Wellferon (Interferon alpha-n1 (Ins))

WELLFERON®

Glaxo Wellcome

Interferon alpha-n1 (Ins)

Biological Response Modifier

Action And Clinical Pharmacology: Wellferon is a highly purified blend of natural human alpha interferons, obtained from human lymphoblastoid cells following induction with Sendai virus. Wellferon resembles human leukocyte interferon in that it is a mixture of natural alpha subtypes but differs in that these are present in different proportions. It also differs from recombinant alpha interferon preparations made from bacteria or other host cells, which contain only a single subtype.

The mechanism by which the alpha interferons achieve their antitumor effect is unknown. The alpha interferons have an antiproliferative effect on both normal and malignant cells. It can be shown in vitro that they inhibit cell replication; a dose response effect can also be shown in in vivo (animal) and in vitro models. Following removal of interferon from the cellular environment, normal cell replication again resumes. If inhibition of cell replication is an important antitumor mechanism of action, it would be mandatory to achieve a chronic steady state of circulating interferon activity; the daily administration of doses of 1 to 3 Mu/minduces such a steady state. Larger doses induce higher levels but whether this is clinically beneficial has not been determined.

The mode of action of alpha-interferon in the treatment of chronic hepatitis B and chronic hepatitis C (NonA NonB) infection is poorly understood, but seems to consist of both a direct antiviral effect and immune-modulatory actions.

Interferon alpha-n1 (Ins) has been administered to patients with a variety of malignancies at doses of 0.1 to 50 Mu/mby i.m., s.c. and i.v. routes and at doses up to 200 Mu/mby 24 hour infusion. Serum pharmacokinetic analyses have been studied systematically in 2 of these trials and, within the limits of the idiosyncrasies inherent in individual bioassay systems and the difference noted in individual subjects, provide the basis for this analysis of the pharmacodynamics of drug therapy.

In the very few patients examined, there has been little CSF activity demonstrable following either i.m. or i.v. administration.

The alpha interferons (presumably also Wellferon) are catabolized by renal tubular cells and essentially all of the interferon appearing in the glomerular ultrafiltrate is removed during passage through the renal tubules. The clearance of serum interferon activity parallels the glomerular filtration rate, being cleared at a rate, under normal circumstances of 100 mL/min.

Indications And Clinical Uses: REG>: For the treatment of patients with hairy cell leukemia, juvenile laryngeal papillomatosis, condylomata acuminata, chronic hepatitis B and chronic hepatitis C infections.

Hairy Cell Leukemia: Hairy cell leukemia (HCL) is a rare disease of variable course. Approximately 10 to 20% of HCL patients never require therapy. These are usually older patients without splenomegaly and granulocyte counts above 1 000 cells/mm The remaining 80 to 90% of the patients will require therapy during the course of their disease. It is a leukemia usually refractory to therapies conventionally given for malignant disease. Splenectomy frequently induces temporary remissions in patients who present with splenomegaly and pancytopenia. Subsequent relapse almost invariably follows and prognosis is then poor. The overall median survival of HCL patients is only 50 months and 40% of them die within 2 years of diagnosis.

Recent experience with interferon suggests it may have a major impact on the disease. Quesada, using 3 mega units (1 Mu=1 million units)/day of Cantell alpha interferon, reported substantial clinical improvement in 20 of 20 patients.

Infections occurred frequently in many patients prior to therapy. Thereafter they were uncommon, occurring usually during the first month or two of treatment. General well-being and performance status rose as hematological parameters improved in the majority of patients.

Febrile episodes and flu-like side effects were frequently seen at the start of treatment but were mostly mild thereafter. Fatigue was the commonest side effect during prolonged treatment but was usually not severe. Serious adverse reactions were extremely rare. Overall, severe side effects were experienced on only 6% of all patient treatment-days, over half of which were completely free from side effects. These became less common as treatment progressed.

Juvenile Laryngeal Papillomatosis: Juvenile laryngeal papillomatosis is an uncommon disease which is usually characterized by frequently persistent regrowth of benign papillomata in the epithelium of the respiratory tract. It is a widespread disease and the threat of airway obstruction frequently necessitates surgical intervention with usually good short-term results. The human papilloma viral etiology of this disease has been well documented by several investigators.

A multicentre, controlled trial of interferon alpha-n1 (lns) at 5 Mu/mdaily for 28 doses followed by a maintenance dosage 3 times weekly for 5 months was carried out in 66 patients including adults and children greater than 1 year of age. Disease measurements and clinical severity were significantly reduced by interferon alpha-n1 (lns).

