Rhophylac: Uses, Dosage & Side Effects

What Is Rhophylac and What Is It Used For?

The active substance in Rhophylac is human anti-D (Rh0) immunoglobulin, a concentrated solution of IgG antibodies purified from the plasma of hyperimmunized human donors. These antibodies are highly specific for the Rh(D) antigen, a protein found on the surface of red blood cells in approximately 85% of the world population (the prevalence varies by ethnic background: roughly 85% of white Europeans, 92% of Black individuals of African descent and 99% of East Asian populations are Rh(D)-positive). The remaining individuals are Rh(D)-negative and lack this antigen.

Rh(D) negativity itself causes no health problem for the individual, but it creates a specific clinical risk: if an Rh(D)-negative person is exposed to Rh(D)-positive red blood cells — most commonly during a pregnancy with an Rh(D)-positive baby, but also through an incompatible blood transfusion or through needle-sharing in intravenous drug use — their immune system will recognize the Rh(D) antigen as foreign and can produce permanent anti-D antibodies. This immune response is called Rh(D) alloimmunization or Rh sensitization. Once a person is sensitized, the antibodies remain for life and any future Rh(D)-positive red cells (fetal or transfused) will be rapidly destroyed.

In a subsequent pregnancy, maternal anti-D antibodies of the IgG class readily cross the placenta and bind to Rh(D)-positive fetal red blood cells, causing their destruction by the fetal reticuloendothelial system. The resulting condition is called hemolytic disease of the fetus and newborn (HDFN), which ranges from mild fetal anemia and neonatal jaundice to severe fetal anemia, fetal hydrops and stillbirth. Before routine anti-D prophylaxis was introduced in the late 1960s, HDFN affected roughly 1% of all pregnancies in Rh(D)-negative women and was a leading cause of perinatal mortality. The introduction of prophylactic anti-D immunoglobulin is one of the most important advances in modern obstetrics and has reduced the incidence of severe Rh(D) HDFN by more than 90%.

Rhophylac works by passive immunization. When injected into an Rh(D)-negative recipient who has been (or may have been) exposed to Rh(D)-positive red cells, the preformed anti-D antibodies bind to the surface of those fetal or transfused cells and target them for rapid clearance by phagocytes in the spleen and liver. Because the Rh(D)-positive cells are removed before the recipient’s own B lymphocytes can mount an active immune response, the recipient does not form her own anti-D antibodies and remains unsensitized. Protection is temporary, but by preventing the initial sensitizing event it gives permanent protection for the index pregnancy and preserves the option of safe future pregnancies.

Rhophylac is approved by the European Medicines Agency (EMA), national competent authorities in most European countries, the U.S. Food and Drug Administration (FDA) and numerous other regulators worldwide for the following indications:

Prevention of Rh(D) Alloimmunization in Pregnancy

This is the principal indication. Rhophylac is used for routine antenatal prophylaxis around week 28–30 of pregnancy and for postnatal prophylaxis within 72 hours after the delivery of an Rh(D)-positive baby. It is also used after any potentially sensitizing event during pregnancy, including miscarriage, threatened miscarriage, therapeutic termination of pregnancy, ectopic pregnancy, molar pregnancy, antepartum bleeding, external cephalic version, abdominal trauma (including motor vehicle accidents and falls) and invasive procedures such as amniocentesis, chorionic villus sampling, fetal blood sampling and intrauterine transfusion. The dose and timing depend on the gestational age and the estimated volume of fetal-maternal hemorrhage.

The evidence base is exceptionally strong. Multiple Cochrane systematic reviews (Crowther & Middleton; McBain, Crowther & Middleton) confirm that anti-D prophylaxis given postnatally to Rh(D)-negative women with Rh(D)-positive babies reduces the incidence of Rh(D) alloimmunization in subsequent pregnancies from approximately 12–16% to less than 2%, and that adding routine antenatal prophylaxis further reduces first-trimester or third-trimester “silent” sensitization to below 0.3%.

Prevention of Rh(D) Alloimmunization in Non-Pregnant Individuals

Rhophylac is also indicated for Rh(D)-negative recipients of an incompatible transfusion of Rh(D)-positive red blood cells, platelets containing Rh(D)-positive red blood cells, or other Rh(D)-positive blood products. Such transfusions are normally avoided but may occur in an emergency when matched blood is not immediately available. A large dose is given (typically calculated at 100 IU per 1 mL of Rh(D)-positive red cells transfused) as soon as possible, ideally within 72 hours.

