Ravulizumab - Indication, Contraindications, Warnings, and Precautions

Overview:

Ravulizumab is a novel and promising therapeutic agent for dealing with atypical hemolytic uremic syndrome, which impairs kidney function by triggering the formation of small blood clots. The supreme authority responsible for drug regulation in the United States, the Food and Drug Administration (FDA), endorsed the usage of Ravulizumab for atypical hemolytic uremic syndrome on October 18, 2019. Currently, the generic drug formulation is being marketed under various brand names. In addition to its application in patients with atypical hemolytic uremic syndrome, it is conventionally advised for paroxysmal nocturnal hemoglobinuria (premature red blood cell rupture triggered by abnormal immune functions) and myasthenia gravis (collapsed muscle strength).

Drug Group:

Ravulizumab falls in the drug group of humanized monoclonal antibodies. These monoclonal antibodies are laboratory-synthesized proteins that mimic or resemble that of human antibodies. These animal-derived monoclonal antibodies are then subjected to humanization, which diminishes the potentiality for body reactions. Humanized monoclonal antibodies possess enhanced safety features without compromising the protein’s therapeutic efficacy.

Available Doses and Dosage Forms:

• Dosage Form: Ravulizumab is made available in solution form for infusion. Intravenous infusion, where the medicine is introduced directly into the person’s vein, is the preferred route for Ravulizumab dispensation.

• Available Doses: Ravulizumab is available in vials in three distinct concentrations for intravenous introduction. Three hundred milligrams (mg) per 30 milliliters (ml), 300 mg per 3 ml, and 1100 mg per 11 ml are the marketed dosages of Ravulizumab.

For Patients:

What Is Atypical Hemolytic Uremic Syndrome?

Atypical hemolytic uremic syndrome (aHUS) is a peculiar condition that disrupts kidney functioning and eventually precipitates kidney failure, where the organ fails to perform its routine functions. The abnormal functioning of the body’s immune system leads to the development of blood clots inside the blood vessels, where it is not intended to form clots. Thus, formed blood clots are denoted as intravascular blood clots. These blood clots can potentially clog the tiny blood vessels in vital organs like kidneys, thus checking blood flow and perfusion. It is often accompanied by thrombocytopenia (pronounced collapse in platelet count) and hemolytic anemia (collapsed red blood cell count induced by premature rupture of those cells). Atypical blood clot formation takes up active platelets in the blood, precipitating an appreciable decline in the platelets available in the circulating blood. This decline is projected in the form of thrombocytopenia. These blood clots clog and restrict the blood flow through the vessels, which forces the red blood cells to wedge through the tiny gap between the blood clot and the blood vessel's wall. This wedging often tears and ruptures the red cells, leading to premature lysis of the red cells and giving rise to hemolytic anemia.

It is a genetically influenced condition where the abnormal immune function is triggered by altered genetic makeup. Alteration in the CFH (complement factor H) gene is identified to be the most frequently encountered genetic association of atypical hemolytic uremic syndrome. These gene alterations favor exaggerated activation of certain immune pathways. Belly pain, urine with blood streaks, diarrhea, and puffy legs are some of the frequently encountered manifestations of atypical hemolytic uremic syndrome.

How Does Ravulizumab Work?

Ravulizumab is proven to be effective against atypical hemolytic uremic syndrome. Ravulizumab disrupts the complement pathway (the pathway that mediates immune response), which triggers an exaggerated immune response. The drug molecule attaches with a specific complement protein and thus impedes the progression of the cascade. Ravulizumab ends complement overactivation and hence is considered a complement inhibitor.

What Is the Dosage of Ravulizumab?

The concerned physician determines the dosage of Ravulizumab after considering the condition for which it is advised, the body weight of the patient, and the patient’s general health status. The dosage regimen consists of an initial loading dose and subsequent maintenance doses. After the loading dose, there should be a gap of 14 days to start with the maintenance dose. Maintenance doses must be repeated at a specific interval of four to eight weeks. The duration of Ravulizumab therapy and the time gap between subsequent maintenance doses are often determined by considering the patient’s body weight.

How Effective Is Ravulizumab?

Ravulizumab can produce prompt and prolonged complement inhibition, thus sustaining a sustained check on exaggerated complement-mediated immune function. More than 80 percent of the patients treated with Ravulizumab exhibited normalization in the blood profile, including platelet and red blood cell count. It elicited a drastic decline in blood clot formation. The efficacy and safety aspects of Ravulizumab proportionate with other standard therapies for atypical hemolytic uremic syndrome, like Eculizumab.

