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1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

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Amedeo Influenza





Zanamivir

Bernd Sebastian Kamps and Christian Hoffmann


(Green links: Free full-text articles)

Introduction

Zanamivir is an orally inhaled powder currently approved in 19 countries for the treatment of, and in two for the prophylaxis of influenza A and B. Zanamivir is a competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza viruses. It closely mimics sialic acid, the natural substrate of the neuraminidase (Varghese 1992, Varghese 1995).

Zanamivir is administered via inhalation, resulting in direct delivery to the respiratory tract, where the concentration has been calculated to be more than 1,000 times as high as the IC50 for neuraminidase. The inhibitory effect starts within 10 seconds.

When systemic involvement of influenza infection is suspected - as has recently been suggested by some reports on avian H5N1 influenza in humans (de Jong 2005) - zanamivir might not be the suitable drug.

Over the last few years, a number of events have resulted in changes to the zanamivir prescribing information which now contains warnings of bronchospasm, dyspnoea, rash, urticaria and allergic type reactions, including facial and oropharyngeal oedema. However, apart from these rare episodes, the drug has a good safety profile if begun early (Hayden 1997).

Co-administration of orally inhaled zanamivir with inactivated trivalent influenza vaccine does not seem to adversely affect the production of antihaemagglutinin antibodies (Webster 1999); a protective antibody response develops within 12 days (Cox 2001).

 

Structure

The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-en onic acid. It has the following structural formula:

 

Pharmacokinetics

Data on orally inhaled zanamivir indicate that 10-20 % of the active compound reaches the lungs. The rest is deposited in the oropharynx and approximately 4 % to 17 % of the inhaled dose is systemically absorbed. The peak serum concentrations are reached within 1 to 2 hours following a 10 mg dose. Plasma protein binding is limited (< 10 %). Zanamivir is excreted unchanged in the urine with the excretion of a single dose completed within 24 hours (Cass 1999b). The serum half-life of zanamivir after administration by oral inhalation ranges from 2.5 to 5.1 hours.

Studies have demonstrated that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation (Calfee 1999).

Toxicity

Zanamivir has a good safety profile and the overall risk of occurrence of any respiratory event is low (Loughlin 2002). Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use (Freund 1999).

Recommended dosages of zanamivir usually do not adversely affect pulmonary function in patients with respiratory disorders. However, in some patients, bronchospasm and a decline in lung function (FEV1 or peak expiratory flow) have been reported after usage of zanamivir. In most cases, these patients had underlying pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Because of the risk of serious adverse events, zanamivir is not generally recommended for the treatment of patients with underlying airways disease. Zanamivir should also be discontinued in patients who develop bronchospasm or who have a decline in respiratory function. If symptoms are severe, immediate treatment and hospitalisation may be required.

Allergic reactions, including oropharyngeal oedema and serious skin rashes may rarely occur during treatment with zanamivir. In these cases, the drug should be stopped and appropriate treatment instituted.

The frequency of other side effects has been reported to be roughly identical in both treatment and placebo groups: diarrhoea, nausea, dizziness, headaches, less frequently malaise, abdominal pain, and urticaria occurred at similar frequencies and could be related to lactose vehicle inhalation. The most frequent laboratory abnormalities in Phase 3 treatment studies included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness (Relenza 2003).

However, in children aged 5 to 12 years, nasal signs and symptoms (zanamivir 20 %, placebo 9 %), cough (zanamivir 16 %, placebo 8 %), and throat/tonsil discomfort and pain (zanamivir 11 %, placebo 6 %) were reported more frequently with zanamivir than placebo. In a subset with chronic respiratory disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 out of 7 zanamivir recipients and 5 out of 12 placebo recipients.

The following adverse reactions have been identified during post-marketing use of zanamivir, but it is not possible to reliably estimate their frequency or establish a cause relationship to zanamivir exposure (Relenza 2003):

  • Allergic or allergic-like reaction, including oropharyngeal oedema.
  • Arrhythmias, syncope.
  • Seizures.
  • Bronchospasm, dyspnoea

Zanamivir has not been studied in pregnant women. In animal studies, zanamivir has not been shown to cause birth defects or other problems.

In rats, zanamivir is excreted in milk, but zanamivir has not been studied in nursing mothers and there is no information as to the possible excretion of zanamivir in human milk.

Efficacy

Inhaled zanamivir reduces the median time to alleviation of major influenza symptoms by up to 2.5 days if taken within 48 h of symptom onset. These benefits appear to be particularly marked in severely ill patients and in individuals ≥ 50 years of age, who have underlying illnesses, or who are considered high risk. Patients with a lower temperature or less severe symptoms appear to derive less benefit from treatment with zanamivir.

