progress slowly, and are typically asymptomatic. During clinical trials, these changes were usually reversible when monitoring and discontinuation guidelines were followed. Liver aminotransferase elevations may reverse spontaneously while continuing treatment with sitaxentan sodium.

The mechanism of liver toxicity is not fully documented and it might vary between endothelin receptor antagonists. Appropriate care should be exercised when initiating sitaxentan in patients who discontinued other endothelin receptor antagonists due to liver enzyme abnormalities (see section 4.8).

Because treatment-associated elevations of AST and/or ALT are a marker for potential serious liver injury, liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals. If AST and/or ALT are > 3 x ULN prior to initiation of therapy, or direct bilirubin is> 2 x ULN, use of sitaxentan is contraindicated (see section 4.3). Recommendations in case of treatment-emergent ALT/AST elevations: If ALT/AST measurements rise to the following levels then changes to the monitoring or treatment are given: >3 and > 5 and >8 x ULN: treatment must be stopped and reintroduction of Thelin is not to be considered. If liver transferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, anorexia, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in total bilirubin > 2x ULN, treatment should be stopped and re-introduction of Thelin is not to be considered. Re-introduction of treatment: Re-introduction of treatment with Thelin should only be considered if the potential benefits of treatment with Thelin outweigh the potential risks and when liver aminotransferase levels are within pre-treatment values. The advice of a hepatologist is recommended. Re-introduction must follow the guidelines detailed in section 4.2. Aminotransferase levels must then be checked within 3 days after re-introduction, then again after a further 2 weeks, and thereafter according to the recommendations above.

Pre-existing liver impairment

Studies in patients with pre-existing liver impairment have not been conducted. Thelin is contraindicated in patients with elevated liver aminotransferases prior to initiation of treatment (> 3 x ULN), or with elevated direct bilirubin> 2 x ULN prior to initiation of treatment, see section 4.3.

Bleeding

There is an increased risk of bleeding with Thelin, mainly in the form of epistaxis and gingival bleeding.

Vitamin K antagonists

Thelin increases the plasma levels of Vitamin K antagonists such as warfarin, acenocoumarol and fenprocoumon (see section 4.5).

Drugs which inhibit Organic Anion Transporting Polypeptides (OATP)

The extent of interaction with potent OATP inhibitors (e.g. some statins, proteinase inhibitors, tuberculostatics) is unknown. As this could result in raised plasma levels of sitaxentan sodium, patients in need of the combination should be closely monitored for adverse events related to sitaxentan sodium (see section 4.5).

Oral contraceptive agents

Thelin increases oestrogen exposure when given concomitantly with oral contraceptive agents (see Section 4.5). Therefore, especially in women who smoke, there is an increased risk for thromboembolism. Given a theoretical higher risk for thromboembolism, traditional concomitant use of vitamin K antagonists should be considered.

Pregnancy

Due to possible teratogenicity, Thelin must not be initiated in women of child-bearing potential unless they practise reliable contraception. If necessary, pregnancy testing should be undertaken (see Section 4.6).

Pulmonary veno-occlusive disease (PVOD)

No data are available with Thelin in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should signs of pulmonary oedema occur when Thelin is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.

Haemoglobin concentration

Treatment with Thelin was associated with a dose-related decrease in haemoglobin (see section 4.8). Most of this decrease of haemoglobin concentration was detected during the first few weeks of treatment and haemoglobin levels stabilized by 4 weeks of Thelin treatment. It is recommended that haemoglobin concentrations be checked prior to treatment, after 1 and 3 months, and every 3 months thereafter. If a marked decrease in haemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.

Excipients

Thelin tablets contain lactose monohydrate. 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

Sitaxentan sodium is metabolised in the liver by cytochrome P450 CYP2C9 and CYP3A4/5 isoenzymes. Sitaxentan sodium is an inhibitor of CYP2C9 and, to a lesser extent, CYP2C19, CYP3A4/5 and CYP2C8. Plasma concentrations of drugs principally metabolized by CYP2C9 may be increased during sitaxentan sodium co-administration. Co-administration with drugs metabolized by CYP2C19 or CYP3A4/5 is not expected to result in clinically significant drug interactions. Sitaxentan sodium does not affect the p-glycoprotein transporter, but it is postulated to be a substrate of OATP transporter proteins.