Condylomata Acuminata: Condylomata acuminata, or genital warts, are considered by most investigators to be sexually transmitted lesions and associated with certain types of human papilloma viruses. These warty, benign neoplasms are contagious and approximately 70% of sexual partners have or develop lesions. It is estimated that 1 to 10% of women in the US of childbearing age have genital warts.

The spontaneous regression of condylomata acuminata has been well known but poorly understood. Up to one-third of primary genital warts have regressed within 6 months, but the remaining two-thirds may grow in size or spread to other anatomical sites. Many forms of therapy over the years have produced mixed results. Such therapies as topical podophyllin, antimetabolites, cautery, cryotherapy and surgery have all presented varying degrees of success along with painful experiences and leave some scar tissue. More recently preliminary studies followed by more controlled studies on the use of various interferons have indicated that interferon alpha-n1 (lns) could be an active and safe and helpful therapeutic agent in the treatment of this condition. Complete or partial response was observed in 70 to 80% of 176 women evaluated at 7 weeks of treatment; similar rate of response was observed in 62 women followed up to 11 weeks. During a 6 month evaluation of 30 patients (23 women and 7 men) 20 individuals (67%) retained complete or partial response. Longer follow-up observation will be necessary to fully evaluate the therapeutic potential of interferon alpha-n1 (lns). Studies of interferon alpha-n1 (lns) as an adjunct to laser surgery also merit further study.

Chronic Hepatitis B: Hepatitis B infection, acquired through contact with blood or other body fluids from a person carrying the hepatitis B virus (HBV), is prevalent at rates that vary worldwide. The severity of the overt acute clinical attack varies and appears to be inversely related to subsequent development of the chronic carrier stage, which is defined as the persistence of hepatitis B surface antigen (HBsAg) beyond 6 months from the onset of infection. In patients with chronic active hepatitis (CAH) disease progression is observed in 20 to 70% over a 2-year to 7-year period with an estimated mortality of 25 to 50%. The high proportion of chronic carriers of HBV who give no history of an acute hepatitis attack indicates that subclinical episodes are frequent.

The effect of interferon alpha-n1 (Ins) regimens of 3 months or more on the serological, biochemical and histological manifestations of the disease have been clearly demonstrated. A treated patient is more than 3 times as likely to be clear of HBeAg at 1 year. In excess of around one third of patients treated with interferon alpha-n1 (Ins) clear HBeAg at 1 year. This will be accompanied by biochemical and histological remission.

Recent experience with interferon for the treatment of chronic hepatitis B suggests that interferon alpha-n1 (Ins) has shown a significant increase in the HBeAg seroconversion rate using prednisolone pretreatment.

Chronic Hepatitis C: Hepatitis C virus (HCV) is a common cause of acute and chronic hepatitis, both post-transfusional and sporadic. HCV infection has a high tendency to chronicity. In 40 to 50% of patients with post-transfusion hepatitis, the infection becomes chronic, and in 20% of these cases the disease progresses to cirrhosis. There is also a high proportion of HCV-related cases of hepatocellular carcinoma. At all stages of the disease, ALT levels are characteristically elevated above the normal range, consistent with hepatocyte damage, and usually fluctuate. Insidious evolution of chronic hepatitis C to cirrhosis is emerging as a consistent observation, even though patients may be asymptomatic and have only marginal elevations of aminotransferase levels.

Clinical experience shows that interferon alpha-n1 (lns) therapy can result in an ALT response at the end of treatment in up to 50% of patients. Approximately half of these patients will maintain a sustained ALT response, post-treatment.

Almost 50% of HCV infected patients treated with interferon alpha-n1 (lns) show sustained improvement in liver inflammation on histological examination.

Interferon alpha-n1 (lns) is indicated for the treatment of patients with chronic hepatitis C (NonA NonB) infection. Efficacy has been established on the basis of normalization of serum aminotransferases, clearance of serum HCV RNA and by improvements in liver histology.

Contra-Indications: Should not be given to patients known to be hypersensitive to the preparation or any of its components.

Other than known hypersensitivity, there are no contraindications to the use of interferon alpha-n1 (Ins) injection, in hairy cell leukemia, condylomata acuminata or juvenile laryngeal papillomatosis. However, extreme caution is advised when treating patients with concurrent hepatic, renal, cardiovascular or CNS disease or with a history of pre-existing mental disturbance. Care should be exercised in patients with asthma as exacerbation of the disease has been reported on isolated occasions following interferon administration.

Interferon alpha-n1 (Ins) should not be used to treat chronic hepatitis B infection in patients who have poor hepatic reserve, since successful elimination of serological markers of active viral replication is often preceded by an acute, hepatitis-like illness.