Treatment of Immune (Idiopathic) Thrombocytopenic Purpura

In several countries, but not all, anti-D immunoglobulin is approved as a second-line treatment for chronic immune thrombocytopenic purpura (ITP) in Rh(D)-positive, non-splenectomized patients with platelet counts below a defined threshold. The mechanism differs completely from Rh prophylaxis: anti-D binds to Rh(D)-positive red cells, which are then preferentially cleared by Fc-gamma receptor-bearing macrophages in the spleen. This “blocks” the reticuloendothelial system, so antibody-coated platelets are destroyed more slowly, and platelet counts rise. A typical platelet response occurs within 1–2 days and lasts 2–5 weeks. This use is less common than Rh prophylaxis and carries specific risks (see Side Effects section).

What Should You Know Before Receiving Rhophylac?

Contraindications

There are relatively few absolute contraindications to Rhophylac, but they are clinically important.

• Hypersensitivity: Do not use if the recipient has a known severe allergy (including anaphylactic reaction) to the active substance, to human immunoglobulins in general, or to any of the excipients (human albumin, glycine, sodium chloride, water for injections).
• Rh(D)-positive recipient for Rh prophylaxis: Rhophylac has no benefit in Rh(D)-positive individuals when used for Rh sensitization prophylaxis and should not be given for this indication. (In ITP, the opposite is true: only Rh(D)-positive, non-splenectomized patients benefit from this mechanism.)
• Already sensitized recipient: If the recipient has already developed her own anti-D antibodies (as detected on an indirect antiglobulin / antibody screen), anti-D immunoglobulin prophylaxis is ineffective and not indicated. Weakly positive results attributable to previously administered anti-D do not count as sensitization.
• Known IgA deficiency with anti-IgA antibodies: Anti-D immunoglobulin products contain residual IgA. Patients with selective IgA deficiency who have developed antibodies against IgA may have severe reactions (including anaphylaxis) when receiving any IgA-containing product.

Warnings and Precautions

Tell your doctor or nurse before receiving Rhophylac if any of the following apply:

• Previous reaction to immunoglobulin or blood products: If you have ever had an unusual reaction to any human immunoglobulin preparation, plasma product or blood transfusion, your healthcare team needs to know before administering Rhophylac. Patients who have had a prior mild reaction should be observed for at least 20–30 minutes after injection.
• Selective IgA deficiency: People with low or absent IgA may form anti-IgA antibodies and are at higher risk of allergic reactions to immunoglobulin products. Tell your doctor if you have a known immune deficiency.
• Bleeding disorders or anticoagulation: The preferred route of administration is intramuscular. In patients with severe thrombocytopenia or other bleeding disorders, an intramuscular injection can cause a painful hematoma. In these cases, Rhophylac can be given by slow intravenous injection instead, which is licensed for this product.
• Prior administration of live attenuated vaccines: Rhophylac can interfere with the immune response to live attenuated virus vaccines (see Drug Interactions).
• Risk of transmissible agents: Because Rhophylac is derived from human plasma, the theoretical risk of transmitting blood-borne pathogens (viruses, prions) cannot be entirely excluded, although modern manufacturing and testing have made this risk extremely low. Vaccination against hepatitis A and hepatitis B is recommended for patients expected to receive repeated doses.

During and after administration, tell the clinic staff or seek urgent medical help if you experience:

• Sudden widespread rash, hives or itching; swelling of the lips, tongue or throat; difficulty breathing; wheezing; chest tightness; or feeling faint — these may be signs of a rare but serious allergic reaction (anaphylaxis).
• Back pain, flank pain, dark (tea-colored) urine, or a decrease in urine output after IV administration — these may suggest intravascular hemolysis.
• Fever with chills and muscle aches soon after the injection.
• A painful lump, redness or swelling that worsens at the injection site after 24–48 hours.

Pregnancy and Breastfeeding

Rhophylac is specifically designed for use in pregnancy and has an excellent safety record in pregnant women and their offspring. The anti-D IgG given to the mother does cross the placenta but at the recommended prophylactic doses does not cause clinically significant hemolysis in an Rh(D)-positive fetus. Routine antenatal anti-D prophylaxis at 28–30 weeks of gestation, as well as targeted doses following sensitizing events, are recommended by WHO, ACOG, RCOG, FIGO and the national obstetric societies of nearly every country with access to the product.

Rhophylac can be used during breastfeeding without interruption. Small amounts of IgG are present in breast milk, but they are not absorbed through the infant’s intact gastrointestinal tract and do not cause harm.

Children and Adolescents

Rhophylac is not routinely used in children, as pregnancy-related prophylaxis and transfusion-related prophylaxis are adult indications. In the rare situation where an Rh(D)-negative child receives an Rh(D)-incompatible transfusion or an Rh(D)-positive component containing red blood cells (for example, Rh(D)-positive platelets), anti-D immunoglobulin prophylaxis can be given and is dose-adjusted according to the volume of red cells transfused.

