Nexavar

sorafenib

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Nexavar

Hepatocellular Carcinoma 

Nexavar® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Renal Cell Carcinoma

Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Nexavar Dosage and Administration

The recommended daily dose of Nexavar is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of Nexavar. When dose reduction is necessary, the Nexavar dose may be reduced to 400 mg once daily. If additional dose reduction is required, Nexavar may be reduced to a single 400 mg dose every other day [see Warnings and Precautions (5)].

Suggested dose modifications for skin toxicity are outlined in Table 1.

Table 1: Suggested Dose Modifications for Skin Toxicity

Skin Toxicity Grade	Occurrence	Suggested Dose Modification
Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities	Any occurrence	Continue treatment with Nexavar and consider topical therapy for symptomatic relief
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities	1st occurrence	Continue treatment with Nexavar and consider topical therapy for symptomatic relief If no improvement within 7 days, see below
	No improvement within 7 days or 2nd or 3rd occurrence	Interrupt Nexavar treatment until toxicity resolves to Grade 0–1 When resuming treatment, decrease Nexavar dose by one dose level (400 mg daily or 400 mg every other day)
	4th occurrence	Discontinue Nexavar treatment
Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living	1st or 2nd occurrence	Interrupt Nexavar treatment until toxicity resolves to Grade 0–1 When resuming treatment, decrease Nexavar dose by one dose level (400 mg daily or 400 mg every other day)
	3rd occurrence	Discontinue Nexavar treatment

No dose adjustment is required on the basis of patient age, gender, or body weight.

Concomitant strong CYP3A4 inducers: Avoid concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), when possible, because inducers can decrease the systemic exposure to sorafenib [see Drug Interactions (7.1)].

 

Dosage Forms and Strengths

Tablets containing sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib.

Nexavar tablets are round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side.

Contraindications

• Nexavar is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of Nexavar.


• Nexavar in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions (5.8)].

Warnings and Precautions

Risk of Cardiac Ischemia and/or Infarction

In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in Nexavar patients compared with 1.3% in the placebo group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the Nexavar group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischemia and/or infarction.

Risk of Hemorrhage

An increased risk of bleeding may occur following Nexavar administration. In the HCC study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in Nexavar patients and 4% in placebo patients. Bleeding with a fatal outcome from any site was reported in 2.4% of Nexavar patients and 4% in placebo patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the Nexavar group and 8.2% of patients in the placebo group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in Nexavar patients, and 1.3% and 0.2%, respectively, in placebo patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. If any bleeding necessitates medical intervention, permanent discontinuation of Nexavar should be considered.

Risk of Hypertension

Monitor blood pressure weekly during the first 6 weeks of Nexavar. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of Nexavar-treated patients and 4.3% of patients in the placebo group. In RCC Study 1, hypertension was reported in approximately 16.9% of Nexavar-treated patients and 1.8% of patients in the placebo group. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of Nexavar. Permanent discontinuation due to hypertension occurred in 1 of 297 Nexavar patients in the HCC study and 1 of 451 Nexavar patients in RCC Study 1.

Risk of Dermatologic Toxicities

Hand-foot skin reaction and rash represent the most common adverse reactions attributed to Nexavar. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with Nexavar. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Nexavar, or in severe or persistent cases, permanent discontinuation of Nexavar. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 of 297 Nexavar patients with HCC and 3 of 451 Nexavar patients with RCC.

Risk of Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking Nexavar. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue Nexavar.

Warfarin

Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Nexavar. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes.

Wound Healing Complications

No formal studies of the effect of Nexavar on wound healing have been conducted. Temporary interruption of Nexavar is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of Nexavar following major surgical intervention. Therefore, the decision to resume Nexavar following a major surgical intervention should be based on clinical judgment of adequate wound healing.

Increased Mortality Observed with Nexavar Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer

In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of sorafenib compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and gemcitabine/ cisplatin alone (HR 1.22, 95% CI 0.82-1.80). The use of sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of Nexavar has not been established in patients with non-small cell lung cancer.

Risk of QT Interval Prolongation

 Nexavar can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias.  Avoid Nexavar in patients with congenital long QT syndrome. Monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) [see Clinical Pharmacology (12.2)].

Risk of Fetal Harm

There are no adequate and well-controlled studies in pregnant women using Nexavar. However, based on its mechanism of action and findings in animals, Nexavar may cause fetal harm when administered to a pregnant woman.  Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing potential to avoid becoming pregnant while on Nexavar because of the potential hazard to the fetus [see Use in Specific Populations (8.1)] .

Adverse Reactions

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

• Cardiac ischemia, infarction [see Warnings and Precautions (5.1)]


• Hemorrhage [see Warnings and Precautions (5.2)]


• Hypertension [see Warnings and Precautions (5.3)]


• Hand-foot skin reaction and rash [see Warnings and Precautions (5.4)]


• Gastrointestinal perforation [see Warnings and Precautions (5.5)]


• QT Interval Prolongation [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.2)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in sections 6.1 and 6.2 reflect exposure to Nexavar in 748 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297) or advanced renal cell carcinoma (N=451).

The most common adverse reactions (≥20%), which were considered to be related to Nexavar, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.

Adverse Reactions in HCC Study

Table 2 shows the percentage of patients with HCC experiencing adverse reactions  that were reported in at least 10% of patients and at a higher rate in the Nexavar arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 39% of patients receiving Nexavar compared to 24% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 6% of patients receiving Nexavar compared to 8% of patients receiving placebo.

Table 2 Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Nexavar Arm than the Placebo Arm – HCC Study

	Nexavar			Placebo
	N=297			N=302
Adverse Reaction NCI-CTCAE v3 Category/Term	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Any Adverse Reaction	98	39	6	96	24	8
Constitutional symptoms
Fatigue	46	9	1	45	12	2
Weight loss	30	2	0	10	1	0
Dermatology/skin
Rash/desquamation	19	1	0	14	0	0
Pruritus	14	<1	0	11	<1	0
Hand-foot skin reaction	21	8	0	3	<1	0
Dry skin	10	0	0	6	0	0
Alopecia	14	0	0	2	0	0
Gastrointestinal
Diarrhea	55	10	<1	25	2	0
Anorexia	29	3	0	18	3	<1
Nausea	24	1	0	20	3	0
Vomiting	15	2	0	11	2	0
Constipation	14	0	0	10	0	0
Hepatobiliary/pancreas
Liver dysfunction	11	2	1	8	2	1
Pain
Pain, abdomen	31	9	0	26	5	1

Hypertension was reported in 9% of patients treated with Nexavar and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of Nexavar treated patients and 1% of placebo treated patients. No patients were reported with CTCAE Grade 4 reactions in either treatment group.