Effects of other medicinal products on Thelin

Organic Anion Transporting Polypeptides (OATP) Inhibitors: Co-administration with ciclosporin A, a potent OATP inhibitor, resulted in a 6-fold increase in C_min and a 67% increase in AUC of sitaxentan therefore the use of Thelin in patients receiving systemic ciclosporin A is contraindicated (see section 4.3). Clearance of ciclosporin A was unchanged.

The extent of interaction with other OATP inhibitors (some HMG CoA reductase inhibitors eg, atorvastatin, protease inhibitors eg, ritonavir, tuberculostatics eg, rifamycin) is unknown but could result in raised plasma levels of sitaxentan. The clinical significance of this is unknown. Patients in need of the combination should be closely monitored. Moreover, Clinical interaction studies with nelfinavir, a moderately potent OATP inhibitor, and pravastatin, a low affinity OATP inhibitor, did not result in clinically significant changes in sitaxentan plasma levels.

Fluconazole (inhibitor of CYP2C19, CYP2C9 and CYP3A4/5): Co-administration of Thelin and fluconazole had no effect on the clearance of sitaxentan sodium.

Ketoconazole (substrate and inhibitor of CYP3A4/5): Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or ketoconazole.

Nelfinavir (substrate of CYP3A4/5, CYP2C19): Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or nelfinavir. The clearance of nelfinavir was not clinically significantly changed in one subject that was classified as a CYP2C19 poor metaboliser.

Effects of Thelin on other medicinal products

Warfarin (vitamin K antagonist, substrate of CYP2C9): Concomitant treatment with sitaxentan sodium resulted in a 2.4 fold increase in S-warfarin exposure. Subjects receiving warfarin achieve therapeutic anticoagulation (International Normalised Ratio [INR] target) with lower doses of the anticoagulant in the presence of sitaxentan sodium. It is expected that a similar increase in anticoagulant effect will be seen with warfarin analogues, including acenocoumarol, fenprocoumon and fluindione. When initiating vitamin K antagonist therapy in a patient taking sitaxentan sodium, it is recommended to start at the lowest available dose. In patients already taking a vitamin K antagonist, it is recommended that the dose of the vitamin K antagonist be reduced when starting sitaxentan sodium. In all cases, INR should be monitored on a regular schedule. Increases in the vitamin K antagonist dose should be done in small increments to reach an appropriate target INR. If INR is not properly monitored and increased exposure to vitamin K antagonists remains undetected, severe or life-threatening bleeding episodes may occur.

Oral contraceptives (substrate of CYP3A4/5): Concomitant administration of Thelin and Ortho-Novum 1/35 (1 mg norethindrone/ 0.035 mg ethinyl estradiol) resulted in increases in exposure to ethinyl estradiol (substrate of CYP3A4/5) and norethindrone (CYP3A4/5) of 59 % and 47%, respectively. However, sitaxentan sodium did not affect the anti-ovulatory activity of the oral contraceptive as assessed by the plasma concentrations of follicle stimulating hormone (FSH), luteinising hormone (LH), and progesterone (see section 4.4).

Sildenafil (substrate of CYP3A4): A single dose of sildenafil 100 mg coadministered with Thelin increased C_max and AUC of sildenafil by 18% and 28%, respectively. There was no change in C_max or AUC for the active metabolite, n-desmethylsildenafil. These changes in sildenafil plasma concentrations were not considered clinically significant. Interaction with sildenafil may be serious if hypotension occurs beyond a safe level. Study results suggest that the dose of sildenafil does not need to be adjusted during concomitant administration with sitaxentan sodium.

Nifedipine (substrate of CYP3A4/5): The clearance of nifedipine was not clinically significantly changed when given concomitantly with Thelin. This was tested for low-dose nifedipine only. Therefore, at higher doses of nifedipine, an increase in exposure cannot be excluded.

Omeprazole (substrate of CYP2C19): Concomitant administration of Thelin with omeprazole increased the omeprazole AUC0-24 by 30%; C_max was unchanged. The change in AUC was not considered clinically significant.

Digoxin (substrate of p-Glycoprotein): Concomitant administration of Thelin did not alter the pharmacokinetics of digoxin indicating no effect on the p-glycoprotein transporter

No clinical interaction study was performed with a substrate of CYP 2C8. Therefore an interaction with such a drug cannot be excluded.

4.6 Pregnancy And Lactation

Pregnancy

There are no human data regarding the use of sitaxentan sodium during pregnancy. Sitaxentan sodium caused teratogenicity in rats (see section 5.3). Potential effects in humans are unknown. Thelin should not be used during pregnancy unless clearly necessary ie, in case no alternative treatment options are available.

