Xiapex 0.9 mg powder and solvent for solution for injection

1. Name Of The Medicinal Product

Xiapex 0.9 mg powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

Each vial of powder contains 0.9 mg of collagenase clostridium histolyticum*.

*A formulation of two collagenase enzymes co-expressed and harvested from anaerobic fermentation of a phenotypically selected strain of Clostridium histolyticum bacterium.

Excipients:

Sodium injected per joint:

Metacarpophalangeal (MP) joints: 0.9 mg.

Proximal interphalangeal (PIP) joints: 0.7 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

(Powder for injection).

The powder is a white lyophilised powder.

The solvent is a clear colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Xiapex is indicated for the treatment of Dupuytren's contracture in adult patients with a palpable cord.

4.2 Posology And Method Of Administration

Xiapex must be administered by a physician appropriately trained in the correct administration of the product and experienced in the diagnosis and management of Dupuytren's disease.

Posology

The recommended dose of Xiapex is 0.58 mg per injection into a palpable Dupuytren's cord. The volume of reconstituted Xiapex to be administered into the Dupuytren's cord differs depending on the type of joint being treated (see Table 1).

Approximately 24 hours after injection, a finger extension procedure may be performed, as necessary, to facilitate cord disruption. If a satisfactory response has not been achieved, the injection and finger extension procedures may be repeated after approximately 4 weeks. Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. Only one cord must be treated at a time. If the disease has resulted in multiple contractures, treatment of each cord must be undertaken in a sequential order, as determined by the physician. Clinical study experience with Xiapex is currently limited to up to 3 injections per cord and up to 8 injections in total.

Patients should be instructed to return to see their physician the next day for an examination of the injected hand and a finger extension procedure to disrupt the cord.

Special population

Elderly

Due to the lack of quantifiable systemic exposure of Xiapex no dose adjustment is necessary. No overall differences in safety or effectiveness were observed between elderly and younger patients.

Hepatic Impairment

Due to the lack of quantifiable systemic exposure, no dose adjustment is necessary.

Renal Impairment

Due to the lack of quantifiable systemic exposure, no dose adjustment is necessary.

Paediatric population

There is no relevant use of Xiapex in the paediatric population aged 0-18 years for the treatment of Dupuytren's contracture.

Method of administration

Intralesional use.

For single use only

Volume for reconstitution

Xiapex must only be reconstituted with the solvent provided and to the appropriate volume prior to use:

- For metacarpophalangeal (MP) joints use 0.39 ml of solvent.

- For proximal interphalangeal (PIP) joints use 0.31 ml of solvent (see Table 1).

Volume for injection

- For cords affecting MP joints each dose is administered in an injection volume of 0.25 ml.

- For cords affecting PIP joints, each dose is administered in an injection volume of 0.20 ml.

Table 1. Volumes needed for reconstitution and administration
Joint to be treated	Solvent required for reconstitution	Injection volume to deliver Xiapex 0.58 mg dose†
MP joints	0.39 ml	0.25 ml
PIP joints	0.31 ml	0.20 ml
†Note that injection volume for delivery of a 0.58 mg dose is less than the total volume of solvent used for reconstitution.

Patients should be instructed:

• Not to flex or extend the fingers of the injected hand to reduce extravasation of Xiapex out of the cord until the finger extension procedure is completed.

• Not to attempt to disrupt the injected cord by self manipulation at any time.

• To elevate the injected hand as much as possible until the day after the finger extension procedure.

Detailed instructions for the physician in the preparation of the medicinal product for injection (reconstitution procedure) are provided in section 6.6.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Allergic reactions

In the double blind portion of the three phase 3 placebo-controlled clinical studies, 17% of Xiapex-treated patients had mild allergic reactions (i.e. pruritus). Although there were no severe allergic reactions observed in the Xiapex studies (e.g., those associated with respiratory impairment, hypotension, or end-organ dysfunction) physicians must be prepared to address any severe local or systemic allergic reactions including the potential for anaphylaxis that may occur following injection. Whilst there is no evidence from the clinical data of an increased risk of serious allergic reactions upon repeated injections, the potential for such reactions following repeated use cannot be excluded.

Tendon rupture or other serious injury to the injected extremity

Xiapex must only be injected into the Dupuytren's cord. Because Xiapex lyses collagen, care must be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection of Xiapex into collagen containing structures may result in damage to those structures, and possible permanent injury such as tendon rupture or ligament damage. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion must not be more than 2 to 3 mm in depth and not more than 4 mm distal to the palmar digital crease. Patients should be instructed to promptly contact the physician if there is trouble bending the finger after the swelling goes down (symptoms of tendon rupture).

Patients with Dupuytren's contractures that adhere to the skin may be at higher risk of skin lesions as a result of the pharmacological effect of Xiapex and the finger extension procedure on the skin overlying the targeted cord.

