Caelyx 2 mg / ml concentrate for solution for infusion

1. Name Of The Medicinal Product

Caelyx 2 mg/ml concentrate for solution for infusion

2. Qualitative And Quantitative Composition

One ml of Caelyx contains 2 mg doxorubicin hydrochloride in a pegylated liposomal formulation.

Caelyx, a liposome formulation, is doxorubicin hydrochloride encapsulated in liposomes with surface-bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protects liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood circulation time.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion

The suspension is sterile, translucent and red.

4. Clinical Particulars

4.1 Therapeutic Indications

Caelyx is indicated:

- As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk.

- For treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen.

- In combination with bortezomib for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant.

- For treatment of AIDS-related Kaposi's sarcoma (KS) in patients with low CD₄ counts (< 200 CD₄ lymphocytes/mm³) and extensive mucocutaneous or visceral disease.

Caelyx may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline).

4.2 Posology And Method Of Administration

Caelyx should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.

Caelyx exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Breast cancer/Ovarian cancer:

Caelyx is administered intravenously at a dose of 50 mg/m² once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

Multiple Myeloma: Caelyx is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.

For doses < 90 mg: dilute Caelyx in 250 ml 5 % (50 mg/ml) glucose solution for infusion.

For doses

To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent Caelyx infusions may be administered over a 60-minute period.

In those patients who experience an infusion reaction, the method of infusion should be modified as follows:

5 % of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes.

AIDS-related KS:

Caelyx is administered intravenously at 20 mg/m² every two-to-three weeks. Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannot be ruled out. Treatment of patients for two-to-three months is recommended to achieve a therapeutic response. Continue treatment as needed to maintain a therapeutic response.

The dose of Caelyx is diluted in 250 ml 5 % (50 mg/ml) glucose solution for infusion and administered by intravenous infusion over 30 minutes.

For all patients:

If the patient experiences early symptoms or signs of infusion reaction (see sections 4.4 and 4.8), immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.

Do not administer Caelyx as a bolus injection or undiluted solution. It is recommended that the Caelyx infusion line be connected through the side port of an intravenous infusion of 5 % (50 mg/ml) glucose to achieve further dilution and minimise the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with in-line filters. Caelyx must not be given by the intramuscular or subcutaneous route (see section 6.6).

To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Caelyx dose modification secondary to these adverse effects are provided in the tables below. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).

The tables for PPE (Table 1) and stomatitis (Table 2) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner.

The table for haematological toxicity (Table 3) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is addressed in 4.8.

Guidelines For Caelyx Dose Modification

Table 1. PALMAR – PLANTAR ERYTHRODYSESTHESIA
	Week After Prior Caelyx Dose
Toxicity Grade At Current Assessment	Week 4	Week 5	Week 6
Grade 1 (mild erythema, swelling, or desquamation not interfering with daily activities)	Redose unless patient has experienced a previous Grade 3 or 4 skin toxicity, in which case wait an additional week	Redose unless patient has experienced a previous Grade 3 or 4 skin toxicity, in which case wait an additional week	Decrease dose by 25 %; return to 4 week interval
Grade 2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter)	Wait an additional week	Wait an additional week	Decrease dose by 25 %; return to 4 week interval
Grade 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing)	Wait an additional week	Wait an additional week	Withdraw patient
Grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalization)	Wait an additional week	Wait an additional week	Withdraw patient

Table 2. STOMATITIS
	Week after Prior Caelyx Dose
Toxicity Grade At Current Assessment	4	5	6
Grade 1 (painless ulcers, erythema, or mild soreness)	Redose unless patient has experienced a previous Grade 3 or 4 stomatitis in which case wait an additional week	Redose unless patient has experienced a previous Grade 3 or 4 stomatitis in which case wait an additional week	Decrease dose by 25 %; return to 4 week interval or withdraw patient per physician's assessment
Grade 2 (painful erythema, oedema, or ulcers, but can eat)	Wait an additional week	Wait an additional week	Decrease dose by 25 %; return to 4 week interval or withdraw patient per physician's assessment
Grade 3 (painful erythema, edema, or ulcers, but cannot eat)	Wait an additional week	Wait an additional week	Withdraw patient
Grade 4 (requires parenteral or enteral support)	Wait an additional week	Wait an additional week	Withdraw patient