Lactation

Sitaxentan sodium was detected in the plasma of breast fed pups from female rats treated with sitaxentan sodium, indicating that sitaxentan sodium was present in the breast milk. It is unknown whether or not sitaxentan sodium is excreted into human milk. Women should not breastfeed while using Thelin.

Women of child-bearing potential

Treatment must not be initiated in women of child-bearing potential unless they practice reliable contraception, due to possible teratogenicity. If necessary, pregnancy testing should be undertaken.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. A known undesirable effect is dizziness, which could influence the ability to drive or use machines.

4.8 Undesirable Effects

General description

Safety of Thelin has been evaluated in clinical trials of more than 1200 patients with PAH, as well as post-marketing safety data. At the recommended dose during placebo-controlled trials in pulmonary arterial hypertension PAH, the most common adverse drug reactions considered to be at least possibly related to Thelin treatment were headache in 15% of patients, and peripheral oedema and nasal congestion, each in 9% of patients.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are reported as very common (common (> 1/100, < 1/10), uncommon (> 1/1,000, rare (> 1/10,000, very rare (

Adverse reactions

System Organ Class / Adverse reaction	Frequency
Blood and lymphatic system disorders
Haemoglobin decrease (rarely resulting in anaemia), haematocrit decrease	Uncommon
Nervous system disorders
Headache	Very common
Insomnia, dizziness	Common
Vascular disorders
Gingival bleeding, flushing	Common
Respiratory, thoracic, and mediastinal disorders
Nasal congestion, epistaxis	Common
Gastrointestinal disorders
Nausea, constipation, upper abdominal pain, vomiting, dyspepsia and diarrhoea	Common
Hepatobiliary disorders
Liver aminotransferases increase, bilirubin increase (associated with liver aminotransferase increase)	Common
Symptomatic hepatitis	Rare
Skin and subcutaneous tissue
Rash (various types and presentations)	Rare
Musculoskeletal and connective tissue disorders
Muscle cramp	Common
General disorders and administration site conditions
Fatigue, oedema (most commonly peripheral)	Common
Investigations
INR increase (with concomitant vitamin K antagonist therapy). Prothrombin time (PT) increase (with concomitant vitamin K antagonist therapy).	Common

Increased Liver Aminotransferases (see section 4.4)

Elevations of AST and/or ALT are associated with sitaxentan sodium. In phase 2 and 3 oral studies in patients with PAH, elevations in ALT and/or AST> 3 ULN were observed in 5% of placebo-treated patients (N = 155) and 7% of Thelin 100 mg-treated patients (N = 887). Elevations in ALT values> 5 ULN were 4% (36/887) for sitaxentan 100 mg QD and 0.6% in the placebo group (1/155).

The Sitaxentan population also included patients (N = 53) who had discontinued another endothelin receptor antagonist due to liver function abnormalities. This specific group had a higher risk (19%; N = 10/53) of developing elevations in ALT and/or AST> 3 x ULN indicating that appropriate care should be exercised when initiating sitaxentan in this patient population.

Decreased Haemoglobin (see section 4.4)

The overall mean decrease in haemoglobin concentration for Thelin -treated patients was 0.5 g/dl (change to end of treatment). In placebo-controlled studies, marked decreases in haemoglobin > 15% decrease from baseline with value < lower limit of normal) were observed in 7% of patients treated with Thelin (N = 149) and 3% of placebo-treated patients (N = 155). A decrease in haemoglobin concentration by at least 1 g/dl was observed in 60% of patients treated with Thelin as compared to 32% of placebo-treated patients.

Post marketing experience

Adverse events reported during the post-marketing period to date have been similar to those reported in clinical trials. Cases of concurrent elevations of transaminases (ALT and/or AST) > 8 x ULN and total bilirubin > 2 x ULN have been reported following administration of sitaxentan sodium. This may lead to hepatic failure, which can be fatal, and highlights the need for regular monitoring of transaminases and bilirubin.

4.9 Overdose

There is no specific experience with the management of Thelin overdose. In the event of overdose, symptomatic and supportive measures should be employed.

During clinical trials, Thelin was given as a daily oral dose of 1000 mg/day for 7 days to healthy volunteers. The most common adverse effects at this dose were headache, nausea, and vomiting.