For chronic hepatitis C infection, the following contraindications exist: severe pre-existing cardiac disease, severe renal or hepatic dysfunction, epilepsy and/or compromised CNS function, chronic hepatitis with advanced decompensated cirrhosis of the liver, and chronic hepatitis in patients who are being or have recently been treated with immunosuppressive agents excluding short-term “steroid withdrawal”.

Extreme caution is advised when using alpha interferons in the treatment of patients with concurrent hepatic, renal, cardiovascular or CNS disease, or patients with a history of pre-existing mental disturbances.

Suicidal behavior has been observed rarely in patients receiving alpha-interferons. Therapy should be discontinued in patients exhibiting or at risk of suicidal behavior.

Care should be exercised in patients with asthma as exacerbation of the disease has been reported on isolated occasions following interferon administration.

It is important to monitor the blood count closely in patients during the first 6 weeks of treatment, following which the suppressive effects of alpha interferons on the bone marrow will be overtaken by the improving leukemic state, leading towards a normalization of hematological parameters.

During treatment of chronic hepatitis B and chronic hepatitis C (NonA NonB) infection, it is important to monitor blood count and liver function throughout treatment.

For those patients being considered for prednisolone pretreatment therapy, the physician should refer to the precautions and warnings section of the prednisolone prescribing information for a description of the known prednisolone precautions and warnings.

Pregnancy: No information is available on the use of interferon alpha-n1 (lns) in human pregnancy. In view of the profound effects of the drug on human metabolism and physiology, interferon alpha-n1 (lns) should be considered as a drug which might result in damage to the fetus and patients should therefore be advised accordingly. The expected clinical benefit of treatment to the patient must be balanced against any possible hazard to the developing fetus.

In view of the long clinical course of chronic hepatitis B infection and the availability of hepatitis B immunization for the neonate, use of interferon alpha-n1 (Ins) to treat chronic hepatitis B infection during pregnancy is not recommended.

Lactation: There is no information on the effect of the drug on human lactation.

Children: The safety and effectiveness of interferon alpha-n1 (lns) in patients under 18 years of age have not been established in the treatment of hairy cell leukemia, Condylomata acuminata or chronic hepatitis C infections.

Interferon alpha-n1 (lns) is well tolerated in children in the treatment of chronic hepatitis B infection and 2 recent treatment vs no treatment studies, efficacy was demonstrated. In contrast to use in adults, steroid pretreatment in children was not associated with increased efficacy.

Geriatrics: Elderly patients may be less tolerant of the side effects of interferon, particularly those effects which are cumulative. These patients should be seen frequently while receiving treatment; interferon alpha-n1 (lns) dosage should be reduced or even stopped if patients are unduly sensitive to side effects.

Drug Interactions: Alpha interferons may alter the activity of certain enzymes. In particular, they reduce the activity of P450 cytochromes. The metabolism of drugs such as cimetidine, phenytoin, warfarin, theophylline, diazepam and propranolol by these enzyme systems may therefore be impaired in patients receiving alpha interferons. Several cytotoxic drugs e.g., cyclophosphamide, are also metabolized by these enzymes.

Progressive renal failure has been reported in patients receiving concurrent high dose acyclovir. Concurrent administration of interferon with drugs which act on the CNS has occasionally resulted in unexpectedly severe changes in mental state. Concurrent administration of interferon with drugs which act on the CNS has occasionally resulted in unexpectedly severe changes in mental state.

Concurrent administration of immunosuppressive drugs (including corticosteroids), which may enhance viral replication, should be avoided during treatment of chronic hepatitis B infection with interferon alpha-n1 (Ins). Although concurrent use of prednisolone and interferon alpha-n1 (Ins) is not recommended, prednisolone pretreatment is permitted for the hepatitis B indication (see Dosage).

In the treatment of chronic hepatitis B infection, the occurence of an acute, hepatitis-like illness (see Contraindications) presents the theoretical risk of additive interaction with hepatotoxic drugs and of further impairment of hepatic drug metabolism.

Information to Be Provided to the Patient: Because of the possibility of severe or even fatal adverse reactions to interferon therapy, patients should be informed not only of the benefits but also of the potential risks of treatment with interferon alpha-n1 (lns). Patients should also be advised that the clinical activity of different brands of interferon may not be comparable and that different brands of interferon should not be used in a single-treatment regimen.