Table 3. HAEMATOLOGICAL TOXICITY (ANC OR PLATELETS) – MANAGEMENT OF PATIENTS WITH BREAST OR OVARIAN CANCER
GRADE	ANC	PLATELETS	MODIFICATION
Grade 1	1,500 – 1,900	75,000 – 150,000	Resume treatment with no dose reduction.
Grade 2	1,000 – < 1,500	50,000 – < 75,000	Wait until ANC
Grade 3	500 – < 1,000	25,000 – < 50,000	Wait until ANC
Grade 4	< 500	< 25,000	Wait until ANC

For multiple myeloma patients treated with Caelyx in combination with bortezomib who experience PPE or stomatitis, the Caelyx dose should be modified as described in Table 1 and 2 above respectively. Table 4, below provides the schedule followed for other dose modifications in the clinical trial in the treatment of patients with multiple myeloma receiving Caelyx and bortezomib combination therapy. For more detailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib.

Table 4. DOSAGE ADJUSTMENTS FOR CAELYX + BORTEZOMIB COMBINATION THERAPY - PATIENTS WITH MULTIPLE MYELOMA
Patient Status	Caelyx	Bortezomib
Fever 3	Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25 %.	Reduce next dose by 25 %.
On any day of medicine administration after Day 1 of each cycle: Platelet count < 25,000/mm3 Hemoglobin < 8 g/dl ANC < 500/mm3	Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25 % in the following cycles if bortezomib is reduced for hematologic toxicity.*	Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25 % in following cycles.
Grade 3 or 4 non-hematologic medicine related toxicity	Do not dose until recovered to Grade < 2 and reduce dose by 25 % for all subsequent doses.	Do not dose until recovered to Grade < 2 and reduce dose by 25 % for all subsequent doses.
Neuropathic pain or peripheral neuropathy	No dosage adjustments.	See the SPC for bortezomib.

*for more information on bortezomib dosing and dosage adjustment, see the SPC for bortezomib

Patients with impaired hepatic function: Caelyx pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the Caelyx dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programs as follows: at initiation of therapy, if the bilirubin is between 1.2 - 3.0 mg/dl, the first dose is reduced by 25 %. If the bilirubin is> 3.0 mg/dl, the first dose is reduced by 50 %. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e., if reduced by 25 % for the first dose, increase to full dose for cycle 2; if reduced by 50 % for the first dose, increase to 75 % of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Caelyx can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range. Prior to Caelyx administration, evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.

Patients with impaired renal function: As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required. Population pharmacokinetic data (in the range of creatinine clearance tested of 30 - 156 ml/min) demonstrate that Caelyx clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 ml/min.

AIDS-KS patients with splenectomy: As there is no experience with Caelyx in patients who have had splenectomy, treatment with Caelyx is not recommended.

Paediatric patients: The experience in children is limited. Caelyx is not recommended in patients below 18 years of age.

Elderly patients: Population based analysis demonstrates that age across the range tested (21 – 75 years) does not significantly alter the pharmacokinetics of Caelyx.

4.3 Contraindications

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

Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

4.4 Special Warnings And Precautions For Use

Cardiac toxicity: It is recommended that all patients receiving Caelyx routinely undergo frequent ECG monitoring. Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for the suspension of Caelyx therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e., endomyocardial biopsy, must be considered.

More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated Angiography (MUGA). These methods must be applied routinely before the initiation of Caelyx therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Caelyx that exceeds a lifetime cumulative anthracycline dose of 450 mg/m².

The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during anthracycline therapy are to be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If a test result indicates possible cardiac injury associated with Caelyx therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

In patients with cardiac disease requiring treatment, administer Caelyx only when the benefit outweighs the risk to the patient.

Exercise caution in patients with impaired cardiac function who receive Caelyx.

Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction has substantially decreased relative to pre-treatment values and/or left ventricular ejection fraction is lower than a prognostically relevant value (e.g. < 45 %), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac damage.

Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy.

Caution must be observed in patients who have received other anthracyclines. The total dose of doxorubicin hydrochloride must also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g. 5-fluorouracil. Cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m² in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.

The cardiac safety profile for the dosing schedule recommended for both breast and ovarian cancer (50 mg/m²) is similar to the 20 mg/m² profile in patients with AIDS-KS (see section 4.8).

Myelosuppression: Many patients treated with Caelyx have baseline myelosuppression due to such factors as their pre-existing HIV disease or numerous concomitant or previous medications, or tumours involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of 50 mg/m², myelosuppression was generally mild to moderate, reversible, and was not associated with episodes of neutropaenic infection or sepsis. Moreover, in a controlled clinical trial of Caelyx vs. topotecan, the incidence of treatment related sepsis was substantially less in the Caelyx-treated ovarian cancer patients as compared to the topotecan treatment group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer receiving Caelyx in a first-line clinical trial. In contrast to the experience in patients with breast cancer or ovarian cancer, myelosuppression appears to be the dose-limiting adverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of Caelyx therapy, and at a minimum, prior to each dose of Caelyx.