Use in patients with coagulation disorders

Xiapex must be used with caution in patients with coagulation disorders or those taking anticoagulants. In the three double-blind, placebo-controlled phase 3 studies, 73% of Xiapex-treated patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site. The efficacy and safety of Xiapex in patients receiving anticoagulant medicinal products other than up to 150 mg acetylsalicylic acid per day prior to Xiapex administration is not known. Use of Xiapex in patients who have received anticoagulants (with the exception of up to 150 mg acetylsalicylic acid daily) within 7 days prior to receiving an injection of Xiapex is not recommended.

Immunogenicity

As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. During clinical studies, blood samples from patients with Dupuytren's contracture were tested at multiple time points for antibodies to the protein components of the medicinal product (AUX-I and AUX-II). At 30 days post the first injection, 92% of patients had circulating antibodies detected against AUX-I and 86% of patients against AUX-II. After a third or fourth injection, all subjects developed positive antibodies to both AUX-I and AUX-II. No apparent correlation of antibody development to clinical response or adverse reactions was observed. Since the enzymes in XIAPEX have some sequence homology with human matrix metalloproteinases (MMPs), anti-drug antibodies (ADA) could theoretically interfere with human MMPs. No safety concerns related to the inhibition of endogenous MMPs have been observed, in particular no adverse events indicating the development or exacerbation of autoimmune diseases or the development of a musculoskeletal syndrome (MSS). Whilst there is no clinical evidence from the current safety data of a musculoskeletal syndrome developing following the administration of XIAPEX, the potential for it to occur cannot be excluded. If this syndrome were to develop, it would occur progressively and is characterized by one or more of the following signs and symptoms: arthralgia, myalgia, joint stiffness, stiffness of the shoulders, hand oedema, palmar fibrosis and thickening or nodules forming in the tendons.

Long-term safety

Long-term safety of Xiapex is not fully characterised. The impact of treatment with Xiapex on subsequent surgery, if needed, is not known.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the lack of quantifiable systemic exposure, no formal medicinal product interaction studies with Xiapex have been performed.

Whilst there is no clinical evidence of an interaction between tetracycline and anthracycline/anthraquinolone antibiotics and anthraquinone derivatives and Xiapex, such derivatives have been shown to inhibit matrix metalloproteinase-mediated collagen degradation at pharmacologically relevant concentrations in vitro. Therefore, use of Xiapex in patients who have received tetracycline antibiotics (e.g. doxycycline) within 14 days prior to receiving an injection of Xiapex is not recommended.

4.6 Pregnancy And Lactation

Pregnancy and fertility

For Xiapex no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, or embryonal/ foetal development, (see section 5.3). Parturition or postnatal development studies in animals were not conducted since human pharmacokinetic studies show that Xiapex levels are not quantifiable in the systemic circulation following injection into a Dupuytren's cord (see section 5.1). Patients develop ADAs after repeated administration, the cross-reactivity of which versus endogenous MMPs involved in pregnancy and labour cannot be excluded. The potential risk for humans on parturition and postnatal development is unknown. Therefore the use of Xiapex is not recommended in pregnancy and treatment should be postponed until after pregnancy.

Breast-feeding

No effect on the breastfed newborn/infant is anticipated since the systemic exposure of the breast-feeding woman to Xiapex is negligible. Xiapex can be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Xiapex may have a major influence on the ability to drive and use machines due to the swelling and pain which may impair the use of the treated hand. Other minor influences on the ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache that have also been reported following injection of Xiapex. Patients must be instructed to avoid potentially hazardous tasks such as driving or using machines until it is safe to do so or as advised by the physician.

4.8 Undesirable Effects

Xiapex 0.58 mg was studied in patients with Dupuytren's contracture in three randomised, double-blind, placebo-controlled studies. The double-blind study population comprised 409 patients of whom 272 received Xiapex 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to 89 years) and 80% of patients were male.

The most frequently reported adverse reactions during the Xiapex clinical studies were local injection site reactions such as oedema peripheral (local to the injection site), contusion (including ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very common, occurring in the vast majority of patients, were mostly mild to moderate in severity and generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture (3 cases), tendonitis (1 case), other ligament injury (1 case) and complex regional pain syndrome (1 case) related to the medicinal product were reported.

Table 2 presents adverse reactions listed by system organ class and frequency categories, using the following convention: very common (

Table 2: Tabulated list of adverse reactions.