When patients are advised by their physicians to administer interferon alpha-n1 (lns) by self-injection, adequate instruction in s.c. administration practices should be provided. Patients should be cautioned against reusing syringes and needles. If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed on needle, syringe, and container disposal procedures and should be advised of the importance of following correct disposal procedures.

Patients should be advised that anti-inflammatory analgesics (e.g., acetaminophen and ibuprofen) may alleviate some of the discomforts associated with initial treatment with interferon alpha-n1 (lns). Patients receiving interferon alpha-n1 (lns) should also be advised to stay well hydrated, especially during the initial stages of treatment.

Adverse Reactions: Interferon alpha-n1 (Ins) is a highly active mediator of biological events and its use may be associated with severe side effects, particularly when large doses are administered.

The most frequently reported side effects of interferon alpha-n1 (lns) and other alpha interferon preparations consist of fever, chills, occasionally rigors, headache, malaise and myalgia, all reminiscent of an attack of influenza. These acute side effects can usually be reduced or eliminated by concurrent administration of acetaminophen and tend to diminish with continuing therapy. In contrast however, continuing therapy can lead to lethargy, weakness, arthralgia and fatigue accompanied by anorexia and weight loss.

Alpha interferons have a suppressive effect on the bone marrow leading to a fall in the white blood count, particularly the granulocytes, the platelet count and, less commonly, the hemoglobin concentration. Additionally, abnormalities in the blood clotting mechanism have occurred. These effects can lead to an increased risk of infection, hemorrhage and thrombosis.

Marked effects on the CNS may occur; these include abnormal EEGs with excess slow wave activity, severe depression including rarely suicidal behavior, confusion, apathy and coma. Occasionally seizures occur which may be precipitated by fever in children. A few reports of movement disorders (including extrapyramidal and cerebellar dysfunction) have been reported in cancer patients receiving interferon alpha-n1 (lns).

The administration of alpha interferons may give rise to hypotension, hypertension, or arrhythmias in certain individuals. Severe cardiovascular events reported in patients receiving alpha interferons include myocardial infarction, cerebrovascular accident and peripheral ischemia. Nausea, vomiting and diarrhea occur sporadically.

Alpha interferons can lead to an elevation in liver-related enzymes; this is usually transient but occasionally is marked and persistent. Hepatic necrosis has been reported on very rare occasions.

Rare occurrences of renal failure and/or nephrotic syndrome have been seen in patients treated with interferon alpha-n1 (lns). These patients had all been suffering from myelomatosis and had varying degrees of prior renal dysfunction.

After repeated very high doses (100 to 200 Mu) i.v. by infusion, hypocalcemia and hyperkalemia have occurred.

Reactions at injection sites have been reported in some patients, and alopecia occurs occasionally as a late side effect.

Other events which have been reported in patients receiving alpha interferons include late development of lymphomas, Raynaud’s phenomenon, urticaria, erythema nodosum, skin rashes, mucositis and isolated peripheral nerve defects and disturbances of antidiuretic hormone levels.

Isolated cases of various autoimmune phenomena e.g., immune thrombocytopenia, hemolytic anemia, hypothyroidism, diabetes mellitus have occurred following alpha-interferon administration. In some patients with pre-existing autoimmune phenomena, isolated cases of exacerbations have been seen.

Adverse Reactions with Prednisolone Pretreatment: Information regarding the adverse events associated with prednisolone pretreatment therapy is limited. Physicians should refer to the data sheet for prednisolone for a description of known prednisolone-associated adverse reactions.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are no reports of overdose but repeated large doses of interferon are associated with profound lethargy, fatigue, prostration and coma. Such patients should be hospitalized for observation and given appropriate supportive treatment. tag_DosageDosage

Dosage And Administration: Hairy Cell Leukemia: For remission induction, the dose recommended is 3 Mu given daily by i.m. injection. The s.c. route has also been used successfully and has been found to be more convenient for patient self-administration.

After normalization or marked improvement in peripheral hematological indices (commonly 12 to 16 weeks), the dose may be administered 3 times weekly, during which time further improvement in the bone marrow is to be anticipated. Prolonged treatment for 6 months or more may be required to clear hairy cells from the bone marrow.

Hematological recovery is to be expected in patients who have failed splenectomy as well as in those with palpable splenomegaly in whom reduction in spleen size is to be anticipated.

Juvenile Laryngeal Papillomatosis: Adjunctive therapy with interferon alpha-n1 (Ins) injection, is recommended only with routine surgical management. Some very severely affected patients requiring surgery every 1 to 4 months may not respond to interferon alpha-n1 (Ins) even on prolonged treatment, but treatment up to and beyond 1 year has been reported to show continued improvement. Careful clinical and periodic endoscopic evaluation of disease should continue.