Persistent severe myelosuppression, may result in superinfection or haemorrhage.

In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen, opportunistic infections were apparently more frequent during treatment with Caelyx. Patients and doctors must be aware of this higher incidence and take action as appropriate.

As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with doxorubicin. Therefore, any patient treated with doxorubicin should be kept under haematological supervision.

Given the difference in pharmacokinetic profiles and dosing schedules, Caelyx should not be used interchangeably with other formulations of doxorubicin hydrochloride.

Infusion-associated reactions: Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like or anaphylactoid-like reactions, with symptoms including asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the infusion of Caelyx. Very rarely, convulsions also have been observed in relation to infusion reactions (see section 4.8). Temporarily stopping the infusion usually resolves these symptoms without further therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids, adrenaline, and anticonvulsants), as well as emergency equipment should be available for immediate use. In most patients treatment can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely recur after the first treatment cycle. To minimise the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/minute (see section 4.2).

Diabetic patients: Please note that each vial of Caelyx contains sucrose and the dose is administered in 5 % (50 mg/ml) glucose solution for infusion.

For common adverse events which required dose modification or discontinuation see section 4.8.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal medicinal product interaction studies have been performed with Caelyx, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies. Exercise caution in the concomitant use of medicinal products known to interact with standard doxorubicin hydrochloride. Caelyx, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anti-cancer therapies. During clinical trials in patients with solid tumours (including breast and ovarian cancer) who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted. In patients with AIDS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with standard doxorubicin hydrochloride. Caution must be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time.

4.6 Pregnancy And Lactation

Pregnancy: Doxorubicin hydrochloride is suspected to cause serious birth defects when administered during pregnancy. Therefore, Caelyx should not be used during pregnancy unless clearly necessary.

Women of child-bearing potential must be advised to avoid pregnancy while they or their male partner are receiving Caelyx and in the six months following discontinuation of Caelyx therapy (see section 5.3).

Lactation: It is not known whether Caelyx is excreted in human milk. Because many medicinal products, including anthracyclines, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, therefore mothers must discontinue nursing prior to beginning Caelyx treatment. Health experts recommend that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects On Ability To Drive And Use Machines

Caelyx has no or negligible influence on the ability to drive and use machines. However, in clinical studies to date, dizziness and somnolence were associated infrequently (< 5 %) with the administration of Caelyx. Patients who suffer from these effects must avoid driving and operating machinery.

4.8 Undesirable Effects

The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m² every 4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 44.0 % - 46.1 %. These effects were mostly mild, with severe (Grade III) cases reported in 17 % - 19.5 %. The reported incidence of life-threatening (Grade IV) cases was < 1 %. PPE infrequently resulted in permanent treatment discontinuation (3.7 % - 7.0 %). PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. Improvement usually occurs in one - two weeks, and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of 50 - 150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE, however, these therapies have not been evaluated in phase III trials. Other strategies to prevent and treat PPE, which may be initiated for 4 to 7 days after treatment with Caelyx include keeping hands and feet cool, by exposing them to cool water (soaks, baths, or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or shoes that are tight fitting). PPE appears to be primarily related to the dose schedule and can be reduced by extending the dose interval 1 - 2 weeks (see section 4.2). However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer patient populations, whereas the AIDS-KS Program (20 mg/m² every 2 weeks), myelosuppression (mostly leukopaenia) was the most common side effect (see AIDS-KS). PPE was reported in 16 % of multiple myeloma patients treated with Caelyx plus bortezomib combination therapy. Grade 3 PPE was reported in 5 % of patients. No grade 4 PPE was reported. The most frequently reported (medicine-related treatment-emergent) adverse events in combination therapy (Caelyx + bortezomib) were nausea (40 %), diarrhoea (35 %), neutropaenia (33 %), thrombocytopaenia (29 %), vomiting (28 %), fatigue (27 %), and constipation (22 %).