Hemorrhage/bleeding was reported in 18% of those receiving Nexavar and 20% of placebo patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo group (CTCAE Grade 3 - 3% Nexavar and 5% placebo and CTCAE Grade 4 - 2% Nexavar and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in Nexavar treated patients and 4% of placebo treated patients.

Renal failure was reported in <1% of patients treated with Nexavar and 3% of placebo treated patients.

The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the Nexavar and placebo groups (32% of Nexavar patients and 35% of placebo patients).

Laboratory Abnormalities

The following laboratory abnormalities were observed in patients with HCC:

Hypophosphatemia was a common laboratory finding, observed in 35% of Nexavar-treated patients compared to 11% of placebo patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of Nexavar-treated patients and 2% of patients in the placebo group; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo group. The etiology of hypophosphatemia associated with Nexavar is not known.

Elevated lipase was observed in 40% of patients treated with Nexavar compared to 37% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated amylase was observed in 34% of patients treated with Nexavar compared to 29% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase and amylase elevations were transient, and in the majority of cases Nexavar treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 Nexavar-treated patients (CTCAE Grade 2).

Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was observed in 59% of Nexavar-treated patients and 47% of placebo patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group.

INR elevations were observed in 42% of Nexavar-treated patients and 34% of placebo patients; CTCAE Grade 3 INR elevations were reported in 4% of Nexavar-treated patients and 2% of placebo patients; there was no CTCAE Grade 4 INR elevation in either group.

Lymphopenia was observed in 47% of Nexavar-treated patients and 42% of placebo patients.

Thrombocytopenia was observed in 46% of Nexavar-treated patients and 41% of placebo patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of Nexavar-treated patients and less than 1% of placebo patients.

Adverse Reactions in RCC Study 1

Table 3 shows the percentage of patients with RCC experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the Nexavar arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 31% of patients receiving Nexavar compared to 22% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 7% of patients receiving Nexavar compared to 6% of patients receiving placebo.

Table 3: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Nexavar Arm than the Placebo Arm – RCC Study 1

	Nexavar N=451			Placebo N=451
Adverse Reactions NCI- CTCAE v3 Category/Term	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Any Adverse Reactions	95	31	7	86	22	6
Cardiovascular, General
Hypertension	17	3	<1	2	<1	0
Constitutional symptoms
Fatigue	37	5	<1	28	3	<1
Weight loss	10	<1	0	6	0	0
Dermatology/skin
Rash/desquamation	40	<1	0	16	<1	0
Hand-foot skin reaction	30	6	0	7	0	0
Alopecia	27	<1	0	3	0	0
Pruritus	19	<1	0	6	0	0
Dry skin	11	0	0	4	0	0
Gastrointestinal symptoms
Diarrhea	43	2	0	13	<1	0
Nausea	23	<1	0	19	<1	0
Anorexia	16	<1	0	13	1	0
Vomiting	16	<1	0	12	1	0
Constipation	15	<1	0	11	<1	0
Hemorrhage/bleeding
Hemorrhage – all sites	15	2	0	8	1	<1
Neurology
Neuropathy-sensory	13	<1	0	6	<1	0
Pain
Pain, abdomen	11	2	0	9	2	0
Pain, joint	10	2	0	6	<1	0
Pain, headache	10	<1	0	6	<1	0
Pulmonary
Dyspnea	14	3	<1	12	2	<1

The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the Nexavar and placebo groups (10% of Nexavar patients and 8% of placebo patients).

Laboratory Abnormalities

The following laboratory abnormalities were observed in patients with RCC in Study 1:

Hypophosphatemia was a common laboratory finding, observed in 45% of Nexavar-treated patients compared to 11% of placebo patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of Nexavar-treated patients and 3% of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either Nexavar or placebo patients. The etiology of hypophosphatemia associated with Nexavar is not known.

Elevated lipase was observed in 41% of patients treated with Nexavar compared to 30% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the Nexavar group compared to 7% of patients in the placebo group. Elevated amylase was observed in 30% of patients treated with Nexavar compared to 23% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the Nexavar group compared to 3% of patients in the placebo group. Many of the lipase and amylase elevations were transient, and in the majority of cases Nexavar treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 Nexavar-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group.

Lymphopenia was observed in 23% of Nexavar-treated patients and 13% of placebo patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of Nexavar-treated patients and 7% of placebo patients. Neutropenia was observed in 18% of Nexavar-treated patients and 10% of placebo patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of Nexavar-treated patients and 2% of placebo patients.

Anemia was observed in 44% of Nexavar-treated patients and 49% of placebo patients. CTCAE Grade 3 or 4 anemia was reported in 2% of Nexavar-treated patients and 4% of placebo patients.

Thrombocytopenia was observed in 12% of Nexavar-treated patients and 5% of placebo patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of Nexavar-treated patients and 0% of placebo patients.

Additional Data from Multiple Clinical Trials

The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of Nexavar (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%):

Cardiovascular:Common: congestive heart failure*†, myocardial ischemia and/or infarction Uncommon: hypertensive crisis* Rare: QT prolongation*

Dermatologic:Very common: erythema Common: exfoliative dermatitis, acne, flushing Uncommon: folliculitis, eczema, erythema multiforme, keratoacanthomas/squamous cell cancer of the skin 

Digestive:Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia Uncommon: pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal perforations*, cholecystitis, cholangitis

Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values

General Disorders:Very common: hemorrhage (including gastrointestinal* & respiratory tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain) Common: decreased appetite, influenza-like illness, pyrexia Uncommon: infection

Hematologic:Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal

Hypersensitivity:Uncommon: hypersensitivity reactions (including skin reactions and urticaria)

Metabolic and Nutritional:Very common: hypophosphatemia Common: transient increases in transaminases Uncommon: dehydration, hyponatremia, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hypothyroidism, hyperthyroidism

Musculoskeletal:Common: arthralgia, myalgia

Nervous System and Psychiatric:Common: depression Uncommon: tinnitus, reversible posterior leukoencephalopathy*

Renal and Genitourinary: Common: renal failure

Reproductive:Common: erectile dysfunction Uncommon: gynecomastia

Respiratory:Common: hoarseness Uncommon: rhinorrhea, interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation)

In addition, the following medically significant adverse reactions were uncommon during clinical trials of Nexavar: transient ischemic attack, arrhythmia, thromboembolism. For these adverse reactions, the causal relationship to Nexavar has not been established.

*adverse reactions may have a life-threatening or fatal outcome.

†reported in 1.9% of patients treated with sorafenib (N= 2276).

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval use of Nexavar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN).

Hypersensitivity: Angioedema, anaphylactic reaction

Hepatobiliary disorders: Drug-induced hepatitis, including reports of hepatic failure and death.