Respiratory papillomatosis requires extended treatment; maximum response usually occurs within 6 months, but more prolonged therapy might be required. Doses for children greater than 1 year of age can be estimated from Table I.

Interferon alpha-n1 (Ins) should be administered i.m., daily for 28 days followed by a maintenance dosage 3 times weekly for at least 6 months.

Condylomata Acuminata: An initial dose of 1 to 3 Mu/m(5 Mu) 5 times a week for 2 weeks, followed by 3 times a week for 4 weeks, s.c. It can also be administered i.m. but the s.c. route has been used successfully and has been found to be more convenient for patients’ self-administration. The same dose should then be continued every other day or 3 times weekly for 1 month. As an adjunct to laser surgery or cryosurgery, 1 Mu/mshould be administered daily for 7 days prior to and 7 days following surgical resection of the lesions.

Alternatively, dosing levels may be adjusted to suit an individual’s tolerability. However, daily dosing levels above 5 Mu/mare not recommended for condylomata acuminata patients.

If dose reductions are required due to intolerance, doses as low as 1 Mu/mmay be effective if a similar cumulative dose to that given by the 5 Mu regimen is achieved over longer periods.

Chronic Hepatitis B Infection: A 12-week course of 3 times weekly i.m. or s.c. injections of 10 to 15 Mu (up to 7.5 Mu/mbody surface area) is generally recommended.

Longer periods of treatment for up to 6 months at lower doses of 5 to 10 Mu (up to 5 Mu/mbody surface area) 3 times weekly have been employed and may be preferred for patients who do not tolerate higher doses.

An initial treatment period, employing escalating daily doses usually over 5 days (but up to 28 days with the longer treatment) may be a convenient way of introducing therapy.

Interferon alpha-n1 (Ins) has shown a significant increase in the HBeAg seroconversion rate using prednisolone pretreatment. A tapering prednisolone dose of 0.6 mg/kg/day for 2 weeks, 0.45 mg/kg/day for 1 week and 0.25 mg/kg/day for 1 week is recommended. This is followed by a 2 week no treatment period, prior to the administration of a 12-week course of 3 times weekly i.m. or s.c. injection of 10 Mu interferon alpha-n1 (Ins).

Immunosuppressed Patients: Efficacy against hepatitis B virus infection has not yet been demonstrated in patients whose immune systems are compromised (e.g., by current or recent therapy with immunosuppressive drugs (excluding short-term steroid pretreatment) or due to human immunodeficiency virus (HIV) infection).

Chronic Hepatitis C Infection: A 48-week course of 3 times weekly i.m. or s.c. injections of 5 MU is recommended. For patients who are unable to tolerate this dose, a 3 times weekly injection of 3 MU for the remainder of the 48-week period may be more appropriate. The s.c. route being more acceptable and convenient for patient self administration.

General Administration: Some patients appear to be less troubled by interferon-related side effects if the dose is administered in the evening.

Children: No information is available on the treatment of hairy cell leukemia in children, although preliminary clinical evidence shows that, interferon alpha-n1 (Ins), is tolerated in other childhood conditions.

In the rare event of hairy cell leukemia occurring in children, proportions of the adult dose based on body surface area would be appropriate.

Interferon alpha-n1 (lns) is well tolerated in children in the treatment of chronic hepatitis B infection, dosages of up to 10 Mu/mbody surface area have been administered. An efficacy advantage of treatment vs no treatment has been demonstrated in 2 recent studies, but no advantage of steroid pretreatment was demonstrated in this resistant group of patients.

Geriatrics: Elderly patients may be less tolerant of the side effects of interferon, particularly those effects which are cumulative. These patients should be seen frequently while receiving treatment; interferon alpha-n1 (lns) dosage should be reduced or even stopped if patients are unduly sensitive to side effects.

Availability And Storage: Each vial of clear, colorless solution contains: interferon alpha-n1 (lns) [purified human lymphoblastoid interferon] 3, 5 or 10 mega units. 1 mega unit (Mu)=1´10International Units (IU) of lymphoblastoid interferon. Formulated in 1 mL tris-glycine buffered normal saline with human albumin at a concentration of 1.5 mg/mL as a stabilizer. The final product contains Namalwa cell DNA
Store between 2 to 8°C. Protect from light. The injection contains no preservative. Discard any partly used vials immediately after withdrawal of the required dose. One mL vials of 3, 5 and 10 Mu/mL.

WELLFERON® Glaxo Wellcome Interferon alpha-n1 (Ins) Biological Response Modifier

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