What Are the Things to Inform the Doctor Before Taking the Drug?

Proper communication with the doctor is imperative for the success of Ravulizumab therapy. Before initiating the therapy using Ravulizumab, it is obligatory to inform the doctor regarding the following information:

• Prior hypersensitivity encounters with Ravulizumab or other medicines of the complement inhibitors class need to be discussed with the doctor beforehand as it can pose the risk of triggering an aggravated allergic response upon subsequent encounters.

• The patient should also report any incidences of allergic response to any of the components present in the medicine solution.

• The doctor should be provided with a comprehensive medical history of the patient, encompassing all the illnesses and underlying medical conditions. In addition, if the patient has undergone any surgical interventions in the past, that should also be discussed with the doctor.

• Besides the medical history, the doctor should be informed about the patient's drug history. It should be comprehensive and elaborate, inclusive of herbal medicines, nonprescription medicines, and other dietary supplements, if any. A detailed drug history helps in identifying the potential risk of drug-to-drug interactions in the body, which allows the doctor to look for alternate medicine choices or dose modifications.

• The doctor should be aware of the patient’s pregnancy and lactation status. Undergoing pharmacological therapy during conception carries the risk of harm to the baby in the womb. Hence, the doctor should be informed about it beforehand. Likewise, the medicine can gain access to the breastfed baby’s body when administered to lactating mothers.

How Is Ravulizumab Administered?

Ravulizumab is marketed and distributed in single-dose vials enclosing the infusion liquid. Healthcare professionals do administration of intravenous Ravulizumab. However, the injection solution is also available in preloaded cartridges intended to be injected beneath the skin. The patient can administer preloaded cartridge forms (on-body delivery system) as per the instruction from the concerned doctor. The injection can be made in the stomach or the upper leg region. To achieve a full dose, two units of prefilled cartridges are required. The introduction of the medicine should be slow and steady, taking around ten minutes.

What Are the Side Effects of Ravulizumab?

Ravulizumab can potentially trigger certain adverse effects on the body. Some of the frequently reported side effects of Ravulizumab include the following:

• Infections involving the upper respiratory tract, like runny nose, cough, and sore throat, are the widely encountered side effects concerning Ravulizumab therapy.

• Headache, body pain, particularly in the arms and legs, and joint pain are also noted in Ravulizumab therapy.

• Gastrointestinal issues like diarrhea, compromised hunger, stomach pain, constipation, and vomiting are reported occasionally following the therapy.

• Skin issues like dryness, hair loss, severe tiredness, and giddiness are other less frequent side effects.

• Other alarming side effects are enhanced body temperature (pyrexia) and blood pressure. Pyrexia can manifest as a progressing infection in the body and needs to be thoroughly investigated.

Dietary Considerations:

No specific dietary guidelines need to be adhered to during Ravulizumab therapy. However, the medical condition of each patient is different. Hence, at times, the doctor may advise certain considerations in the dietary habits, taking into account the patient’s health status and concomitant medical conditions. In such cases, it is imperative to stick to the dietary instructions that the concerned doctors suggest.

Missed Dose:

The intravenous infusion of the medicine is done during an appointment with the doctor, except for the on-body delivery system, where the patient can deliver the medicine beneath the skin (subcutaneous). If the patient unintentionally misses one dose, either intravenous infusion or prefilled cartridge delivery, it should be discussed with the doctor immediately. The treatment regimen needs to proceed as per the doctor's instructions. No attempt should be made to take double the intended number of prefilled cartridges.

Overdose:

There is limited information available concerning the overdose issues of Ravulizumab, with zero reported cases. Ravulizumab overdose mandates immediate medical attention. Since the infusion is being carried out in the hospital settlement, immediate intervention is available.

Storage:

Refrigeration is recommended for the storage of Ravulizumab vials. These vials are often supplied in cartoons and can be refrigerated without extracting from their packaging. The cartoon offers protection to the vials from light. Two to eight degrees Celsius (36 to 46 degrees Fahrenheit) is ideal for storing Ravulizumab vials. Shaking and freezing the medicine can impact the drug’s effectiveness and hence is not advised.

For Doctors:

Indication:

• Atypical hemolytic uremic syndrome (for patients over one month of age to adult patients).

• Paroxysmal nocturnal hemoglobinuria (for patients over one month of age to adult patients).