Drug Interactions

Drug Metabolism

Effect of Cytochrome P450 Inducers on Sorafenib

Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days with a single oral dose of Nexavar 400 mg in healthy volunteers resulted in a 37% decrease in the mean AUC of sorafenib.  Other inducers of CYP3A4 activity (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort) can increase the metabolism of sora

Voltarol Gel Patch

1. Name Of The Medicinal Product

Voltarol® Gel Patch 1 %, medicated plaster

2. Qualitative And Quantitative Composition

Each 10 cm x 14 cm medicated plaster contains diclofenac epolamine corresponding to 140 mg of diclofenac sodium (1% w/w).

For excipients, see 6.1.

3. Pharmaceutical Form

Medicated plaster.

White to pale yellow paste spread as a uniform layer onto unwoven support.

4. Clinical Particulars

4.1 Therapeutic Indications

Local symptomatic treatment of pain in epicondylitis and ankle sprain.

4.2 Posology And Method Of Administration

Cutaneous use only

Article I. Posology

Adults

- Treatment of ankle sprains : 1 application a day

- Treatment of epicondylitis: 1 application morning and evening

Article II. Duration of administration

Voltarol Gel Patch is to be used for as short as possible depending on the indication:

- Treatment of ankle sprains : 3 days

- Treatment of epicondylitis : max. 14 days.

If there is no improvement, during the recommended duration of treatment, a doctor should be consulted.

Elderly

This medication should be used with caution in elderly patients who are more prone to adverse events. See also Section 4.4.

Children

Since no specific study has been performed, the use of Voltarol Gel Patch in children under 15 years old is not recommended.

Patients with hepatic or renal insufficiency

For the use of Voltarol Gel Patch in patients with hepatic or renal insufficiency see section 4.4.

Article III. Method of administration

Cut the envelope containing the medicated plaster as indicated. Remove one medicated plaster, remove the plastic film used to protect the adhesive surface and apply it to painful joint or region. If necessary it can be held in place with an elastic net. Carefully reseal the envelope with the sliding closure.

The plaster should be used whole.

4.3 Contraindications

This medicinal product is contraindicated in the following cases:

- Hypersensitivity to diclofenac, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs) or any excipients of the finished medicinal product.

- damaged skin, whatever the lesion involved: exudative dermatitis, eczema, infected lesion, burn or wound.

- from the beginning of the 6th month of pregnancy (see 4.6 Pregnancy and lactation).

- Patients with active peptic ulceration.

4.4 Special Warnings And Precautions For Use

- The medicated plaster should not come into contact with or be applied to the mucosae or the eyes.

- Not for use with occlusive dressing.

- Discontinue the treatment immediately if a skin rash develops after applying the medicated plaster.

- Do not administer concurrently, by either the topical or the systemic route, any medicinal product containing diclofenac or other NSAIDs.

- Although systemic effects should be low, the plaster should be used with caution in patients with renal, cardiac or hepatic impairment, history of peptic ulceration or inflammatory bowel disease or bleeding diathesis. Non-steroidal anti-inflammatory drugs should be used with particular caution in elderly patients who are more prone to adverse events.

- This medicinal product contains methylparahydroxybenzoate and propylparahydroxybenzoate. It may cause allergic reactions (possibly delayed). It also contains propylene glycol, which may cause skin irritation.

- Patients should be warned against exposure to direct and solarium sunlight in order to reduce the risk of photosensitivity.

- Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergenic disease or allergy to acetylsalicylic acid or other NSAID. The medicated plaster should be used with caution in patients with or without chronic asthma in whom attacks of asthma, urticaria or acute rhinitis are precipitated by aspirin or other nonsteroidal anti-inflammatory agents (see 4.3 Contraindications).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In view of the low rate of systemic transfer during normal use of the medicated plasters, the drug interactions reported for oral diclofenac are unlikely to be observed.

4.6 Pregnancy And Lactation

By analogy with the other routes of administration

Pregnancy

There is insufficient experience for the use during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore Voltarol Gel Patch should be avoided during the first 5 months of pregnancy and is contra-indicated from the beginning of the 6th month of pregnancy.

During the last trimester of pregnancy, the use of prostaglandine synthetase inhibitors may result in:

- Inhibition of uterine contractions, prolongation of pregnancy and delivery

- Pulmonary and cardiac toxicity in the foetus (pulmonary hypertension with preterm closing of the ductus arteriosus)

- Renal insufficiency in the foetus with oligohydramnios

- Increased possibility of bleeding in the mother and child and increased oedema formation in the mother.

Lactation

Experimental data regarding excretion of diclofenac epolamine in human or animal milk are not available therefore, Voltarol Gel Patch is not recommended in nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Patients who experienced dizziness or other central nervous disturbances while taking NSAID's should refrain from driving or operating machinery, but this would be very unlikely using topical preparations such as Voltarol Gel Patch.

4.8 Undesirable Effects

Skin disorders are commonly reported.

Skin: pruritus, redness, erythema (including in very rare cases erythema bullosum), rashes, application site reactions, allergic dermatitis.

1252 patients were treated with Voltarol Gel Patch and 734 with Placebo in clinical trials. The following adverse drug reactions were reported:

System Organ Class	Very Common ( >1/10)	Common ( >1/100, <1/10)	Uncommon ( >1/1000, <1/100)	Rare ( >1/10'000,<1/1000)
Skin and subcutaneous tissue disorders		2.95%
- Pruritus		2.3%
- Redness			0.3%
- Erythema				0.05%
- Dermatitis allergic			0.15%
- Petechiae			0.1%
- Dry skin				0.05%
General disorders and administration site conditions		1.05%
- Application site rash			0.5%
- Application site reaction			0.4%
- Feeling hot			0.1%
- Application site edema				0.05%

Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration.

In patients using topical NSAID preparations, in isolated cases, generalised skin rash, hypersensitivity reactions such as angioedema and reactions of anaphylactic type and photosensitivity reactions have been reported.

Systemic absorption of diclofenac is very low compared with plasma levels obtained following administration of oral forms of diclofenac and the likelihood of systemic side-effects reactions (like gastric and renal disorders) occurring with topical diclofenac is very small compared with the frequency of side-effects associated with oral diclofenac. However, where Voltarol Gel Patch is applied to a relatively large area of skin and over a prolonged period, the possibility of systemic side-effects cannot be excluded.

4.9 Overdose

Not applicable

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiinflammatory preparations, non-steroids for topical use.

ATC Code: M02AA15

Diclofenac hydroxyethylpyrrolidine or diclofenac epolamine is a water soluble salt of diclofenac.

Diclofenac is a nonsteroidal anti-inflammatory drug derived from phenylacetic acid which belongs to the aryl carboxylic acid group of compounds.

In the form of a medicated plaster, it has topical anti-inflammatory and analgesic activity.

5.2 Pharmacokinetic Properties

Following cutaneous application of the medicated plaster, diclofenac epolamine is absorbed through the skin.