System organ class	Very common	Common	Uncommon
Infections and infestations			injection site cellulitis
Blood and lymphatic system disorders	lymphadenopathy	lymph node pain	thrombocytopenia
Immune system disorders			hypersensitivity
Psychiatric disorders			disorientation agitation insomnia irritability restlessness
Nervous system disorders		paresthesia hypoesthesia burning sensation dizziness headache	complex regional pain syndrome monoplegia syncope vasovagal tremor
Eye disorders			eyelid oedema
Vascular disorders			haematoma hypotension
Respiratory, thoracic and mediastinal disorders			dyspnoea hyperventilation
Gastrointestinal disorders		nausea	diarrhoea vomiting abdominal pain upper
Skin and subcutaneous tissue disorders	pruritus ecchymosis	blood blister blister rash erythema hyperhidrosis	rash erythematous rash macular eczema swelling face pain of skin skin exfoliation skin lesion skin disorder scab skin discoloration skin tightness
Musculoskeletal and connective tissue disorders	pain in extremity	arthralgia joint swelling myalgia	axillary mass chest wall pain groin pain joint crepitation joint stiffness limb discomfort muscle spasms muscular weakness musculoskeletal discomfort musculoskeletal stiffness neck pain shoulder pain
Reproductive system and breast disorders			breast tenderness hypertrophy breast
General disorders and administration site conditions	oedema peripheral* injection site haemorrhage injection site pain injection site swelling tenderness	axillary pain inflammation injection site inflammation swelling injection site erythema injection site pruritus injection site warmth injection site vesicles	local swelling pyrexia pain discomfort fatigue feeling hot influenza like illness injection site anaesthesia injection site desquamation injection site discoloration injection site irritation injection site nodule injection site reaction malaise
Investigations			lymph node palpable alanine aminotransferase increased aspartate aminotransferase increased body temperature increased
Injury, poisoning and procedural complications	contusion	skin laceration	tendon rupture ligament injury limb injury open wound wound dehiscence

* “oedema peripheral” includes “injection site oedema” and “oedema”

4.9 Overdose

Administration of Xiapex at greater than recommended doses is expected to be associated with increased local reactions at the site of injection. Routine supportive care and symptomatic treatment must be provided in the case of overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other Drugs For Disorders of the Musculo-Skeletal System – Enzymes, ATC code: M09AB02

Xiapex is a lyophilized product for parenteral administration containing collagenase clostridium histolyticum which is comprised of two collagenases in a defined mass ratio. These collagenases, referred to as AUX-I and AUX-II, are representative of the two major collagenase classes (Class I and Class II) produced by Clostridium histolyticum. AUX-I and AUX-II are single polypeptide chains consisting of approximately 1000 amino acids of known sequence with a molecular weight of 114 kDa and 113 kDa respectively as determined by mass spectrometry. The two polypeptides are purified by chromatographic steps customary for the separation and isolation of biotherapeutic proteins to yield a consistent, well characterized and controlled mixture of two collagenase enzymes.

Because the collagen lysis process following Xiapex administration is localized and does not require or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity of Xiapex cannot be evaluated in subjects and therefore, such studies have not been undertaken.

Mechanism of action

Collagenases are proteinases that hydrolyze collagen under physiological conditions. Injection of Xiapex into a Dupuytren's cord, which is comprised mostly of interstitial collagen types I and III, results in enzymatic disruption of the cord. Xiapex is comprised of a mixture of Class I (AUX-I) and Class II (AUX-II) clostridial collagenases in a defined mass ratio. The two classes of collagenases have similar but complementary substrate specificity. Both collagenases effectively cleave interstitial collagen but at different sites on the molecule; additionally, they prefer different conformations (triple helical versus denatured or cleaved). These differences account for the ability of the two classes of enzymes to digest collagen in a complementary manner. Class I collagenases (α, β, γ, and η) are the products of the colG gene, they initiate collagen hydrolysis near the amino and carboxy termini of triple helical domains, and generate large proteolytic fragments. In contrast, the Class II collagenases (δ, ε, and ζ,) are products of colH gene, their initial cleavage sites are located within the interior of the collagen molecule, and generate smaller collagen fragments. Both classes of collagenases readily hydrolyze gelatin (denatured collagen) and small collagen peptides, whereas Class II has higher affinity for small collagen fragments. Class I cleaves insoluble triple helical collagen with higher affinity than Class II collagenase. Together, these collagenases work to provide broad hydrolytic activity towards collagen.

Clinical results

The efficacy of Xiapex 0.58 mg was evaluated in two pivotal randomized, double-blind, placebo-controlled studies, CORD I (AUX-CC-857) and CORD II (AUX-CC-859), in adult patients with Dupuytren's contracture. At study entry, patients in the clinical studies had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20^° to 100^° in a MP joint or 20^° to 80^° in PIP joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. The cord affecting a selected primary joint received up to 3 injections of 0.58 mg of Xiapex or placebo. A finger extension procedure was performed if needed, approximately 24 hours after injection to facilitate disruption of the cord. Each injection was separated by approximately 4 weeks.