When used for prophylaxis, zanamivir significantly reduces the number of families with new cases of influenza compared with placebo, and prevented new cases of influenza in long-term care facilities.

Treatment

The first clinical experience with zanamivir included patients from separate randomised, double-blind studies in 38 centres in North America and 32 centres in Europe in 1994-1995. These studies demonstrated approximately a one-day reduction in the time to alleviation of symptoms in treated patients (4 vs. 5 days) (Hayden 1997). An even larger treatment benefit (3 days) was seen in patients who had severe symptoms at entry (Monto 1999). A 3 day treatment benefit was also observed in patients aged > 50 years, compared with 1 day in patients aged < 50 years. In "high-risk" patients there was a treatment benefit of 2.5 days (Monto 1999). In addition, zanamivir has been shown to be effective in patients at risk of developing influenza-related complications such as age ≥ 65 years and the presence of underlying chronic disease including asthma, chronic obstructive pulmonary disease, cardiovascular disease, diabetes mellitus, and immunocompromise (Lalezari 2001).

Influenza infections may lead to respiratory tract complications that result in antibiotic treatment. A meta-analysis of 7 clinical trials reported that 17 % of placebo recipients developed a respiratory event leading to antibiotic use, mainly for acute bronchitis or acute sinusitis, whereas among zanamivir-treated patients the incidence of respiratory events leading to the use of antimicrobials was 11 % (Kaiser 2000b). However, these finding have not remained unquestioned. In the setting of a large managed care plan (> 2,300 patients treated), the patterns of influenza complications were found to be similar in zanamivir-treated and untreated patients (Cole 2002).

Prophylaxis

A series of randomised trials have proven the efficacy of zanamivir in the prevention of influenza. In a study involving healthy adults, 10 mg once a day or placebo was administered by oral inhalation at the start of the influenza outbreak. Prophylaxis continued for a 4-week period. Zanamivir was 67 % efficacious in preventing clinical influenza (6 % [34/554] clinical influenza in the placebo group vs. 2 % [11/553] in the zanamivir group) and 84 % efficacious in preventing illnesses with fever (Monto 1999b).

Another clinical trial enrolled families with two to five members and at least one child who was five years of age or older. As soon as an influenza-like illness developed in one family member, the family received either zanamivir (10 mg zanamivir inhaled once daily for 10 days) or placebo. In the zanamivir families, 4 % of families had at least one new influenza case, compared with 19 % in the placebo families. The median duration of symptoms was 2.5 days shorter in the zanamivir group than in the placebo group (5.0 vs. 7.5 days) (Hayden 2000). A similar risk reduction was shown in a study where zanamivir was administered after close contact with an index case of influenza-like illness (Kaiser 2000).

In a study of inhaled zanamivir for the prevention of influenza in families, 4 % of zanamivir versus 19 % of placebo households had at least 1 contact who developed symptomatic, laboratory-confirmed influenza (81 % protective efficacy). The protective efficacy was similarly high for individuals (82 %) and against both influenza types A and B (78 % and 85 %, respectively, for households) (Monto 2002).

Children

In a trial on children aged five to twelve years, zanamivir reduced the median time to symptom alleviation by 1.25 days compared with placebo. Zanamivir-treated patients returned to normal activities significantly faster and took significantly fewer relief medications than placebo-treated patients (Hedrick 2000).

Zanamivir is therefore safe in children - if they can take it. Children, especially those under 8 years old, are usually unable to use the delivery system for inhaled zanamivir appropriately (not producing measurable inspiratory flow through the diskhaler or producing peak inspiratory flow rates below the 60 l/min considered optimal for the device). As a lack of measurable flow rate is related to inadequate or frankly undetectable serum concentrations, prescribers should carefully evaluate the ability of young children to use the delivery system when considering prescription of zanamivir. When zanamivir is prescribed for children, it should be used only under adult supervision and with attention to proper use of the delivery system (Relenza 2003).

Special Situations

Special settings in which zanamivir has been used include acute lymphoblastic leukemia (Maeda 2002) and allogeneic stem cell transplantation (Johny 2002). The second report found no toxicity attributable to zanamivir and rapid resolution of influenza symptoms. There was no mortality due to influenza in these patients.

Avian Influenza Strains

In a study performed on mice in 2000, zanamivir was shown to be efficacious in treating avian influenza viruses H9N2, H6N1, and H5N1 transmissible to mammals (Leneva 2001).

Resistance

Development of resistance is rare. To date, no virus resistant to zanamivir has been isolated from immunocompetent individuals after treatment. In addition, all zanamivir-resistant strains selected in vitro to date have diminished viability. Known resistance mutations are both influenza virus subtype and drug specific (McKimm-Breschkin 2003).