The absorption kinetics at steady state show a prolonged release of the active ingredient with a maximum diclofenac plasma level (Cmax) of 17.4 ±13.5 ng/ml, which is reached after about 5 hours (Tmax 5.4±3.7 hours).

Diclofenac is extensively bound to plasma protein (about 99 %).

Systemic transfer in healthy volunteers when using the medicated plaster, compared with oral forms of diclofenac, is of the order of 2%, as estimated from the urinary excretion of the drug and its metabolites and from a between study comparison.

5.3 Preclinical Safety Data

In the rat and rabbit, diclofenac epolamine, epolamine monosubstance and N-oxide epolamine (main metabolite of epolamine in humans) have caused embryotoxicity and increased embryolethality after oral use.

Other preclinical data reveal no special hazard for humans, beyond the information included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Supporting layer:

Unwoven polyester support.

Adhesive layer (active Gel):

Gelatin, povidone (K90), liquid sorbitol (non crystallising), heavy kaolin, titanium dioxide (E171), propylene glycol, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), disodium edetate (E385), tartaric acid, aluminium glycinate, carmellose sodium, sodium polyacrylate, 1,3-butylene glycol, polysorbate 80, Dalin PH perfume (propylene glycol, benzyl salicylate, phenylethyl alcohol, alpha amylcinnamic aldehyde, hydroxycitronellal, phenyethyl phenylacetate, cinnamyl acetate, benzyl acetate, terpineol, cinnamic alcohol, cyclamenaldehyde), purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

After first opening the sealed envelope : 3 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Sealed envelopes made of paper/PE/aluminium/ethylene and methacrylic acid copolymer contain 2 or 5 medicated plasters.

Pack size: 2, 5, 10 and 14 medicated plasters per box.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Remaining active ingredient of the plaster may pose a risk to the aquatic environment. Do not flush used plasters down the toilet. The plasters should be disposed of according to local requirements.

7. Marketing Authorisation Holder

Novartis Consumer Health

Wimblehurst Road

Horsham, West Sussex

RH12 5AB

8. Marketing Authorisation Number(S)

PL 00030/ 0206

9. Date Of First Authorisation/Renewal Of The Authorisation

10 March 2004

10. Date Of Revision Of The Text

14 November 2005

Legal category

POM

fomepizole

Generic Name: fomepizole (foe MEP i zole)

Brand Names: Antizol

What is fomepizole?

Fomepizole is an antidote to certain types of poison.

Fomepizole is used to treat poisoning with ethylene glycol (antifreeze) or methanol (contained in solvents, fuels, and other household or automotive chemicals). Fomepizole is sometimes used together with hemodialysis to rid the body of a poison.

Fomepizole may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about fomepizole?

In a poisoning situation, it may not be possible to tell your caregivers that you are pregnant or breast-feeding before you are treated with fomepizole. However, make sure any doctor caring for your pregnancy or your baby knows that you have received the medication.

Tell your caregivers at once if you have any burning, swelling, or skin changes where the medicine was injected.

To be sure this medication is helping your condition, your blood and urine will need to be tested often. This will help your doctor determine how long to treat you with fomepizole. You will also be watched for any effects of the poisoning, such as problems with vision, breathing, or urination.

What should I discuss with my health care provider before receiving fomepizole?

You should not receive this medication if you are allergic to fomepizole. FDA pregnancy category C. This medication may be harmful to an unborn baby and is not recommended in pregnant women unless clearly needed. It is not known whether fomepizole passes into breast milk or if it could harm a nursing baby.

In a poisoning situation, it may not be possible to tell your caregivers that you are pregnant or breast-feeding before you are treated with fomepizole. However, make sure any doctor caring for your pregnancy or your baby knows that you have received the medication.

How is fomepizole given?

Fomepizole is given as an injection through a needle placed into a vein. You will receive this injection in a hospital or emergency setting. The medicine must be given slowly through an IV infusion, and each dose can take up to 30 minutes to complete.

To be sure this medication is helping your condition, your blood and urine will need to be tested often. This will help your doctor determine how long to treat you with fomepizole. You will also be watched for any effects of the poisoning, such as problems with vision, breathing, or urination.

What happens if I miss a dose?

Since fomepizole is given as needed by a healthcare professional, it is not likely that you will miss a dose.

What happens if I overdose?

Tell your caregivers right away if you think you have received too much of this medicine.

Overdose symptoms may include nausea, dizziness, or a spinning sensation.

What should I avoid while receiving fomepizole?

Follow your doctor's instructions about any restrictions on food, beverages, or activity after you are treated with fomepizole.

Fomepizole 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. Tell your caregivers at once if you have any of these serious side effects (some are effects of the poison and not of fomepizole):

• 
  

  burning, swelling, or skin changes where the medicine was injected;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  fast or slow heart rate, feeling like you may pass out; or

  
  


• 
  

  skin rash, bruising, severe tingling, numbness, pain, muscle weakness.

  
  

Less serious side effects may include:

• 
  

  mild skin rash;

  
  


• 
  

  heartburn, nausea, vomiting, diarrhea;

  
  


• 
  

  loss of appetite;

  
  


• 
  

  dizziness, drowsiness, anxiety, or headache;

  
  


• 
  

  metallic taste in your mouth;

  
  


• 
  

  hangover feeling;

  
  


• 
  

  back pain;

  
  


• 
  

  sore throat;

  
  


• 
  

  ringing in your ears; or

  
  


• 
  

  changes in vision, changes in smell or taste senses.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Fomepizole Dosing Information

Usual Adult Dose for Methanol Poisoning:

Patients not requiring hemodialysis:
Initial dose: 15 mg/kg IV followed by 4 doses of 10 mg/kg IV every 12 hours

Maintenance dose: 15 mg/kg IV every 12 hours thereafter until levels of ethylene glycol or methanol are reduced below 20 mg/dL, and the patient is asymptomatic with normal pH

All doses should be administered as a slow intravenous infusion over 30 minutes.

Usual Adult Dose for Ethylene Glycol Poisoning:

Patients not requiring hemodialysis:
Initial dose: 15 mg/kg IV followed by 4 doses of 10 mg/kg IV every 12 hours

Maintenance dose: 15 mg/kg IV every 12 hours thereafter until levels of ethylene glycol or methanol are reduced below 20 mg/dL, and the patient is asymptomatic with normal pH

All doses should be administered as a slow intravenous infusion over 30 minutes.

Usual Pediatric Dose for Methanol Poisoning:

Children and adolescents not requiring hemodialysis:
Initial dose: 15 mg/kg IV followed by 4 doses of 10 mg/kg IV every 12 hours

Maintenance dose: 15 mg/kg IV every 12 hours thereafter until levels of ethylene glycol or methanol are reduced below 20 mg/dL, and the patient is asymptomatic with normal pH

All doses should be administered as a slow intravenous infusion over 30 minutes.