• Generalized myasthenia gravis (tested positive for anti-acetylcholine receptor antibody).

Dose:

1. Body Weight in the Range of Five to Below 10 Kilograms:

• The recommended loading dose of Ravulizumab is 600 mg.

• A maintenance dose of 300 mg was administered at a dosing interval of four weeks.

2. Body Weight in the Range of 10 to Below 20 Kilograms:

• Loading dose of 600 mg.

• A maintenance dose of 300 mg is advised at a dosing interval of four weeks.

3. Body Weight in the Range of 20 to Below 30 Kilograms:

• 900 mg is the required loading dose.

• A higher maintenance dose of 2100 mg is advised at a dosing interval of eight weeks.

4. Body Weight in the Range of 30 to Below 40 Kilograms:

• 1200 mg is the recommended loading dose for this age range.

• A maintenance dose of 2700 mg needs to be administered at a dosing interval of eight weeks.

5. Body Weight in the Range of 40 to Below 60 Kilograms:

• 2400 mg is the recommended loading dose.

• A maintenance dose of 3000 mg is required at a dosing interval of eight weeks.

6. Bodyweight in the Range of 60 to Below 100 Kilograms:

• The preferred loading dose is 2700 mg.

• A maintenance dose of 3300 mg is required at eight weeks dosing intervals.

7. Body Weight of 100 Kilograms or More:

• 3000 mg is the required loading dose.

• Every eight weeks, a maintenance dose of 3600 is advised.

Dosing Considerations:

Before initiating the Ravulizumab therapy, it is imperative to take a prophylactic vaccine. Vaccines to tackle meningococcal infections should be given prophylactically. If immediate initiation of Ravulizumab is warranted, two weeks of prophylactic coverage using antibacterial drugs are advised. The patient must get the vaccine at least a few weeks before beginning Ravulizumab therapy.

What Are the Pharmacological Aspects of Ravulizumab?

• Mechanism of Action: Being a monoclonal antibody, Ravulizumab curbs the terminal complement. The humanized Ravulizumab molecules are designed to attach specifically to the complement component 5 (C5). This attachment is strong enough to impede the fractionation of C5-competent proteins into C5a and C5b. The C5b molecules are indispensable for generating MAC (membrane attack complex). The MAC complex is an agglomerate of complement components encompassing C5b, C9, C8, C7 and C6. MAC strikes upon the target molecules by perforating their cell membrane, eventually leading to cell rupture, lysis, and cell death. In atypical hemolytic uremic syndrome, the inappropriately triggered complement system lets off numerous membrane attack complexes and destroys the red blood cells and endothelial cells. Ravulizumab hinders MAC formation and thereby checks the MAC-induced destruction and impairment of body cells. This spares the red blood cells, endothelial cells, and other vital cells from lysis.

• Pharmacodynamics: Even with the initial infusion of Ravulizumab, the blood concentration of free (unbounded) complement component 5 exhibits appreciable depreciation, falling below five micrograms per milliliter (mcg/ml). The complete check on the free C5 remains throughout the treatment course in pediatric and adult patients undergoing Ravulizumab therapy.

• Pharmacokinetics: Since the medicine is directly delivered into the circulating bloodstream, it bypasses and escapes the first-pass metabolism. Within 30 minutes following the complete infusion of the initial dose of Ravulizumab, the drug concentration attains the intended concentration in the blood. Periodic maintenance doses keep the target concentration sustained throughout the treatment course. The volume of distribution of Ravulizumab is estimated to be 5.22 liters at a steady state in patients diagnosed with atypical hemolytic uremic syndrome. Being a humanized monoclonal antibody, the catabolic pathway breaks Ravulizumab into simpler amino acid molecules, similar to that of endogenous antibody metabolism. The elimination of Ravulizumab is estimated to be 0.08 liters per day. No relevant sources of information are available concerning the routes through which Ravulizumab is expelled from the body.

Toxicity:

No reliable pieces of information are available concerning the toxicity potential of Ravulizumab. Carcinogenicity, genotoxicity, and mutagenicity of Ravulizumab infusion doses are not exposed because of the limited clinical and non-clinical study reports.

Clinical Studies:

Clinical studies were conducted on pediatric and adult subjects who were detected with atypical hemolytic uremic syndrome to assess the data concerning the effectiveness of the infusion doses of Ravulizumab. The study reports concluded that the therapy of 26 weeks could resolve the hematological discrepancies. The study subjects achieved normalcy in blood parameters. In addition to the hematological parameters, there was a dramatic improvement in kidney functioning following Ravulizumab therapy. Comparative studies were also conducted to evaluate the potency of intravenous and subcutaneous Ravulizumab in tackling atypical hemolytic uremic syndrome, and were reported to be proportionate with one other. The potency of Ravulizumab was on par with that of Eculizumab.