Breast cancer program: 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx (n=254) at a dose of 50 mg/m² every 4 weeks, or doxorubicin (n=255) at a dose of 60 mg/m² every 3 weeks, in a phase III clinical trial (I97-328). The following common adverse events were reported more often with doxorubicin than with Caelyx: nausea (53 % vs. 37 %; Grade III/IV 5 % vs. 3 %), vomiting (31 % vs. 19 %; Grade III/IV 4 % vs. less than 1 %), any alopecia (66 % vs. 20 %), pronounced alopecia (54 % vs.7 %), and neutropaenia (10 % vs. 4 %; Grade III/IV 8 % vs. 2 %).

Mucositis (23 % vs. 13 %; Grade III/IV 4 % vs. 2 %), and stomatitis (22 % vs. 15 %; Grade III/IV 5 % vs. 2 %) were reported more commonly with Caelyx than with doxorubicin. The average duration of the most common severe (Grade III/IV) events for both groups was 30 days or less. See Table 5 for complete listing of undesirable effects reported in Caelyx-treated patients.

The incidence of life threatening (Grade IV) haematologic effects was < 1.0 % and sepsis was reported in 1 % of patients. Growth factor support or transfusion support was necessary in 5.1 % and 5.5 % of patients, respectively (see section 4.2).

Clinically significant laboratory abnormalities (Grades III and IV) in this group was low with elevated total bilirubin, AST and ALT reported in 2.4 %, 1.6 % and < 1 % of patients respectively. No clinically significant increases in serum creatinine were reported.

Table 5. Treatment Related Undesirable Effects Reported in Breast Cancer Clinical Trials (50 mg/m2 every 4 weeks) (Caelyx-treated patients) by Severity, MedDRA System Organ Class and Preferred Term Very Common ( CIOMS III
AE by body system	Breast Cancer All Severities n=254 (	Breast Cancer Grades III/IV n=254 (	Breast Cancer n=404 (1-5 %) not previously reported in clinical trials
Infections and infestations Common Uncommon	Pharyngitis	Pharyngitis	Folliculitis, fungal infection, cold sores (non-herpetic), upper respiratory tract infection
Blood and lymphatic system disorders Common Uncommon	Leukopaenia, anaemia, neutropaenia, thrombocytopaenia	Leukopaenia, anaemia Neutropaenia	Thrombocythemia
Metabolism and nutrition disorders Very Common Common	Anorexia	Anorexia
Nervous system disorders Common Uncommon	Paresthesia Somnolence	Paresthesia	Peripheral neuropathy
Eye Disorders Common			Lacrimation, blurred vision
Cardiac disorders Common			Ventricular arrhythmia
Respiratory, thoracic and mediastinal disorders Common			Epistaxis
Gastrointestinal disorders Very Common Common Uncommon	Nausea, stomatitis, vomiting Abdominal pain, constipation, diarrhoea, dyspepsia, mouth ulceration	Abdominal pain, diarrhoea, nausea, stomatitis Mouth ulceration, constipation, Vomiting	Oral pain
Skin and subcutaneous tissue disorders Very Common Common Uncommon	PPE*, alopecia, rash Dry skin, skin discolouration, pigmentation abnormal, erythema	PPE* Rash Pigmentation abnormal, erythema	Bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin
Musculoskeletal and connective tissue disorders Common			Leg cramps, bone pain, musculoskeletal pain
Reproductive system and breast disorders Common			Breast pain
General disorders and administration site conditions Very Common Common Uncommon	Asthenia, fatigue, mucositis NOS Weakness, fever, pain	Asthenia, mucositis NOS Fatigue, weakness, pain	Oedema, leg oedema.

* palmar-plantar erythrodysesthesia (Hand- foot syndrome).

Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m² in clinical trials. See Table 6 for undesirable effects reported in Caelyx-treated patients.

Table 6 Treatment Related Undesirable Effects Reported in Ovarian Cancer Clinical Trials (50 mg/m2 every 4 weeks) (Caelyx-treated patients) by Severity, MedDRA System Organ Class and Preferred Term Very Common ( CIOMS III
AE by body system	Ovarian Cancer All Severities n=512 (	Ovarian Cancer Grades III/IV n=512 (	Ovarian Cancer n=512 (1-5% )
Infections and infestations Common Uncommon	Pharyngitis	Pharyngitis	Infection, oral moniliasis, herpes zoster, urinary tract infection
Blood and lymphatic system disorders Very Common Common	Leukopaenia, anaemia, neutropaenia, thrombocytopaenia	Neutropaenia Leukopaenia, anaemia, thrombocytopaenia	Hypochromic anaemia
Immune system disorders Common			Allergic reaction
Metabolism and nutrition disorders Very Common Common Uncommon	Anorexia

Phenylhistine DH Expectorant

Generic Name: chlorpheniramine, codeine, and pseudoephedrine (klor fen EER a meen, KOE deen, SOO doe ee FED rin)

Brand Names: Phenylhistine DH Expectorant

What is Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine)?