Not FDA approved; however, safe and effective use in pediatric patients has been reported.

Usual Pediatric Dose for Ethylene Glycol Poisoning:

Children and adolescents not requiring hemodialysis:
Initial dose: 15 mg/kg IV followed by 4 doses of 10 mg/kg IV every 12 hours

Maintenance dose: 15 mg/kg IV every 12 hours thereafter until levels of ethylene glycol or methanol are reduced below 20 mg/dL, and the patient is asymptomatic with normal pH

All doses should be administered as a slow intravenous infusion over 30 minutes.

Not FDA approved; however, safe and effective use in pediatric patients has been reported.

What other drugs will affect fomepizole?

Tell your doctor if you have recently used any of the following drugs:

• 
  

  phenytoin (Dilantin);

  
  


• 
  

  carbamazepine (Carbatrol, Tegretol);

  
  


• 
  

  cimetidine (Tagamet); or

  
  


• 
  

  ketoconazole (Nizoral).

  
  

There may be other drugs that can affect fomepizole. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors.

More fomepizole resources

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

• Fomepizole Monograph (AHFS DI)


• Fomepizole Prescribing Information (FDA)


• Antizol Prescribing Information (FDA)

Compare fomepizole with other medications

• Ethylene Glycol Poisoning
• Methanol Poisoning

Where can I get more information?

• Your doctor or pharmacist can provide more information about fomepizole.

See also: fomepizole side effects (in more detail)

Viazem XL 360mg

1. Name Of The Medicinal Product

VIAZEM XL

2. Qualitative And Quantitative Composition

Diltiazem hydrochloride: 360 mg capsule.

For excipients see section 6.1

3. Pharmaceutical Form

Prolonged release capsule, hard.

Blue-green opaque capsules. Each capsule is printed on the cap and body, in white ink, with Viazem XL 360.

4. Clinical Particulars

4.1 Therapeutic Indications

VIAZEM XL is indicated for the management of stable angina pectoris and the treatment of mild to moderate hypertension.

4.2 Posology And Method Of Administration

Dosage requirements may differ between patients with angina and patients with hypertension. In addition individual patients response may vary, necessitating careful titration. The range of strengths facilitates titration to the optimal dose.

One capsule of VIAZEM XL is to be taken before or during a meal. The dose should be taken at approximately the same time each day.

The capsule should not be chewed but swallowed whole, with a glass of water.

Due to the variability of release profile in individual patients, when changing from one type of sustained release diltiazem preparation to another, it may be necessary to adjust the dose.

Adults:

Hypertension: The usual starting dose is 180 mg once daily. The dose may be increased after 2-4 weeks according to the patient's response and the usual maintenance dose is 240mg-360mg once daily. The maximum daily dose is 360 mg. However, the single daily doses of 300 mg and 360 mg should only be administered to patients when no satisfactory therapeutic effect has been effected with lower doses and after the benefit risk-ratio has been carefully assessed by the doctor.

Angina: Care should be taken when titrating patients with stable angina in order to establish the optimal dose. The usual starting dose is 180 mg once daily. The dose may be increased after 2-4 weeks according to the patient's response. The maximum daily dose is 360 mg. However, the single daily doses of 300 mg and 360 mg should only be administered to patients when no satisfactory therapeutic effect has been effected with lower doses and after the benefit risk-ratio has been carefully assessed by the doctor.

Elderly and patients with impaired hepatic or renal function:

Plasma levels of diltiazem can be increased in the elderly, and in patients with impaired hepatic renal or hepatic function. In these cases, the starting dose should be one 120mg VIAZEM XL capsule once daily. Heart rate should be monitored and if it falls below 50 beats per minute, the dose should not be increased. Dose adjustment may be required to obtain a satisfactory clinical response.

Children:

Safety and efficacy in children have not been established.

4.3 Contraindications

Diltiazem depresses atrioventricular node conduction and is therefore contraindicated in patients with severe bradycardia (less than 50 bpm), sick sinus syndrome, congestive heart failure, and left ventricular failure with second or third degree AV or sino-atrial block, except in the presence of a functioning pacemaker. Diltiazem is also contraindicated in left ventricular failure with pulmonary stasis as diltiazem may have mild negative effects on contractility.

Diltiazem is contraindicated in acute complicated myocardial infarction (e.g. bradycardia hypotension, congestive heart failure/reduced LV function), pulmonary congestion, hypotension (<90 mmHg systolic) cerebrovascular accident, cardiac shock and unstable angina pectoris.

Diltiazem is contraindicated in pre-excitation syndrome (e.g. WPW) accompanied with atrial flutter, fibrillation and in digitalis intoxication, as diltiazem may precipitate ventricular tachycardia.

Diltiazem should not be used in patients with known hypersensitivity to diltiazem.

Diltiazem should not be used during pregnancy, by women of child-bearing potential, or by women who are breastfeeding.

4.4 Special Warnings And Precautions For Use

Patients treated with beta-adrenoreceptor blocking drugs and patients with conduction disturbances (bradycardia, bundle branch block, first degree AV block, prolonged PR interval) should only be treated with VIAZEM XL after special consideration due to the risk of serious bradyarrhythmias.

This product should be used with caution in patients with hepatic dysfunction. Abnormalities of liver function may appear during therapy. The higher single daily doses of VIAZEM XL capsules 300mg and 360mg should not be administered to patients with impaired renal and/or hepatic function and to elderly patients (prolonged half life of elimination) because there is no experience on the use of such high dosages in these patient categories.

In patients undergoing long-term therapy with cyclosporin, plasma levels of cyclosporin should be monitored when concurrent administration of diltiazem is initiated, or discontinued or if the dose of diltiazem is changed.

Abnormally short transit time through the gastrointestinal tract could lead to incomplete release of contents of the capsule e.g. in chronic conditions with associated diarrhoea such as Crohns disease or ulcerative colitis.

Patients with rare heriditary problems of fructose intolerances, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Combinations contraindicated as a safety measure:

In animals, fatal ventricular fibrillations are constantly seen during administration of verapamil and dantrolene via the i.v. route. The combination of a calcium antagonist and dantrolene is therefore potentially dangerous. The concurrent iv administration of beta-adrenergic blocking agents with diltiazem should be avoided because an additive effect on SA and AV conduction and ventricular function will occur. The use of such a combination requires ECG monitoring especially at the beginning of treatment.

Combinations requiring safety precautions:

In common with other calcium antagonists, when diltiazem is used with drugs which may induce bradycardia or with antiarrhythmic drugs (e.g. amiodarone) or other antihypertensive drugs, the possibility of an additive effect should be borne in mind. Inhalation anaesthetics should be used with caution during diltiazem therapy. Tri/tetracyclic antidepressants and neuroleptics may increase the antihypertensive effects of diltiazem whilst the concomitant use of lithium with diltiazem may lead to neurotoxicity (extrapyramidal effects). Rifampin and other hepatic enzyme inducers may reduce the bioavailability of diltiazem and high doses of Vitamin D and/or high intake of calcium salts leading to elevated serum calcium levels may reduce the response to diltiazem.