In an open-label hypertension study, 10 patients received 480 mg twice daily (approximately a 10

In an open-label PAH study, one fatal case of hepatic failure has been reported after chronic dosing of sitaxentan at 600 mg/day administered as 300 mg bid.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antihypertensives, ATC code: C02KX03

Mechanism of action

Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide in the lung, and can also promote fibrosis, cell proliferation, cardiac hypertrophy, and remodelling and is pro-inflammatory. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), as well as other cardiovascular disorders and connective tissue diseases, including scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension, and atherosclerosis, suggesting a pathogenic role of ET

ET-1 actions are mediated through endothelin A receptors (ETA), present on smooth muscle cells, and endothelin B receptors (ETB), present on endothelial cells. Predominant actions of ET

Thelin is a potent (Ki 0.43 nM) and highly selective ETA antagonist (approximately 6,500-fold more selective for ETA as compared to ETB).

Efficacy

Two randomized, double-blind, multi-centre, placebo-controlled trials were conducted to demonstrate efficacy. STRIDE-1, which included 178 patients, compared 2 oral doses of Thelin (100 mg once daily and 300 mg once daily) with placebo during 12 weeks of treatment. The 18 week STRIDE-2 trial, conducted in 246 patients, included 4 treatment arms: placebo once daily, Thelin 50 mg once daily, Thelin 100 mg once daily, and open-label bosentan twice daily (efficacy-rater blinded, administered according to the approved package insert).

STRIDE-4 included 98 patients randomised to sitaxentan sodium 50 mg, 100 mg, and placebo once daily for 18 weeks. Efficacy endpoints included sub maximal exercise capacity, WHO functional class and Time to Clinical Worsening for all studies, and haemodynamics for STRIDE-1.

Patients had moderate to severe (NYHA/WHO functional class II-IV) PAH resulting from idiopathic pulmonary arterial hypertension (IPAH, also known as primary pulmonary hypertension), connective tissue disease (CTD), or congenital heart disease (CHD).

In these studies, the study medicine was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen, and vasodilators (eg, calcium channel blockers, ACE inhibitors). Patients with pre-existent hepatic disease and patients using non-conventional PAH treatments (eg, iloprost) were excluded.

Sub-maximal exercise capacity: This was assessed by measuring distance walked in 6 minutes (6

Haemodynamic parameters: These were assessed in STRIDE-1 for both functional class II and III patients. Compared with placebo treatment, Thelin resulted in statistically significant improvement in pulmonary vascular resistance (PVR) and cardiac index (CI) after 12 weeks of treatment (see below).

Treatment Comparison of Change from Baseline in PVR, and CI at Week 12 by Functional Class – STRIDE 1: Sitaxentan 100 mg Versus Placebo
Functional Class	Median Difference from Placebo (95% CI)	P-Value
PVR (dyne*sec/cm5 )
II		0.032
III		< 0.001
CI (L/min/m2 )
II	0.5 (0.2, 0.8)	0.003
III	0.3 (0.1, 0.5)	0.015

Systemic vascular resistance (-276 dynes*sec/cm⁵ (16%)) was improved after 12 weeks of treatment. The reduction in mean pulmonary artery pressure of 3 mmHg (6%) was not statistically significant.

The effect of Thelin on the outcome of the disease is unknown.

Functional Class: A reduction in symptoms of PAH were observed with sitaxentan sodium 100 mg treatment. Improvements in functional class were observed across all studies (STRIDE-1, STRIDE-2 & STRIDE-4).

Long-term survival:There are no randomised studies to demonstrate beneficial effects on survival of treatment with sitaxentan sodium. However, patients completing STRIDE-2 were eligible to enrol in open-label studies (STRIDE-2X and STRIDE-3). A total of 145 patients were treated with sitaxentan sodium 100 mg and their long term survival status was assessed for a minimum of 3 years. In this total population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 96%, 85% and 78% respectively. These survival estimates were similar in the subgroup of patients with PAH associated with CTD for the Thelin treated group (98%, 78% and 67% respectively). The estimates may have been influenced by the initiation of new or additional PAH therapies, which occurred in 24% of patients at one year.

5.2 Pharmacokinetic Properties

Absorption

Sitaxentan sodium is rapidly absorbed following oral administration. In PAH patients, peak plasma concentrations are generally achieved within 1-4 hours. The absolute bioavailability of Thelin is between 70 and 100%. When administered with a high fat meal, the rate of absorption (C_max) of Thelin was decreased by 43% and the T_max delayed (2-fold increase) compared to fasted conditions, but the extent of absorption was the same.