Chlorpheniramine is an antihistamine that reduces the effects of natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Codeine is a narcotic cough suppressant that affects the signals in the brain that trigger cough reflex.

Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, codeine, and pseudoephedrine is used to treat cough, sneezing, itching, watery eyes, runny nose, stuffy nose, and sinus congestion caused by allergies, the common cold, or the flu.

Chlorpheniramine, codeine, and pseudoephedrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine)?

Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not take this medication with alcohol, other narcotic medications, sedatives, tranquilizers, muscle relaxers, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result. Codeine may be habit-forming and should be used only by the person it was prescribed for. Keep the medication in a secure place where others cannot get to it. Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Chlorpheniramine, pseudoephedrine, and cough suppressants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or cough suppressant. This medication may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

What should I discuss with my healthcare provider before taking Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine)?

Do not use this medication if you are allergic to codeine or other narcotic medicines such as fentanyl (Actiq, Duragesic), hydromorphone (Dilaudid, Palladone), methadone (Methadose, Dolophine), morphine (Kadian, MS Contin, Oramorph, and others), oxycodone (Oxycontin), and oxymorphone (Opana). Do not use a cough or cold medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

To make sure you can safely take chlorpheniramine, codeine, and pseudoephedrine, tell your doctor if you have any of these other conditions:

• 
  

  kidney or liver disease;

  
  


• 
  

  heart disease or high blood pressure;

  
  


• 
  

  enlarged prostate or urination problems;

  
  


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  asthma, COPD, sleep apnea, or other breathing disorders;

  
  


• 
  

  a history of head injury or brain tumor;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  low blood pressure;

  
  


• 
  

  gallbladder disease;

  
  


• 
  

  Addison's disease or other adrenal gland disorders;

  
  


• 
  

  mental illness; or

  
  


• 
  

  a history of drug or alcohol addiction.

  
  

It is not known whether this medication will harm an unborn baby. Codeine may cause addiction or withdrawal symptoms in a newborn if the mother takes the medication during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant while using chlorpheniramine, codeine, and pseudoephedrine. Codeine may be habit forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Codeine can pass into breast milk and may harm a nursing baby. The use of codeine by some nursing mothers may lead to life-threatening side effects in the baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Cough or cold medicine is usually taken for only a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one.

Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need surgery, tell the surgeon ahead of time if you have taken a cough or cold medicine within the past few days.

This medication can cause unusual results with allergy skin tests. Tell any doctor who treats you that you are taking an antihistamine.

Store at room temperature, away from heat, light, and moisture.

Keep track of the amount of medicine used from each new bottle. Codeine is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

What happens if I miss a dose?

Since cough or cold medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of codeine can be fatal. Overdose symptoms may include extreme dizziness or drowsiness, confusion, feeling restless or nervous, cold and clammy skin, warmth or tingly feeling, nausea, vomiting, weak or shallow breathing, slow heart rate, pinpoint pupils, fainting, or seizure (convulsions).

What should I avoid while taking Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine)?

This medication may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Do not take this medication with alcohol, other narcotic medications, sedatives, tranquilizers, muscle relaxers, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result. Drinking alcohol can increase drowsiness caused by chlorpheniramine or codeine.

Avoid becoming overheated or dehydrated during exercise and in hot weather.

Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Chlorpheniramine, pseudoephedrine, and cough suppressants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or cough suppressant.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using chlorpheniramine, codeine, and pseudoephedrine and call your doctor at once if you have a serious side effect such as:

• 
  

  fast, pounding, or uneven heartbeats;

  
  


• 
  

  shallow breathing, slow heartbeats;

  
  


• 
  

  severe dizziness, fainting, anxiety, restless feeling, nervousness, or tremor;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

  
  


• 
  

  urinating less than usual or not at all; or

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  dry mouth;

  
  


• 
  

  nausea, vomiting, stomach pain, constipation, loss of appetite;

  
  


• 
  

  mild dizziness, drowsiness, problems with memory or concentration;

  
  


• 
  

  warmth, tingling, or redness under your skin;

  
  


• 
  

  feeling restless or excited (especially in children);

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  skin rash or itching.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Phenylhistine DH Expectorant (chlorpheniramine, codeine, and pseudoephedrine)?