Diltiazem is metabolised by CYP3A4 and could, by competitive inhibition of CYP3A4, affect the pharmacokinetics of other drugs metabolised by this enzyme. In addition inhibitors and inducers of CYP3A4 may affect the pharmacokinetics of diltiazem.

Diltiazem prolongs the sedative effect of medazolam and triazolam via metabolic interaction and decreases nifedipine clearance by 50%. Diltiazem may cause increases in the levels of digitoxin. Diltiazem has been shown to increase the bioavailability of imipramine by 30% probably due to inhibition of its first pass metabolism.

Diltiazem has been used safely in combination with diuretics, ACE-inhibitors and other anti-hypertensive agents. It is recommended that patients receiving these combinations should be regularly monitored. Concomitant use of diltiazem with alpha-blockers such as prazosin should be strictly monitored because of the possible synergistic hypotensive effect of the combination.

Case reports have suggested that blood levels of carbamazepine, cyclosporin, theophylline and phenytoin may be increased when given concurrently with diltiazem. Care should be exercised in patients taking these drugs. In common with other calcium antagonists diltiazem may cause small increases in plasma levels of digoxin. In patients taking H₂-antagonists concurrently with diltiazem there may be increased levels of diltiazem.

Magnification of the hypotensive and lipothymic effects (summation of vasodilator properties) of nitrate derivatives can occur. In patients on calcium inhibitors, prescriptions of nitrate derivatives should be made at progressively increasing doses. Diltiazem treatment has been continued without problem during anaesthesia, but diltiazem may potentiate the activity of curare-like and depolarising neuromuscular blocking agents, therefore the anaesthetist should be informed that the patient is receiving a calcium antagonist.

4.6 Pregnancy And Lactation

Pregnancy:

Diltiazem should not be taken during pregnancy. Women of child bearing-potential should exclude the possibility of pregnancy before commencing treatment by taking suitable contraceptive measures if necessary. In animal tests, Diltiazem was found to have a tetratogenic effects in some species of animal.

Diltiazem may suppress the contractility of the uterus. Definite evidence that this will prolong partus in full-term pregnancy is lacking. A risk of hypoxia in the foetus may arise in the event of hypotension in the mother and reduced perfusion of the uterus due to redistribution of blood flow due to peripheral vasodilatation. In animal experiments diltiazem has exhibited teratogenic effects in some animal species. In the absence of adequate evidence of safety in human pregnancy, VIAZEM XL should not be used in pregnancy or in women of childbearing potential.

Lactation:

Diltiazem is excreted in breast milk in concentrations similar to those in serum. If the use of diltiazem is considered essential, an alternative method of infant feeding should be instituted.

4.7 Effects On Ability To Drive And Use Machines

There are no studies on the effect of diltiazem when driving vehicles or operating machines. It should be taken into account that occasionally asthenia/fatigue and dizziness may occur. Treatment of hypertension with this medicinal product requires regular monitoring. Individual different reactions may affect the ability to drive. This risk should be considered especially at the beginning of treatment, when changing the drug, or in combination with alcohol.

4.8 Undesirable Effects

Certain undesirable effects may lead to suspension of treatment: sinus bradycardia, sino-atrial heart block, 2nd and 3rd degree atrioventricular heart block, skin rash, oedema of the lower limbs.

In hypertensive patients, adverse effects are generally mild and transient and are most commonly vasodilatory related events.

The following have been described in decreasing order of frequency: lower limb oedema, headache, hot flushes/flushing, asthenia/fatigue, palpitations, malaise, minor gastro-intestinal disorders (dyspepsia, abdominal pain, dry mouth, nausea, vomiting, diarrhoea, constipation) and skin rash. Erythema multiform and Stevens Johnson syndrome have been reported infrequently in patients receiving diltiazem hydrochloride. Vasodilatory related events (in particular, oedema) are dose-dependent and appear to be more frequent in elderly subjects.

Rare cases of symptomatic bradycardia and exceptionally sino-atrial block and atrioventricular block, hypotension, syncope, reduced left ventricular function have also been recorded. Isolated cases of hallucinations, depression, insomnia, hyperglycaemia and impotence have been reported.

Experience with use in other indications and with other formulations has shown that skin rashes are usually localised and are limited to cases of erythemia, urticaria or occasionally desquamative erthema, with or without fever, which regress when treatment is discontinued.

Isolated cases of moderate and transient elevations of liver transaminases have been observed at the start of treatment. Isolated cases of clinical hepatitis have been reported which resolved with cessation of therapy.

Dizziness, pruritis, nervousness, paraesthesia, articular/muscular pain, photo sensitisation, hypotension, gingival hyperplasia, and gynaecomastia, have also been observed.

4.9 Overdose

The clinical consequences of overdose can be severe hypotension leading to collapse, and sinus bradycardia which may be accompanied by isorhythmic dissociation and atrioventricular conduction disturbances. Observation in a coronary care unit is advisable. Vasopressors such as adrenaline may be indicated in patients exhibiting profound hypotension. Calcium gluconate may help reverse the effects of calcium entry blockade. Atropine administration and temporary cardiac pacing may be required to manage bradycardia and/or conduction disturbances.

Glucagon can be used in cases of established hypoglycaemia.

Diltiazem and its metabolites are very poorly dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diltiazem is classified as a calcium channel blocker, benziothiazepine derivative, C08DB01, under the ATC classification. It selectively reduces calcium entry through voltage-dependent calcium-n channels into vascular smooth muscle cells and myocardial cells. This lowers the concentration of intracellular calcium which is available to activate contractile proteins. This action of diltiazem results in dilation of coronary arteries causing an increase in myocardial oxygen supply. It reduces cardiac work by moderating the heart rate and by reducing systemic vasculary resistance thus reducing oxygen demand. Diltiazem also prolongs AV conduction and has mild effects on contractility. Clinical data on morbidity and mortality are not available.

5.2 Pharmacokinetic Properties

Multiple dose pharmacokinetic studies have shown that the kinetics of VIAZEM XL are non-linear within the 120mg-360mg dosage range. Diltiazem is well absorbed, but has a highly saturable first pass effect leading to a variable absolute bioavailability, which is on average 35%. The saturable first pass effect results in higher than expected systemic exposure with increasing doses.

The protein binding is 80 to 85% and the volume of distribution is 5.0 l/kg.