The primary endpoint of each study was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to 5° or less of normal, approximately 4 weeks after the last injection of that joint. Other endpoints included

Xiapex demonstrated a clinically significant benefit compared to placebo in the proportion of patients achieving the primary endpoint of a reduction in the contracture of all joints treated to 5° or less, approximately 4 weeks after the last injection (MP plus PIP, MP only, PIP only). For patients who achieved a contracture of the selected joint to 5° or less, the mean number of injections required to achieve this was 1.5 in the 2 studies. Xiapex also demonstrated a clinically significant benefit compared to placebo in decreasing the degree of contracture and increasing both the range of motion from baseline for all joints treated (MP plus PIP, MP only, PIP only) and the subject global assessment of treatment satisfaction.

Table 3 provides demographic and baseline characteristics for the study population and Tables 4-5 provide the results of the major efficacy endpoints measured in the 2 double-blind placebo controlled studies CORD I (AUX-CC-857) and CORD II (AUX-CC-859).

Table 3.

Demographic and baseline characteristics

Phase 3 Double-Blind, Placebo controlled studies (CORD I, CORD II)

VARIABLE	Xiapex (N=249)	Placebo (N=125)
Age (years)
Mean	62.7	64.2
Age category (years), n (%)
< 45	9 (3.6)	5 (4.0)
45 – 54	33 (13.2)	17 (13.6)
55 – 64	103 (41.4)	44 (35.2)
65 – 74	82 (33.0)	40 (32.0)
	22 (8.8)	19 (15.2)
Gender, n (%)
Male	210 (84.3)	91 (72.8)
Female	39 (15.7)	34 (27.2)
Family history of Dupuytren's disease, n (%)
Yes	107 (43.0)	62 (49.6)
No	142 (57.0)	63 (50.4)
Physician Rating of Severity at Baseline
Mild	38 (15.4 %)	21 (16.8 %)
Moderate	148 (59.9 %)	71 (56.8 %)
Severe	61 (24.7 %)	33 (26.4 %)
Missing1	2 (0.8 %)	-
Note: Includes all patients who received at least 1 injection of double-blind study medicinal product (Xiapex 0.58 mg or placebo). 1 Not used to calculate physician rating of severity at baseline percentage – actual denominator of N=247 used.

Table 4.

Percentage of patients who achieved reduction in contracture to 5° or less

(Last injection)

TREATED PRIMARY JOINTS	CORD I	CORD II
Xiapex	Placebo	Xiapex	Placebo
All Joints p-value	N=203c	N=103c	N=45	N=21
64.0 % <0.001	6.8 % -	44.4 % <0.001	4.8 % -
MP Jointsa p-value	N=133	N=69	N=20	N=11
76.7 % <0.001	7.2 % -	65.0 % 0.003	9.1 % -
PIP Jointsb p-value	N=70	N=34	N=25	N=10
40.0 % <0.001	5.9 % -	28.0 % 0.069	0.0 % -
a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).

Table 5.

Mean increase in range of motion from baseline

(Last injection)

TREATED PRIMARY JOINTS	CORD I	CORD II
Xiapex	Placebo	Xiapex	Placebo
All Joints	N=203 c	N=103 c	N=45	N=21
Mean Baseline (SD) Mean Final (SD) Mean increase (SD)	43.9 (20.1) 80.7 (19.0) 36.7 (21.0)	45.3 (18.7) 49.5 (22.1) 4.0 (14.8)	40.3 (15.2) 75.8 (17.7) 35.4 (17.8)	44.0 (16.5) 51.7 (19.6) 7.6 (14.9)
MP Jointsa	N=133	N=69	N=20	N=11
Mean Baseline (SD) Mean Final (SD) Mean increase (SD)	42.6 (20.0) 83.7 (15.7) 40.6 (20.0)	45.7 (19.2) 49.7 (21.1) 3.7 (12.6)	39.5 (11.8) 79.5 (11.1) 40.0 (13.5)	41.4 (20.8) 50.0 (21.5) 8.6 (14.7)
PIP Jointsb	N=70	N=34	N=25	N=10
Mean Baseline (SD) Mean Final (SD) Mean increase (SD)	46.4 (20.4) 74.9 (23.1) 29.0 (20.9)	44.4 (17.9) 49.1 (24.4) 4.7 (18.5)	41.0 (17.7) 72.8 (21.3) 31.8 (20.1)	47.0 (10.3) 53.5 (18.3) 6.5 (15.8)
a Metacarpophalangeal joint; b Proximal interphalangeal joint; c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment). All p-values < 0.001 for all comparisons between Xiapex and placebo, except for PIP joints in Study CORD II which was not eligible for statistical testing due to a hierarchical testing procedure.