Contraindications of Ravulizumab

• Patients who have had known allergic encounters with Ravulizumab are not supposed to take the drug, as it can trigger hypersensitivity reactions.

• Patients who are diagnosed to have Neisseria meningitidis infection, either active or unresolved, are absolute contraindications for Ravulizumab therapy.

• Patients who cannot be provided with vaccine protection against meningococcal infections cannot undergo therapy using Ravulizumab. Unvaccinated patients are contraindicated for Ravulizumab therapy as it can potentially enhance the susceptibility for meningococcal infections.

Warnings and Precautions:

• Fatal Meningococcal Infections: Ravulizumab therapy exposes one to meningococcal infections, which can potentially endanger one's life. It can be precipitated in the form of meningitis or septicemia. It is the most critical warning concerning the use of Ravulizumab. The therapy using Ravulizumab should be initiated only after the patient is vaccinated for meningococcal infections. The vaccination should be employed at least a couple of weeks before Ravulizumab therapy commencement, which offers satisfactory prophylaxis. However, getting a meningococcal vaccine does not completely eradicate the danger of meningococcal infections. Therefore, employ due diligence throughout the treatment regimen. The patient must be made aware of the signs of developing meningococcal infections to catch hold of the infection as soon as possible.

• Post-discontinuation Surveillance: Even after cessation of the Ravulizumab therapy regimen, exercise close surveillance for a minimum of one-year duration. During the surveillance period, the patient must be tracked for clinical manifestations of thrombotic microangiopathy (TMA). Furthermore, hematologic surveillance is also indispensable for monitoring disparities in the platelet count and other hematological parameters. In the event of TMA remission, Ravulizumab therapy needs to be initiated again, along with appropriate supportive interventions.

• Openness to Infections: Since Ravulizumab works by checking the activities in the immune systems, it makes an individual vulnerable to potential infections, particularly Haemophilus influenzae and Streptococcus pneumonia. The pediatric population is more vulnerable than the adult population, so vaccinating against these infections is advised.

• Reactions to Intravenous Infusion: There are reports of exaggerated reactivity to Ravulizumab infusion, ranging from minor reactions to multiorgan instability. Blood pressure fluctuations, back pain, and sleepiness are some of the frequently reported reactions. However, in certain patients, trouble breathing and cardiac abnormalities may precipitate during the infusion, necessitating the infusion's cessation.

Drug Interactions of Ravulizumab

The introduction of another medicine or therapeutic procedure can interact with and interrupt the potency of Ravulizumab. The following are some of the potent drug interactions concerning Ravulizumab:

• When Ravulizumab therapy is initiated with other therapeutic procedures like plasma exchange, it curbs the Ravulizumab’s blood concentration. Thus, it depreciates the medicine’s effectiveness. So, in such cases, it calls for additional Ravulizumab doses to achieve the intended serum concentration. The interactions are the same when Ravulizumab is clubbed with intravenous immunoglobulin administration.

• Simultaneous administration of Ravulizumab with Efgartigimod (neonatal Fc receptor blocker) depletes the concentration of Ravulizumab and thereby collapses its effectiveness. The interaction must be closely tracked to detect notable depreciation in the Ravulizumab’s blood concentration.

Specific Considerations:

• Ravulizumab During Pregnancy: No clinical study reports are available concerning the safety aspect of Ravulizumab when the infusion is carried out on an expectant mother. Any drug exposure carries a threat to the baby in the womb when administered to pregnant women. Hence, Ravulizumab therapy is generally not preferred for expectant mothers. However, the doctor evaluates the therapeutic necessity for the maternal body and the possibility of fetal harm and advises accordingly.

• Ravulizumab During Lactation: Lactating mothers are advised to cease nursing during the therapy using Ravulizumab temporarily. Breastfeeding can be reinstated after a time-lapse of about eight months following the last dose of Ravulizumab. However, no clear information is available concerning the transmission of Ravulizumab into the baby’s body through breast milk.

• Ravulizumab in Pediatric Population: Ravulizumab is proven to be efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome over one month of age. The efficacy parameters in pediatric patients are proportionate with those in adult patients.