Tell your doctor about all other medicines you use, especially:

• 
  

  cimetidine (Tagamet);

  
  


• 
  

  rifampin (Rifadin, Rifater, Rifamate, Rimactane);

  
  


• 
  

  zidovudine (Retrovir, AZT);

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil, Vanatrip, Limbitrol), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others;

  
  


• 
  

  aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others);

  
  


• 
  

  a diuretic (water pill), or blood pressure medication;

  
  


• 
  

  a beta blocker such as atenolol (Tenormin, Tenoretic), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Dutoprol, Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others;

  
  


• 
  

  bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

  
  


• 
  

  medication to treat irritable bowel syndrome;

  
  


• 
  

  medicines to treat psychiatric disorders, such as chlorpromazine (Thorazine), haloperidol (Haldol), pimozide (Orap), or thioridazine (Mellaril); or

  
  


• 
  

  seizure medication such as phenytoin (Dilantin) or phenobarbital (Luminal, Solfoton).

  
  

This list is not complete and other drugs may interact with chlorpheniramine, codeine, and pseudoephedrine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Phenylhistine DH Expectorant resources

• Phenylhistine DH Expectorant Side Effects (in more detail)
• Phenylhistine DH Expectorant Use in Pregnancy & Breastfeeding
• Phenylhistine DH Expectorant Drug Interactions
• 0 Reviews for Phenylhistine DH Expectorant - Add your own review/rating

• Chlorpheniramine/Codeine/Pseudoephedrine Liquid MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Phenylhistine DH Expectorant with other medications

• Cold Symptoms

Where can I get more information?

• Your pharmacist can provide more information about chlorpheniramine, codeine, and pseudoephedrine.

See also: Phenylhistine DH Expectorant side effects (in more detail)

Pyrethrins/Piperonyl Gel

Pronunciation: pye-REE-thrins/pye-PEER-i-nil
Generic Name: Pyrethrins/Piperonyl
Brand Name: Examples include RID and Lice Treatment

Pyrethrins/Piperonyl Gel is used for:

Treating head, pubic (crab), or body lice.

Pyrethrins/Piperonyl Gel is a pediculicide combination. It works by interfering with the nerves of the lice, which causes death of the lice.

Do NOT use Pyrethrins/Piperonyl Gel if:

• you are allergic to any ingredient in Pyrethrins/Piperonyl Gel

Contact your doctor or health care provider right away if any of these apply to you.

Before using Pyrethrins/Piperonyl Gel:

Some medical conditions may interact with Pyrethrins/Piperonyl Gel. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances, including ragweed


• if you have skin irritation

Some MEDICINES MAY INTERACT with Pyrethrins/Piperonyl Gel. Because little, if any, of Pyrethrins/Piperonyl Gel is absorbed into the blood, the risk of it interacting with another medicine is low.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Pyrethrins/Piperonyl Gel may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Pyrethrins/Piperonyl Gel:

Use Pyrethrins/Piperonyl Gel as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Pyrethrins/Piperonyl Gel is for external use only. Pyrethrins/Piperonyl Gel is not to be used for lice in the eyebrows or eyelashes. Contact a doctor if lice are present in these areas.


• Use Pyrethrins/Piperonyl Gel on dry hair.


• Apply to the affected area until all hair is completely wet. Allow Pyrethrins/Piperonyl Gel to remain on the affected area for no more than 10 minutes. Add sufficient warm water to form a lather and shampoo as usual. Rinse completely. Close eyes tightly and protect them with a washcloth or towel when rinsing Pyrethrins/Piperonyl Gel out of the hair.


• Use a fine-toothed comb to remove dead lice or eggs (nits) from hair.


• Check daily for any lice or eggs that you missed.


• Repeat this treatment in 7 to 10 days to kill any newly hatched lice.


• If infestation continues, contact a doctor for other treatments.


• If you miss a dose of Pyrethrins/Piperonyl Gel, use it as soon as you remember. Continue to use it as directed by your doctor.

Ask your health care provider any questions you may have about how to use Pyrethrins/Piperonyl Gel.

Important safety information:

• Do not get Pyrethrins/Piperonyl Gel in your eyes, vagina, nose, or mouth. If you get Pyrethrins/Piperonyl Gel in your eyes, flush them with cool tap water.


• Do not inhale Pyrethrins/Piperonyl Gel. Use Pyrethrins/Piperonyl Gel in a well-ventilated area.


• All hats, scarves, coats, clothes, underwear, and bed linens should be dry cleaned or washed in hot water and dried on the hot cycle of the dryer for at least 20 minutes. Hair combs and brushes should also be cleaned in hot water.