Physician-rated change in contracture severity was reported as very much improved or much improved in 86% and 80% of the subjects in the Xiapex group compared to 3% and 5% of subjects in the placebo group for the CORD I and CORD II studies, respectively (p<0.001). Based on the Patient Global Assessment of Treatment Satisfaction, more than 85% of subjects in the CORD I and CORD II studies reported either being quite satisfied or very satisfied with their treatment with Xiapex versus

Promethazine

Generic Name: Promethazine hydrochloride

Dosage Form: oral solution
Promethazine Hydrochloride Oral Solution

Promethazine Description

Each teaspoonful (5 mL) of Promethazine HCl Oral Solution contains 6.25 mg Promethazine HCl in a flavored syrup base with a pH between 4.7 and 5.2. Alcohol 7%. The inactive ingredients present are ascorbic acid, citric acid, D&C Yellow No. 10, edetate disodium, ethyl alcohol, FD&C Blue No. 1, FD&C Red No. 40, glycerin, methylparaben, pineapple flavor, purified water, sodium benzoate, sodium citrate, sucralose, and sucrose.

Promethazine HCl is a racemic compound; the molecular formula is C17H20N2S•HCl and its molecular weight is 320.89.

Promethazine HCl, a phenothiazine derivative, is chemically designated as 10-[2- (Dimethylamino)propyl] phenothiazine monohydrochloride. Its structural formula is:

Promethazine HCl occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is freely soluble in water and soluble in alcohol.

Promethazine - Clinical Pharmacology

Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties.

Promethazine is an H1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects.

Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of Promethazine and N-desmethylPromethazine are the predominant metabolites appearing in the urine.

Indications and Usage for Promethazine

Promethazine HCl Oral Solution is useful for:

Perennial and seasonal allergic rhinitis.

Vasomotor rhinitis.

Allergic conjunctivitis due to inhalant allergens and foods.

Mild, uncomplicated allergic skin manifestations of urticaria and angioedema.

Amelioration of allergic reactions to blood or plasma.

Dermographism.

Anaphylactic reactions, as adjunctive therapy to epinephrine and other standard measures, after the acute manifestations have been controlled.

Preoperative, postoperative, or obstetric sedation.

Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery.

Therapy adjunctive to meperidine or other analgesics for control of postoperative pain.

Sedation in both children and adults, as well as relief of apprehension and production of light sleep from which the patient can be easily aroused.

Active and prophylactic treatment of motion sickness.

Antiemetic therapy in postoperative patients.

Contraindications

Promethazine HCl Oral Solution is contraindicated for use in pediatric patients less than two years of age.

Promethazine HCl Oral Solution is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to Promethazine or to other phenothiazines.

Antihistamines are contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.

Warnings

Promethazine HCl Oral Solution should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression.


Postmarketing cases of respiratory depression, including fatalities, have been reported with use of Promethazine in pediatric patients less than 2 years of age. A wide range of weight-based doses of Promethazine have resulted in respiratory depression in these patients.


Caution should be exercised when administering Promethazine to pediatric patients 2 years of age and older. It is recommended that the lowest effective dose of Promethazine be used in pediatric patients 2 years of age and older and concomitant administration of other drugs with respiratory depressant effects be avoided.

CNS Depression

Promethazine HCl Oral Solution may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of Promethazine HCl (see PRECAUTIONS – Information for Patients and Drug Interactions).

Respiratory Depression

Promethazine HCl Oral Solution may lead to potentially fatal respiratory depression.

Use of Promethazine HCl Oral Solution in patients with compromised respiratory function (e.g. COPD, sleep apnea) should be avoided.

Lower Seizure Threshold

Promethazine HCl Oral Solution may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression

Promethazine HCl Oral Solution should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when Promethazine HCl Oral Solution has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with Promethazine HCl alone or in combination 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 Promethazine HCl, antipsychotic drugs, if any, 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.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of Promethazine HCl should be carefully considered.

Use in Pediatric Patients

Promethazine HCl Oral Solution is contraindicated for use in pediatric patients less than two years of age.

Caution should be exercised when administering Promethazine HCl Oral Solution to pediatric patients 2 years of age and older because of the potential for fatal respiratory depression. Respiratory depression and apnea, sometimes associated with death, are strongly associated with Promethazine products and are not directly related to individualized weight-based dosing, which might otherwise permit safe administration. Concomitant administration of Promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients.

Antiemetics are not recommended for treatment of uncomplicated vomiting in pediatric patients, and their use should be limited to prolonged vomiting of known etiology. The extrapyramidal symptoms which can occur secondary to Promethazine HCl Oral Solution administration may be confused with the CNS signs of undiagnosed primary disease, e.g., encephalopathy or Reye’s syndrome. The use of Promethazine HCl Oral Solution should be avoided in pediatric patients whose signs and symptoms may suggest Reye’s syndrome or other hepatic diseases.