Diltiazem is metabolised by CYP3A4 in the liver and 70% of the dose is excreted in urine, mainly as metabolites. The plasma levels of the two main metabolites, N-monodesmethyldiltiazem and desacetyldiltiazem, represent 35% and 15% of diltiazem levels respectively. The metabolites contribute around 50% of the clinical effect. Plasma clearance of diltiazem is approximately 0.5 l/h/kg. Plasma half-life of diltiazem is approximately 5-7 hours.

VIAZEM XL capsules allow a prolonged absorption of diltiazem and maximum levels are reached within 6 to 12 hours. Concomitant food intake with VIAZEM XL does not influence the pharmacokinetics of diltiazem. For most patients, chronic administration of VIAZEM XL 300mg once daily, results in therapeutic diltiazem levels (50-200ng/ml) over 24 hours. However, the inter-individual variability is high and individual dose adjustment based on therapeutic response is therefore necessary.

5.3 Preclinical Safety Data

Tests on reproductive functions in animals show that diltiazem decreases fertility in rats and that it is teratogenic in mice, rats and rabbits. Exposure during late pregnancy induces dystocia and a decrease in the number of live newborns in rats.

Detailed mutagenicity and carcinogenicity tests proved negative.

6. Pharmaceutical Particulars

6.1 List Of Excipients

- Sucrose Stearate

- Microcrystalline cellulose

- Povidone

- Magnesium Stearate

- Talc

- Titanium dioxide

- Hypromellose

- Polysorbate 80

- Polyacrylate dispersion 30% (dry)

- Simethicone emulsion

- Gelatine capsule

Gelatin capsule colours

Gelatin capsule markings (printed radially):

White printing ink contains:

Shellac, Ethyl Alcohol, Isopropyl Alcohol, n-Butyl, Propylene Glycol, Sodium Hydroxide, Polyvinylpyrrolidone, Titanium Dioxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C. Store in original package in a dry place away from any heat source, e.g. direct sunlight, heaters, steam, etc.

6.5 Nature And Contents Of Container

The capsules are packed in PVC/aluminium blisters. Pack sizes are 28 capsules per blister.

6.6 Special Precautions For Disposal And Other Handling

Swallow capsules whole, with a glass of water do not chew.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire RG14 1JN

United Kingdom

8. Marketing Authorisation Number(S)

PL 06831/0232

9. Date Of First Authorisation/Renewal Of The Authorisation

10 June 2009

10. Date Of Revision Of The Text

25 August 2011

Ventolin Inhalation

Generic Name: albuterol (Inhalation route)

al-BUE-ter-ol

Commonly used brand name(s)

In the U.S.

• Accuneb


• ProAir HFA


• Proventil


• Proventil HFA


• ReliOn Ventolin HFA


• Ventolin


• Ventolin HFA

In Canada

• Alti-Salbutamol Inhalation Aerosol


• Apo-Salvent


• Salbutamol


• Salbutamol Nebuamp


• Salbutamol Respirator Solution


• Ventolin Inhaler


• Ventolin Nebules P.F.


• Ventolin Respirator


• Ventolin Rotacaps

Available Dosage Forms:

• Aerosol Powder


• Solution


• Capsule


• Powder

Therapeutic Class: Bronchodilator

Pharmacologic Class: Sympathomimetic

Uses For Ventolin

Albuterol is used to treat or prevent bronchospasm in patients with asthma, bronchitis, emphysema, and other lung diseases. This medicine is also used to prevent wheezing caused by exercise (exercise-induced bronchospasm).

Albuterol belongs to the family of medicines known as adrenergic bronchodilators. Adrenergic bronchodilators are medicines that are breathed in through the mouth to open up the bronchial tubes (air passages) in the lungs. They relieve cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.

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

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, albuterol is used in certain patients with the following medical condition:

• Hyperkalemia (too much potassium in the blood).

Before Using Ventolin

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

Allergies

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

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of albuterol inhalation aerosol (e.g., Proair® HFA) in children 4 years of age and older and albuterol inhalation solution (e.g., Accuneb®) in children 2 years of age and older. However, safety and efficacy have not been established for the aerosol in children younger than 4 years of age and for the solution in children younger than 2 years of age.

Geriatric

No information is available on the relationship of age to the effects of albuterol inhalation solution (e.g., Accuneb®) in geriatric patients.

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of albuterol inhalation aerosol (e.g., Proair® HFA) in geriatric patients. However, elderly patients are more likely to have age-related heart or kidney problems, which may require caution and an adjustment in the dose for patients receiving albuterol.

Pregnancy

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

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol


• Alprenolol


• Arotinolol


• Atenolol


• Atomoxetine


• Befunolol


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Brofaromine


• Bucindolol


• Bupranolol


• Carteolol


• Carvedilol


• Celiprolol


• Clorgyline


• Dilevalol


• Esmolol


• Furazolidone


• Iproniazid


• Isocarboxazid


• Labetalol


• Landiolol


• Lazabemide


• Levobetaxolol


• Levobunolol


• Linezolid


• Mepindolol


• Metipranolol


• Metoprolol


• Moclobemide


• Nadolol


• Nebivolol


• Nialamide


• Nipradilol


• Oxprenolol


• Pargyline


• Penbutolol


• Phenelzine


• Pindolol


• Procarbazine


• Propranolol


• Rasagiline


• Selegiline


• Sotalol


• Talinolol


• Tertatolol


• Timolol


• Toloxatone


• Tranylcypromine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Diabetes or


• Heart or blood vessel disease or


• Heart rhythm problems (e.g., arrhythmia) or


• Hypertension (high blood pressure) or


• Hyperthyroidism (overactive thyroid) or


• Hypokalemia (low potassium in the blood) or


• Seizures, history of—Use with caution. May make these conditions worse.

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

Proper Use of albuterol

This section provides information on the proper use of a number of products that contain albuterol. It may not be specific to Ventolin. Please read with care.

Use this medicine only as directed by your doctor. Do not use more of it and do not use it more often than your doctor ordered. Also, do not stop using this medicine or any asthma medicine without telling your doctor. To do so may increase the chance for breathing problems.

The albuterol inhalation solution (e.g., Accuneb®) should be used with a jet nebulizer that is connected to an air compressor with good air flow. The inhalation solution and nebulizer will come with patient instructions. Read and follow these instructions carefully. Ask your doctor if you have any questions.

To use the inhalation solution in the nebulizer:

• Use one container of solution or mix the exact amount of solution using the dropper provided for each dose.


• Place the inhalation solution in the medicine reservoir or nebulizer cup on the machine.


• Connect the nebulizer to the face mask or mouthpiece.


• Use the face mask or mouthpiece to breathe in the medicine.


• Use the nebulizer for about 5 to 15 minutes, or until the medicine in the nebulizer cup is gone.


• Clean all the parts of the nebulizer after each use.