There is evidence for different patterns of susceptibility and cross-resistance between neuraminidase inhibitors (Mishin 2005, Yen 2005), but no studies have so far evaluated the risk of emergence of cross-resistance in clinical practice.

Drug Interactions

Zanamivir is administered via inhalation and the low level of absorption of the drug results in low serum concentrations and modest systemic exposure to zanamivir after inhalation. Zanamivir is not metabolised, and the potential for clinically relevant drug-drug interactions is low (Cass 1999b). Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes (Relenza 2003). There is no theoretical basis for expecting metabolic interactions between zanamivir and other co-administered compounds (Daniel 1999).

Recommendations for Use

  • Zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza A and B viruses in adults and paediatric patients (EU: 12 years or older; US: 7 years and older) who have been symptomatic for no more than 2 days.
  • Zanamivir is not recommended for the treatment of patients with underlying airways disease (such as asthma or chronic obstructive pulmonary disease).

Zanamivir (Relenza®) is delivered by inhalation because of its low oral bioavailability. Each Relenza® Rotadisk contains 4 double-foil blisters and each blister contains 5 mg of zanamivir (plus 20 mg of lactose which contains milk proteins). The contents of each blister are inhaled using a plastic device called a "Diskhaler". Here, a blister is pierced and zanamivir is dispersed into the air stream when the patient inhales through the mouthpiece. The amount of drug delivered to the respiratory tract depends on patient factors such as inspiratory flow.

Patients should be instructed in the use of the delivery system, and instructions should include a demonstration - which may be difficult in daily medical practice. When prescribed for children, zanamivir should only be used under adult supervision and instruction.

There has been concern over the ability of elderly people to use the inhaling device for zanamivir. A study of 73 patients (aged 71 to 99 years) from wards providing acute elderly care in a large general hospital found that most elderly people could not use the inhaler device and that zanamivir treatment for elderly people with influenza was unlikely to be effective (Diggory 2001).

Dosage

The recommended dose of zanamivir for the treatment of influenza in adults and paediatric patients aged 7 years and older is 10 mg bid (= twice daily 2 consecutive inhalations of one 5-mg blister) for 5 days.

On the first day of treatment, two doses should be taken at least 2 hours apart. On the following days, doses should be taken about 12 hours apart.

No dosage adjustment is required in patients with renal impairment (Cass 1999a).

Patients with pulmonary dysfunction should always have a fast-acting bronchodilator available and discontinue zanamivir if respiratory difficulty develops.

 

Summary

Trade name: Relenza®

Drug class: Neuraminidase inhibitor.

Manufacturer: GlaxoSmithKline.

Indications: zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza A and B viruses in adults and paediatric patients (EU: 12 years or older; US: 7 years and older) who have been symptomatic for no more than 2 days.

Standard Dosage for Treatment: 10 mg bid (= twice daily 2 consecutive inhalations of one 5-mg blister) for 5 days.

Standard Dosage for Prophylaxis: in most countries, zanamivir has not been approved for prophylaxis.

Pharmacokinetics: 10 to 20 percent of the active compound reaches the lungs, the rest is deposited in the oropharynx. 4 % to 17 % of the inhaled dose is systemically absorbed. Peak serum concentrations are reached within 1 to 2 hours. Limited plasma protein binding (< 10 %). Excretion of the unchanged drug in the urine. Serum half-life after administration by oral inhalation is 2.5 to 5.1 hours.

Warning: zanamivir is not recommended for the treatment of patients with underlying airways disease (such as asthma or chronic obstructive pulmonary disease).

Interactions: no clinically significant pharmacokinetic drug interactions are predicted based on data from in vitro studies.

Side effects: zanamivir has a good safety profile and the overall risk for any respiratory event is low.

Patient information: the use of zanamivir for the treatment of influenza has not been shown to reduce the risk of transmission of influenza to others.

There is a risk of bronchospasm, especially in the setting of underlying airways disease, and patients should stop zanamivir and contact their physician if they experience increased respiratory symptoms during treatment such as worsening wheezing, shortness of breath, or other signs or symptoms of bronchospasm. A patient with asthma or chronic obstructive pulmonary disease must be made aware of the risks and should have a fast-acting bronchodilator available.

Patients scheduled to take inhaled bronchodilators at the same time as zanamivir should be advised to use their bronchodilators before taking zanamivir.

Store at 25 C (77 F); excursions permitted at 15 to 30 C (59 to 86 F).

Internet sources:

USA: http://influenzareport.com/link.php?id=5

 






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