Excessively large dosages of antihistamines, including Promethazine HCl Oral Solution, in pediatric patients may cause sudden death (see OVERDOSAGE). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Promethazine HCl Oral Solution in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of Promethazine HCl.

Other Considerations

Administration of Promethazine HCl has been associated with reported cholestatic jaundice.

Precautions

General

Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction.

Promethazine HCl Oral Solution should be used cautiously in persons with cardiovascular disease or with impairment of liver function.

Information for Patients

Patients should be advised to measure Promethazine HCl Oral Solution with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

Promethazine HCl Oral Solution may cause marked drowsiness or impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from Promethazine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.

The concomitant use of alcohol or other central-nervous-system depressants, such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers may enhance impairment (see WARNINGS-CNS Depression and PRECAUTIONS–Drug Interactions).

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

A patient information leaflet is included and summarizes important information about Promethazine.

Drug Interactions

CNS Depressants – Promethazine HCl Oral Solution may increase, prolong, or intensify the sedative action of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving Promethazine HCl. When given concomitantly with Promethazine HCl Oral Solution, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of Promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.

Epinephrine – Because of the potential for Promethazine HCl Oral Solution to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Promethazine HCl Oral Solution overdose.

Anticholinergics– Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

Monoamine Oxidase Inhibitors (MAOI) – Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. This possibility should be considered with Promethazine HCl Oral Solution.

Drug/Laboratory Test Interactions

The following laboratory tests may be affected in patients who are receiving therapy with Promethazine HCl:

Pregnancy Tests

Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.

Glucose Tolerance Test

An increase in blood glucose has been reported in patients receiving Promethazine HCl.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to assess the carcinogenic potential of Promethazine, nor are there other animal or human data concerning carginogenicity, mutagenicity, or impairment of fertility with this drug. Promethazine was nonmutagenic in the Salmonella test system of Ames.

Pregnancy

Teratogenic Effects-Pregnancy Category C

Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of Promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of Promethazine for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.

Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of Promethazine HCl Oral Solution in pregnant women.

Promethazine HCl Oral Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Promethazine HCl Oral Solution administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

Labor And Delivery

Promethazine HCl Oral Solution may be used alone or as an adjunct to narcotic analgesics during labor (see DOSAGE AND ADMINISTRATION). Limited data suggest that use of Promethazine HCl Oral Solution during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect on later growth and development of the newborn is unknown. (See also Nonteratogenic Effects).

Nursing Mothers

It is not known whether Promethazine HCl is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Promethazine HCl Oral Solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Promethazine HCl Oral Solution is contraindicated for use in pediatric patients less than two years of age (see WARNINGS – Boxed Warning and Use in Pediatric Patients).

Promethazine HCl Oral Solution should be used with caution in pediatric patients 2 years of age and older (see WARNINGS-Use in Pediatric Patients).

Geriatric Use

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

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Promethazine HCl Oral Solution and observed closely.

Adverse Reactions

Central Nervous System – Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness, confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported.

Cardiovascular – Increased or decreased blood pressure, tachycardia, bradycardia, faintness.

Dermatologic– Dermatitis, photosensitivity, urticaria.

Hematologic – Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis.

Gastrointestinal– Dry mouth, nausea, vomiting, jaundice.

Respiratory– Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal). (See WARNINGS-Respiratory Depression.)

Other– Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported. (See WARNINGS-Neuroleptic Malignant Syndrome.)

Paradoxical Reactions

Hyperexcitability and abnormal movements have been reported in patients following a single administration of Promethazine HCl. Consideration should be given to the discontinuation of Promethazine HCl and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients.

Overdosage

Signs and symptoms of overdosage with Promethazine HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex).

Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares.

Atropine-like signs and symptoms – dry mouth, fixed, dilated pupils, flushing, as well as gastrointestinal symptoms - may occur.

Treatment

Treatment of overdosage is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs, including respiration, pulse, blood pressure, temperature, and EKG, need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Diazepam may be used to control convulsions. Acidosis and electrolyte losses should be corrected. Note that any depressant effects of Promethazine HCl are not reversed by naloxone. Avoid analeptics which may cause convulsions. The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning if indicated. In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered. EPINEPHRINE SHOULD NOT BE USED, since its use in patients with partial adrenergic blockade may further lower the blood pressure. Extrapyramidal reactions may be treated with anticholinergic antiparkinson agents, diphenhydramine, or barbiturates. Oxygen may also be administered.

Limited experience with dialysis indicates that it is not helpful.

Promethazine Dosage and Administration

It is important that Promethazine HCl Oral Solution is measured with an accurate measuring device (see PRECAUTIONS-Information for Patients). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

Promethazine HCl Oral Solution is contraindicated for children under 2 years of age (see WARNINGS – Boxed Warning and Use in Pediatric Patients).