Driving and Operating Machinery

Rhophylac has no known effect on the ability to drive or operate machinery. Very rarely, patients experience transient dizziness or headache after injection; in such cases, wait until symptoms have resolved before driving.

Important Information About Ingredients

Rhophylac contains small amounts of human albumin and sodium chloride; both are very unlikely to cause problems. Each 2 mL pre-filled syringe contains approximately 7 mg of sodium, which is essentially sodium-free (< 1 mmol) and is not relevant to a sodium-restricted diet. The product does not contain a preservative and must be used immediately after opening.

How Does Rhophylac Interact with Other Drugs?

As a biological product containing immunoglobulin antibodies, Rhophylac is not metabolized by cytochrome P450 enzymes and does not undergo the pharmacokinetic drug-drug interactions typical of small-molecule medications. The two clinically important interactions involve vaccines and laboratory blood testing.

Interaction with Live Attenuated Virus Vaccines

Passively administered anti-D IgG can bind to and neutralize attenuated virus particles before the recipient’s immune system has the opportunity to develop a protective response. This can reduce the effectiveness of live attenuated virus vaccines, including MMR (measles, mumps, rubella), varicella (chickenpox), zoster (shingles), yellow fever and oral poliovirus vaccines. As a general rule:

• Live virus vaccines should be administered before Rhophylac or at least 3 months after Rhophylac, if possible.
• If a live virus vaccine has already been given, Rhophylac should still be administered if clinically indicated (e.g., postnatal Rh prophylaxis must not be delayed), and the vaccine may need to be repeated later.
• Rubella vaccination in the early postpartum period is a common clinical situation. The current consensus is to administer both the postnatal Rhophylac dose and the rubella (or MMR) vaccine as needed but to confirm rubella seroconversion (and re-vaccinate if needed) 3 months later.

Inactivated vaccines (tetanus, diphtheria, pertussis, seasonal influenza, inactivated poliovirus, hepatitis A, hepatitis B, HPV, COVID-19 mRNA or protein subunit vaccines, pneumococcal, meningococcal) are not affected by Rhophylac and can be given at any time without loss of efficacy. The influenza vaccine and hepatitis B vaccine are routinely recommended during pregnancy and should be given on schedule.

Interference with Laboratory Tests

Passively administered anti-D IgG can be detected in the recipient’s blood for up to 6–8 weeks and, occasionally, several months. This may lead to:

• A weakly positive direct antiglobulin test (DAT / Coombs test) in the newborn whose mother received antenatal Rhophylac; this is not an indication of clinically significant hemolytic disease and does not require treatment.
• A weakly positive indirect antiglobulin test (IAT / antibody screen) in the mother for 6–8 weeks after injection; this represents passive antibody and does not indicate active Rh sensitization. Laboratories should be informed of recent anti-D administration so results can be interpreted correctly.
• Apparent, transient elevations of some plasma protein or antibody levels if measured in the days after injection.

Major Interactions

Agents Without Clinically Significant Interaction

What Is the Correct Dosage of Rhophylac?

Rhophylac is supplied as a ready-to-use, clear and colorless to pale-yellow solution in a pre-filled syringe. It is administered by a healthcare professional either as an intramuscular (IM) injection (typically the upper outer quadrant of the buttock or the deltoid muscle) or, if intramuscular injection is contraindicated (e.g., severe thrombocytopenia or bleeding disorder), as a slow intravenous (IV) injection. Both routes are licensed for Rhophylac. The pre-filled syringe must not be administered subcutaneously.

The dose depends on the clinical situation, the estimated volume of Rh(D)-positive red blood cells to which the recipient has been exposed, and in some cases on body weight.

Routine Antenatal Prophylaxis

Postnatal Prophylaxis

Dosing After Sensitizing Events

After Rh(D)-Incompatible Transfusion

Treatment of Immune (Idiopathic) Thrombocytopenic Purpura

Missed Dose

Because Rhophylac is given by a healthcare professional for defined indications, the concept of a “missed dose” differs from daily medications. If a scheduled antenatal dose at 28–30 weeks is missed, it should be given as soon as possible, even if several weeks late. If the postnatal dose is given more than 72 hours after delivery, it still provides partial protection and should be administered up to 10 (and preferably no later than 28) days after delivery. Earlier is always better.

Overdose

When Rhophylac is given in very large doses to an Rh(D)-positive recipient (as in the treatment of ITP or in accidental overdose in an Rh(D)-positive patient given anti-D prophylaxis), intravascular hemolysis may occur. Signs include a fall in hemoglobin, rise in bilirubin, positive direct Coombs test, hemoglobinuria and fatigue. Treatment is supportive: monitoring hemoglobin and renal function, transfusion if anemia is severe, and intravenous hydration. In an Rh(D)-negative recipient, overdose generally does not have clinical consequences beyond occasional mild hemolysis, because there are no Rh(D)-positive red cells to coat.