The albuterol inhalation aerosol (e.g., Proair® HFA) is used with a special inhaler that comes with patient instructions. Read the directions carefully before using this medicine. If you or your child do not understand the directions or are not sure how to use the inhaler, ask your doctor to show you what to do. Also, ask your doctor to check you or your child on a regular basis to make sure you are using it properly.

To use the aerosol inhaler:

• The inhaler should be at room temperature before you use it.


• Insert the metal canister firmly and fully into the clear end of the Proair® HFA mouthpiece. This mouthpiece should not be used with other inhaled medicines.


• Remove the cap and look at the mouthpiece to make sure it is clean.


• Shake the inhaler well and test spray it in the air 3 times before using it for the first time or if the inhaler has not been used for more than 2 weeks.


• To inhale this medicine, breathe out fully, trying to get as much air out of the lungs as possible. Put the mouthpiece just in front of your mouth with the canister upright.


• Open your mouth and breathe in slowly and deeply (like yawning), and at the same time firmly press down once on the top of the canister.


• Hold your breath for about 10 seconds, then breathe out slowly.


• If you are supposed to use more than one puff, wait 1 minute before inhaling the second puff. Repeat these steps for the second puff, starting with shaking the inhaler.


• When you have finished all of your doses, rinse your mouth with water and spit the water out.


• Clean the inhaler mouthpiece at least once a week with warm running water for 30 seconds, and dry it completely.


• If you need to use the inhaler before it is completely dry, shake off the excess water, replace the canister, and spray it 2 times in the air away from the face. Use your regular dose.


• After using the inhaler, wash the mouthpiece again and dry it completely.


• If the mouthpiece becomes blocked, washing it will help.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For inhalation aerosol dosage form (inhaler):
  
  • For preventing bronchospasm:
    
    • Adults, teenagers, and children 4 years of age and older—Two puffs every 4 to 6 hours as needed.
    
    
    • Children younger than 4 years of age—Use and dose must be determined by your child's doctor.
    
    
  
  
  • For preventing exercise-induced bronchospasm:
    
    • Adults, teenagers, and children 4 years of age and older—Two puffs taken 15 to 30 minutes before exercise.
    
    
    • Children younger than 4 years of age—Use and dose must be determined by your child's doctor.
    
    
  
  


• For inhalation solution dosage form (used with a nebulizer):
  
  • For preventing bronchospasm:
    
    • Adults and children older than 12 years of age—2.5 milligrams (mg) in the nebulizer 3 or 4 times per day as needed.
    
    
    • Children 2 to 12 years of age—0.63 to 1.25 mg in the nebulizer 3 or 4 times per day as needed.
    
    
    • Children younger than 2 years of age—Use and dose must be determined by your child's doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the canister at room temperature, away from heat and direct light. Do not freeze. Do not keep this medicine inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.

Keep the medicine in the foil pouch until you are ready to use it. Store at room temperature, away from heat and direct light. Do not freeze.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using Ventolin

It is very important that your doctor check the progress of you or your child at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

This medicine should not be used together with other inhaled medicines that are similar, such as isoproterenol (Isuprel®), levalbuterol (Xopenex™), metaproterenol (Alupent®), pirbuterol (Maxair®), or terbutaline (Brethaire®).

This medicine may cause paradoxical bronchospasm, which means your breathing or wheezing will get worse. Paradoxical bronchospasm may be life-threatening. Stop using this medicine and check with your doctor right away if you or your child have coughing, difficulty breathing, shortness of breath, or wheezing after using this medicine.

Talk to your doctor or get medical help right away if:

• Your symptoms do not improve or they become worse after using this medicine.


• Your inhaler does not seem to be working as well as usual and you need to use it more often.

You or your child may also be taking an antiinflammatory medicine, such as a steroid (cortisone-like medicine), together with this medicine. Do not stop taking the antiinflammatory medicine, even if your asthma seems better, unless you are told to do so by your doctor.

Albuterol may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Stop using this medicine and check with your doctor right away if you or your child develop a skin rash, hives, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Hypokalemia (low potassium in the blood) may occur while you are using this medicine. Check with your doctor right away if you or your child have more than one of the following symptoms: convulsions; decreased urine; dry mouth; increased thirst; irregular heartbeat; loss of appetite; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in the hands, feet, or lips; shortness of breath; or unusual tiredness or weakness.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, and herbal or vitamin supplements.

Ventolin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Fast, irregular, pounding, or racing heartbeat or pulse


• shakiness in the legs, arms, hands, or feet


• trembling or shaking of the hands or feet

Less common

• Abdominal or stomach pain


• bladder pain


• bloody or cloudy urine


• chest discomfort


• chest pain


• cough or hoarseness


• cough producing mucus


• diarrhea


• difficult or labored breathing


• difficulty with swallowing


• dizziness


• feeling of warmth


• fever or chills


• frequent urge to urinate


• hives


• itching


• loss of appetite


• lower back or side pain


• nausea


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• redness of the face, neck, arms, and occasionally, upper chest


• runny nose


• shortness of breath


• skin rash


• sore throat


• swollen, painful, or tender lymph glands in the neck, armpit, or groin


• tightness in the chest


• unusual tiredness or weakness


• weakness


• wheezing

Rare

• Hives or welts


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• noisy breathing


• redness of the skin


• swelling of the mouth or throat


• trouble breathing

Incidence not known

• Agitation


• anxiety


• arm, back, or jaw pain


• chest tightness or heaviness


• confusion


• convulsions


• decreased urine


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• drowsiness


• dry mouth


• extra heartbeats


• fainting


• flushed, dry skin


• fruit-like breath odor


• hallucinations


• headache


• increased hunger


• increased thirst


• increased urination


• irritability


• lightheadedness


• muscle pain or cramps


• nervousness


• nightmares


• numbness or tingling in the hands, feet, or lips


• pounding in the ears


• rapid, deep breathing


• restlessness


• shakiness


• slow or fast heartbeat


• stomach cramps


• sweating


• unexplained weight loss


• unusual feeling of excitement


• vomiting

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

More common

• Body aches or pain


• congestion


• fever


• runny nose


• tender, swollen glands in the neck


• trouble with swallowing


• voice changes

Less common

• Difficult, burning, or painful urination


• earache


• headache, severe and throbbing


• muscle or bone pain


• pain


• redness of the skin


• redness or swelling in the ear


• redness, swelling, or soreness of the tongue


• sleeplessness


• sneezing


• stuffy nose


• swelling


• tenderness


• trouble in holding or releasing urine


• trouble sleeping


• unable to sleep


• warmth on the skin

Rare

• Sleepiness or unusual drowsiness

Incidence not known

• Bad, unusual, or unpleasant (after) taste


• change in taste


• feeling of constant movement of self or surroundings


• gagging


• rough, scratchy sound to voice


• sensation of spinning


• tightness in the throat

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Ventolin Inhalation side effects (in more detail)

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