Allergy

The average oral dose is 25 mg taken before retiring; however, 12.5 mg may be taken before meals and on retiring, if necessary. Single 25 mg doses at bedtime or 6.25 to 12.5 mg taken three times daily will usually suffice.

After initiation of treatment in children or adults, dosage should be adjusted to the smallest amount adequate to relieve symptoms.

The administration of Promethazine HCl in 25 mg doses will control minor transfusion reactions of an allergic nature.

Motion Sickness

The average adult dose is 25 mg taken twice daily. The initial dose should be taken one-half to one hour before anticipated travel and be repeated 8 to 12 hours later, if necessary. On succeeding days of travel, it is recommended that 25 mg be taken on arising and again before the evening meal. For children, 12.5 to 25 mg, twice daily, may be administered.

Nausea and Vomiting

Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see WARNINGS- Use in Pediatric Patients).

The average effective dose of Promethazine HCl Oral Solution for the active therapy of nausea and vomiting in children or adults is 25 mg. When oral medication cannot be tolerated, the dose should be given parenterally (cf. Promethazine Hydrochloride Injection) or by rectal suppository. 12.5 to 25 mg doses may be repeated, as necessary, at 4 to 6 hour intervals.

For nausea and vomiting in children, the usual dose is 0.5 mg per pound of body weight, and the dose should be adjusted to the age and weight of the patient and the severity of the condition being treated.

For prophylaxis of nausea and vomiting, as during surgery and the postoperative period, the average dose is 25 mg repeated at 4 to 6 hour intervals, as necessary.

Sedation

This product relieves apprehension and induces a quiet sleep from which the patient can be easily aroused. Administration of 12.5 to 25 mg Promethazine HCl Oral Solution by the oral route at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation.

Pre- and Postoperative Use

Promethazine HCl Oral Solution in 12.5 to 25 mg doses for children and 50 mg doses for adults the night before surgery relieves apprehension and produces a quiet sleep. For preoperative medication children require doses of 0.5 mg per pound of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug.

Usual adult dosage is 50 mg Promethazine HCl Oral Solution with an appropriately reduced dose of narcotic or barbiturate and the required amount of a belladonna alkaloid.

Postoperative sedation and adjunctive use with analgesics may be obtained by the administration of 12.5 to 25 mg in children and 25 to 50 mg doses in adults.

Promethazine HCl Oral Solution is contraindicated for children under 2 years of age.

How is Promethazine Supplied

Promethazine Hydrochloride Oral Solution, USP, 6.25 mg/5 mL, is a clear, green oral solution supplied as follows:

NDC 57664-146-31    Bottle of 4 fl. oz. (118 mL)

NDC 57664-146-34    Bottle of 16 fl. oz. (473 mL)

Keep bottles tightly closed.

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container (USP/NF) with a child-resistant closure.

Distributed by:

Caraco Pharmaceutical Laboratories, Ltd.

Detroit, Michigan 48202

Manufactured by:

SUN Pharmaceutical Industries, Inc.

Bryan, Ohio 43506

PATIENT INFORMATION LEAFLET


Promethazine HYDROCHLORIDE ORAL SOLUTION, USP 6.25 mg/5 mL

(Promethazine Hydrochloride Syrup, 6.25 mg per 5 mL)

Rx Only

What Is Promethazine HCl Oral Solution?

Promethazine is an antihistamine which can be taken by mouth as an Oral Solution or tablet, rectally as a suppository, or by injection. It can be used for:

• “hay fever,” or, a stuffy runny nose from allergy


• watery, itchy eyes due to inhaled allergies and foods


• mild allergic skin reactions with itching and swelling


• allergic reactions to blood or plasma


• dermographism, a form of hives known as “skin writing”


• serious allergic reactions along with epinephrine and other treatments


• sedation before or after surgery, or during childbirth


• prevention and control of nausea and vomiting after surgery


• along with meperidine (demerol) or other pain medicines


• sedation, relief of anxiety, and production of light sleep from which the patient can be easily aroused


• treatment and prevention of motion sickness

Who Should Not Use Promethazine HCl Oral Solution?

Promethazine should not be given to:

• children under two years of age


• patients who are unconscious


• patients who are allergic to Promethazine, any of the ingredients in Promethazine, or to other phenothiazines


• patients with lung symptoms including asthma


• children who are vomiting unless the vomiting is prolonged and there is a known cause 

What Are The Risks?

The following are the major potential risks and side effects of Promethazine HCl Oral Solution therapy. However, this list is not complete.

• Severe drowsiness and reduced mental alertness. Promethazine HCl Oral Solution may cause drowsiness which may impair your ability to ride a bike, drive a car, or operate machinery. This may be worsened if taken with alcohol or other drugs that also cause central nervous system (CNS) slowing such as sedatives, pain medicines, tranquilizers or certain drugs for depression.