• All members of the household should be examined for the presence of lice and treated if lice are found.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Pyrethrins/Piperonyl Gel during pregnancy. It is unknown if Pyrethrins/Piperonyl Gel is excreted in breast milk. If you are or will be breast-feeding while you are using Pyrethrins/Piperonyl Gel, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Pyrethrins/Piperonyl Gel:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with the proper use of Pyrethrins/Piperonyl Gel. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); eye irritation; infection; persistent skin or scalp irritation; skin tenderness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include coughing; diarrhea; difficulty breathing; headache; nausea; unusual dizziness or drowsiness; vomiting.

Proper storage of Pyrethrins/Piperonyl Gel:

Store Pyrethrins/Piperonyl Gel at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Pyrethrins/Piperonyl Gel out of the reach of children and away from pets.

General information:

• If you have any questions about Pyrethrins/Piperonyl Gel, please talk with your doctor, pharmacist, or other health care provider.


• Pyrethrins/Piperonyl Gel is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Pyrethrins/Piperonyl Gel. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Pyrethrins/Piperonyl resources

• Pyrethrins/Piperonyl Use in Pregnancy & Breastfeeding
• Pyrethrins/Piperonyl Support Group
• 0 Reviews for Pyrethrins/Piperonyl - Add your own review/rating

Compare Pyrethrins/Piperonyl with other medications

• Head Lice
• Lice

Noritate

metronidazole

Dosage Form: Cream

FOR TOPICAL USE ONLY

(NOT FOR OPHTHALMIC USE)

Noritate Description

Metronidazole Cream, 1%, contains metronidazole, USP. Chemically, metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. It has the following structural formula:

Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has a solubility in water of 10 mg/mL at 20°C. Metronidazole is a member of the imidazole class of anti-bacterial agents and is classified as an antiprotozoal and anti-bacterial agent.

Metronidazole Cream, 1%, is an emollient cream; each gram contains 10 mg micronized metronidazole USP, in a base of purified water USP, stearic acid NF, glyceryl monostearate NF, glycerin USP, methylparaben NF, trolamine NF and propylparaben NF.

Noritate - Clinical Pharmacology

Pharmacokinetics

When one gram dose of Metronidazole Cream, 1%, was applied in a single application to the face of 16 healthy volunteers, low concentrations of metronidazole were detected in the plasma of 7 of the volunteers. The mean ± SD Cmax of metronidazole was 27.6 ± 7.3 ng/mL, which is about 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) in the volunteers with detectable metronidazole was 8–12 hours after topical application.

Pharmacodynamics

The mechanisms by which metronidazole acts in reducing inflammatory lesions of rosacea are unknown.

Clinical Studies

Safety and efficacy of Metronidazole Cream, 1%, were evaluated in two randomized vehicle-controlled clinical studies for the treatment of rosacea, which excluded patients who had nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema or ocular involvement and those who had a history of not responding to metronidazole therapy for rosacea. Of the patients included in the efficacy database (n=416), there were 142 men and 274 women. Endpoint efficacy data comparisons for patients treated with daily Metronidazole Cream, 1%, or vehicle applications are listed below.

Inflammatory Lesion Counts and Erythema Severity Scores in Two Clinical Trials for Rosacea

	Metronidazole Cream, 1%				Vehicle
	Study 1		Study 2		Study 1		Study 2
	N	Result	N	Result	N	Result	N	Result
* Statistically significant differences between Metronidazole Cream, 1%, and vehicle groups with p≤0.05. Erythema scores: 0=none, 1=mild, 2=moderate and 3=severe.
Papules + Pustules Count
Baseline	89	15	92	19	50	18	49	17
Week-10	80	7*	82	8	45	15	41	12
Reduction		49%*		58%*		17%		30%
Papules Count
Baseline	89	13	92	17	50	15	49	15
Week-10	80	7*	82	7	45	12	41	11
Reduction		41%*		55%*		14%		28%
Erythema Score
Baseline	89	2.2	92	2.3	50	2.2	49	2.2
Week-10	80	1.3*	82	1.4*	45	1.7	40	1.8
Reduction		42%*		40%*		25%		19%

Safety Studies

Studies of contact sensitization (n=258), phototoxicity (n=21), and photocontact sensitization (n=29) of Metronidazole Cream, 1%, were conducted. No evidence of sensitization or phototoxicity was seen in these studies.

Indications and Usage for Noritate

Metronidazole Cream, 1%, is indicated for the topical treatment of inflammatory lesions and erythema of rosacea.