How Rhophylac Is Given

Rhophylac is supplied as a single-use pre-filled syringe, typically containing 2 mL of solution with 1500 IU (300 mcg) of anti-D immunoglobulin or a 1000 IU (200 mcg) presentation depending on market. The solution should be clear or slightly opalescent, colorless or pale yellow. It must not be used if it appears cloudy, contains visible particles or has been frozen.

For intramuscular use, the deltoid muscle of the upper arm or the upper outer quadrant of the gluteus is selected. The full contents of the syringe are administered. Intramuscular injection should be avoided in patients with a severe bleeding disorder or on full anticoagulation; in these cases, the intravenous route is used.

For intravenous use, the solution is given as a slow injection. Patients should be observed for at least 20–30 minutes after IV administration for any signs of hypersensitivity and, if treated for ITP, for at least 8 hours with urinalysis monitoring for hemoglobinuria.

What Are the Side Effects of Rhophylac?

Like all medicines, Rhophylac can cause side effects, but most people who receive it experience no problems or only a mild, brief reaction at the injection site. The adverse effects listed below are compiled from the Rhophylac Summary of Product Characteristics, clinical trials, and post-marketing surveillance in millions of pregnant women and ITP patients over more than five decades of clinical use.

The side effects are organized by frequency category as determined in clinical trials and post-marketing surveillance.

How Should Rhophylac Be Stored?

As a biological protein product, Rhophylac is sensitive to temperature, light and physical stress. Proper storage is essential to preserve the activity of the anti-D antibodies.

• Temperature: Store in a refrigerator at 2–8°C (35–46°F). The product must not be frozen. If Rhophylac has accidentally been frozen, it must not be used.
• Light: Store in the original outer carton to protect from light.
• Room temperature exposure: Rhophylac may be kept at room temperature (below 25°C) for up to one month (or a period specified on the product label), once only, and must not be returned to the refrigerator after this excursion. This is useful for transport. Always check the product label and pharmacy records.
• Appearance check: Before administration, visually inspect the syringe. The solution should be clear or slightly opalescent and colorless or pale yellow. Do not use if the solution is cloudy, has visible particles, or has changed color.
• Expiry date: Do not use Rhophylac after the expiry date (EXP) printed on the carton and syringe. The expiry date refers to the last day of the stated month.
• Single use: Each pre-filled syringe is for single use only. Any unused portion must be discarded and not stored for a subsequent dose.
• Keep out of the reach and sight of children.
• Disposal: Unused syringes, needles and any waste material must be disposed of in accordance with local biological waste regulations. Pharmacy and clinical staff will handle this.

What Does Rhophylac Contain?

Understanding the full composition of Rhophylac is useful for identifying potential allergens and for patients who want to know exactly what is being administered during pregnancy or for ITP.

• Active substance: Human anti-D (Rh0) immunoglobulin. Each pre-filled syringe contains either 1000 IU (200 micrograms) or 1500 IU (300 micrograms) of anti-D immunoglobulin.
• Protein content: Each pre-filled syringe contains approximately 20 mg of protein, of which at least 95% is human immunoglobulin G (IgG).
• Immunoglobulin subclass distribution: The product is a polyclonal IgG preparation with a physiological subclass distribution (mainly IgG1 and IgG3). Residual IgA is less than 5 micrograms per mL.
• Other ingredients (excipients): Human albumin (as stabilizer), glycine, sodium chloride and water for injections.
• No preservative is added.

Appearance: Rhophylac is supplied as a ready-to-use solution in a pre-filled glass syringe. The solution is clear or slightly opalescent and colorless to pale yellow. Slight opalescence is normal for a protein solution and does not indicate loss of quality.

Pack size: Typical pack sizes contain one pre-filled syringe (2 mL) with a separate needle. In hospital or transfusion-center settings, multi-pack sizes may also be available.

Manufacturer and marketing authorization holder: Rhophylac is manufactured and marketed worldwide by CSL Behring. National distribution arrangements vary by country.

Other Anti-D Immunoglobulin Products

Several other anti-D immunoglobulin products are approved internationally and are clinically equivalent for Rh prophylaxis when dosed appropriately, although they differ in formulation, recommended routes of administration and approved indications. Examples include RhoGAM (Kedrion), HyperRHO (Grifols), WinRho SDF (Emergent BioSolutions; also approved for ITP in some regions), Rhesonativ (Octapharma) and Partobulin SDF (Takeda / Baxter). Always follow the specific prescribing information of the product you receive, because the unit (“IU” vs “mcg”) and the recommended route of administration can differ.