• Serious breathing problems. Promethazine HCl Oral Solution should not be used in patients with poor lung function such as chronic obstructive lung disease or breathing problems while sleeping (sleep apnea).


• Increased risk of seizures. Promethazine HCl Oral Solution should be used with caution in patients with seizures or who are on other medicines which may also increase the risk of seizures.


• Bone-marrow problems and blood cell production. Promethazine HCl Oral Solution should not be used in patients with bone-marrow problems or used with other drugs that affect the bone marrow's production of blood cells.


• Neuroleptic malignant syndrome. This potentially deadly syndrome includes symptoms such as fever, muscle rigidity, mental changes, changes in pulse or blood pressure, fast heartbeat, increased sweating or irregular heart rhythm.


• The most common side effects are drowsiness, changes in blood pressure, skin reactions, blood cell changes and breathing problems. Increased excitability or abnormal movements may occur after one dose of Promethazine. If they do, consult your doctor about using another medicine. 

What Should I Tell My Healthcare Professional?

Before you start taking Promethazine HCl Oral Solution, tell your healthcare professional if you:

• have narrow-angle glaucoma


• have an enlarged prostate


• have a stomach ulcer


• have an intestinal blockage


• have a bladder blockage


• have heart problems


• have liver problems


• have breathing or lung problems


• have sleep apnea (breathing problems when sleeping)


• have seizures


• drink alcohol


• are trying to become pregnant, are already pregnant, or are breast-feeding 

Can Other Medicines Or Food Affect Promethazine?

Promethazine HCl Oral Solution and certain other medicines can interact with each other. Tell your healthcare professional about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how Promethazine works or Promethazine may affect how your other medicines work. Know the medicines you take. Keep a list of them with you to show your healthcare professional.

Especially tell your healthcare professional if you take:

• medicines that affect your brain such as anti-anxiety medicine, sleeping pills, pain medicines, sedatives, narcotics, antidepressants or tranquilizers


• epinephrine


• a monoamine oxidase inhibitor (MAOI) which is used to treat depression or other mental disorders


• medicines called anticholinergics

Storage

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container (USP/NF) with a child-resistant closure.

Distributed by:

Caraco Pharmaceutical Laboratories, Ltd.

Detroit, Michigan 48202

Manufactured by:

SUN Pharmaceutical Industries, Inc.

Bryan, Ohio 43506

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 57664 -146 -34

Promethazine Hydrochloride Oral Solution, USP

6.25 mg/5 mL

(Promethazine Hydrochloride Syrup, 6.25 mg per 5 mL)

Alcohol 7% v/v

16 fl oz (473 mL)

Rx Only

DO NOT USE IF INNER FOIL SEAL PRINTED “SEALED FOR YOUR

PROTECTION” IS BROKEN OR MISSING.

Each teaspoonful (5mL) contains 6.25 mg of Promethazine Hydrochloride, USP. Alcohol 7% v/v.

Usual Dosage: See accompanying package insert.

WARNINGS: KEEP THIS AND ALL DRUGS OUT OF THE REACH OF

CHILDREN.

In case of accidential overdose, seek professional assistance or contact a Poison Control Center

immediately.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.]

KEEP TIGHTLY CLOSED. PROTECT FROM LIGHT.

Dispense in a tight, light-resistant container (USP/NF) with a child-resistant closure.

Dist. By: Caraco Pharmaceutical Laboratories, Ltd., Detroit, Michigan 48202

Mfg. by: SUN Pharmaceutical Industries, Inc., Bryan, Ohio 43506

5975L01                                                                                                Iss. 05/09

Promethazine HYDROCHLORIDE  Promethazine hydrochloride  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 57664-146 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Promethazine HYDROCHLORIDE (Promethazine) Promethazine HYDROCHLORIDE 6.25 mg  in 5 mL

Inactive Ingredients Ingredient Name Strength ASCORBIC ACID   CITRIC ACID MONOHYDRATE   D&C YELLOW NO. 10   EDETATE DISODIUM   ALCOHOL   FD&C BLUE NO. 1   FD&C RED NO. 40   GLYCERIN   METHYLPARABEN   WATER   SODIUM BENZOATE   SODIUM CITRATE   SUCRALOSE   SUCROSE

Product Characteristics Color GREEN Score      Shape Size Flavor PINEAPPLE Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 57664-146-31 118 mL In 1 BOTTLE None 2 57664-146-34 473 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA040891	03/13/2009

Labeler - Caraco Pharmaceutical Laboratories, Ltd. (146974886)

Registrant - SUN Pharmaceutical Industries, Inc. (621283733)

Establishment
Name	Address	ID/FEI	Operations
SUN Pharmaceutical Industries, Inc.		621283733	Analysis, Manufacture

Revised: 05/2011Caraco Pharmaceutical Laboratories, Ltd.

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