Distribution

Sitaxentan sodium is more than 99% protein bound to plasma proteins, predominantly albumin. The degree of binding is independent of concentration in the clinically relevant range. Sitaxentan sodium does not penetrate into erythrocytes and does not appear to cross the blood-brain barrier.

Metabolism and Elimination

Following oral administration to healthy volunteers, sitaxentan sodium is highly metabolised. The most common metabolic products are at least 10 times less potent as ET_A antagonists than sitaxentan sodium in a standard in vitro test of activity. In vitro, sitaxentan sodium is metabolized by CYP2C9 and CYP3A4/5.

In vitro studies using human liver microsomes or primary hepatocytes show that sitaxentan sodium inhibits CYP2C9, and, to a lesser extent, CYP 2C8, CYP2C19 and CYP3A4/5.

Approximately 50-60% of an oral dose is excreted in the urine with the remainder eliminated in the faeces. Less than 1% of the dose is excreted as unchanged active ingredient. The terminal elimination half-life (t_½) is 10 hours. Steady state in volunteers is reached within about 6 days.

No unexpected accumulation in the plasma was observed after multiple dosing at the recommended dose of 100 mg once daily. However, at doses of 300 mg or higher, non-linear pharmacokinetics result in disproportionately higher plasma concentrations of sitaxentan sodium.

Special Populations

Based on results of the population pharmacokinetic analysis and pooled pharmacokinetic data over several studies, it was found that gender, race, and age do not clinically significantly affect the pharmacokinetics of sitaxentan sodium.

Liver Function Impairment

The influence of liver impairment on the pharmacokinetics of sitaxentan sodium has not been evaluated. Refer to section 4.3.

5.3 Preclinical Safety Data

In repeated-dose toxicity studies, dose-related liver changes (weight, centrilobular hypertrophy, occasionally necrosis), induction of hepatic drug metabolising enzymes and slightly decreased erythron parameters were seen in mice, rats and dogs. At high doses, dose-related increases in prothrombin time (PT) and activated partial thromboplastin time (APTT) were also seen, most prominently in rats, and coagulopathy (bleedings) in rats and dogs, but not mice. The significance of these findings for humans is unknown.

Testicular tubular atrophy was observed in rats, but not in mice or dogs. In the 26-week study, moderate to marked diffuse seminiferous tubular atrophy was present at a very low incidence, whereas in the 99-week study there was a dose-related, slightly increased incidence of minimal to mild focal atrophy at doses providing 29 to 94 times the human exposure.

Reproduction toxicity has been evaluated in rats only. Thelin did not affect fertility in males and females. Thelin was teratogenic at the lowest tested dose in rats, corresponding to exposures more than 30 times the human exposure. Dose-dependent malformations of the head, mouth, face and large blood vessels occurred. A NOAEL has not been established.

Administration of Thelin to female rats from late-pregnancy through lactation reduced pup survival, and caused testis tubular aplasia and delayed vaginal opening at the lowest exposure tested (17

In vitro and in vivo tests on genetic toxicology did not provide any evidence for a clinically relevant genotoxic potential.

Thelin was not carcinogenic when administered to rats for 97-99 weeks or when administered to p53(+/-) transgenic mice for 6 months.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Cellulose, microcrystalline (E460)

Lactose monohydrate

Hypromellose (E464)

Sodium starch glycolate

Magnesium stearate (E470b)

Disodium phosphate, anhydrous (E339)

Ascorbyl palmitate (E304)

Disodium edetate

Monobasic sodium phosphate (E339)

Film coat:

Stearic acid (E570b)

Hypromellose (E464)

Cellulose, microcrystalline (E460)

Titanium dioxide (E171)

Yellow iron oxide dehydrate (E172)

Red iron oxide dehydrate (E172)

Talc (E553b)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

PVC/ACLAR/paper-backed aluminium blisters containing 14 tablets.

Cartons contain 14, 28, 56, or 84 tablets.

High-density polyethylene (HDPE) bottles containing 28 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Sandwich,

Kent, CT13 9NJ

United Kingdom

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/06/353/001

EU/1/06/353/002

EU/1/06/353/003

EU/1/06/353/004

EU/1/06/353/005

9. Date Of First Authorisation/Renewal Of The Authorisation

10 August 2006

10. Date Of Revision Of The Text

July 2010

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments.

Ref: 4_0