Contraindications

Metronidazole Cream, 1%, is contraindicated in those patients with a history of hypersensitivity to metronidazole or to any other ingredient in this formulation.

Precautions

General

If a reaction suggesting local skin irritation occurs, patients should be directed to discontinue use of the medication. Conjunctivitis associated with topical use of metronidazole on the face has been reported. Contact with the eyes should be avoided. Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia.

Information For Patients

Patients using Metronidazole Cream, 1%, should receive the following information and instructions:

1. This medication is to be used as directed.


2. It is for external use only.


3. Avoid contact with the eyes.


4. Cleanse affected area(s) before applying Metronidazole Cream, 1%.


5. This medication should not be used for any disorder other than that for which it is prescribed.


6. Patients should report any adverse reaction to their physician.

Drug Interactions

Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when Metronidazole is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. (See CLINICAL PHARMACOLOGY, Pharmacokinetics section)

Carcinogenesis, Mutagenesis and Impairment of Fertility

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats but not in studies involving hamsters.

In several long term studies in mice, oral doses of approximately 225 mg/m2/day or greater (approximately 37 times the human topical dose on a mg/m2 basis) were associated with an increase in pulmonary tumors and lymphomas. Several long term oral studies in the rat have shown statistically significant increases in mammary and hepatic tumors at doses >885 mg/m2/day (144 times the topical human dose).

Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-related increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in patients with Crohn's disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohn's disease treated with the drug for 8 months.

In one published study, using albino hairless mice, intraperitoneal administration of metronidazole at a dose of 45 mg/m2/day (approximately 7 times the human topical dose on a mg/m2 basis) was associated with an increase in ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity studies have been performed with Metronidazole or any marketed metronidazole formulations.

Pregnancy

Teratogenic Effects

Pregnancy Category B

There are no adequate and well controlled studies with the use of Metronidazole in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole to rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, Metronidazole should be used during pregnancy only if clearly needed.

Nursing Mothers

After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those achieved after oral metronidazole, 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 and the risk to the infant.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Adverse Reactions

Safety data from 302 patients who used Metronidazole (n=200) or vehicle control (n=102) once daily in clinical trials and experienced an adverse event considered to be treatment-related include: application site reaction (Metronidazole 1, vehicle 1), condition aggravated (Metronidazole 1, vehicle 0), paresthesia (Metronidazole 0, vehicle 1), acne (Metronidazole 1, vehicle 0), dry skin (Metronidazole 0, vehicle 2). The majority of adverse reactions were mild to moderate in severity.

Two patients treated with Metronidazole once daily discontinued treatment because of adverse events: one for a severe flare of comedonal acne and one for rosacea aggravated.

Additional clinical adverse effects reported spontaneously since the drug was marketed are uncommon and include tingling or numbness of extremities, allergic reactions, skin and eye irritation, rash, headache, nausea and dry mouth.

Noritate Dosage and Administration

Areas to be treated should be cleansed before application of Metronidazole Cream, 1%. Apply and rub in a thin film of Metronidazole Cream, 1%, once daily to entire affected area(s). Patients may use cosmetics after application of Metronidazole Cream, 1%.

How is Noritate Supplied

Cream - 60 gram aluminum tube NDC 66993-940-61.

Keep out of the reach of children.

Storage Conditions

Store at controlled room temperature: 20 to 25°C (68 to 77°F).

Manufactured by:

Dermik Laboratories

a business of sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

Manufactured for:

Prasco Laboratories

Cincinnati, OH 45249 USA

Revised April 2007

© 2007 sanofi-aventis U.S. LLC

METRONIDAZOLE  metronidazole  cream

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 66993-940 Route of Administration TOPICAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength metronidazole (metronidazole) Active 10 MILLIGRAM  In 1 GRAM water Inactive   stearic acid Inactive   glyceryl monostearate Inactive   glycerin Inactive   methylparaben Inactive   trolamine Inactive   propylparaben Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 66993-940-61 60 g (GRAM) In 1 TUBE None

Revised: 12/2008Prasco Laboratories

More Noritate resources

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

• Noritate Concise Consumer Information (Cerner Multum)


• Noritate Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• MetroCream Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• MetroGel-Vaginal Concise Consumer Information (Cerner Multum)


• Metrocream


• Metrogel-Vaginal Advanced Consumer (Micromedex) - Includes Dosage Information


• Metrolotion


• Rozex Emulsion MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Noritate with other medications

• Perioral Dermatitis
• Rosacea